GENETIC POLYMORPHISMS ASSOCIATED WITH VENOUS THROMBOSIS, METHODS OF DETECTION AND USES THEREOF

Abstract
The present invention is based on the discovery of genetic polymorphisms that are associated with venous thrombosis. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.
Description
FIELD OF THE INVENTION

The present invention is in the field of thrombosis diagnosis and therapy. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with venous thrombosis (VT) and related pathologies. Based on differences in allele frequencies in the patient population relative to normal individuals, the naturally-occurring SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analyses. In particular, the SNPs of the present invention are useful for identifying an individual who is at an increased or decreased risk of developing venous thrombosis and for early detection of the disease, for providing clinically important information for the prevention and/or treatment of venous thrombosis, for screening and selecting therapeutic agents, and for predicting a patient's response to therapeutic agents. The SNPs disclosed herein are also useful for human identification applications. Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided.


BACKGROUND OF THE INVENTION

Venous Thrombosis (VT)


The development of a blood clot is known as thrombosis. Venous thrombosis (VT) is the formation of a blood clot in the veins. VT may also be referred to as venous thromboembolism (VTE). Over 200,000 new cases of VT occur annually. Of these, 30 percent of patients die within three days; one in five suffer sudden death due to pulmonary embolism (PE) (Seminars in Thrombosis and Hemostasis, 2002, Vol. 28, Suppl. 2) (Stein et al., Chest 2002; 122(3):960-962, further describes PE). Caucasians and African-Americans have a significantly higher incidence than Hispanics, Asians or Pacific Islanders (White, Circulation 107(23 Suppl 1):I4-8 Review, 2003).


Several conditions can lead to an increased tendency to develop blood clots in the veins or arteries (National Hemophilia Foundation, HemAware newsletter, Vol. 6 (5), 2001), and such conditions may be inherited (genetic) or acquired. Examples of acquired conditions are surgery and trauma, prolonged immobilization, cancer, myeloproliferative disorders, age, hormone therapy, and even pregnancy, all of which may result in thrombosis (Seligsohn et al., New Eng J Med 344(16):1222-1231, 2001 and Heit et al., Thromb Haemost 2001; 86(1):452-463). Family and twin studies indicate that inherited (genetic) causes account for about 60% of the risk for DVT (Souto et al., Am J Hum Genet. 2000; 67(6):1452-1459; Larsen et al., Epidemiology 2003; 14(3):328-332). Inherited causes include polymorphisms in any of several different clotting, anticoagulant, or thrombolytic factors, such as the factor V gene (the factor V Leiden (FVL) variant), prothrombin gene (factor II), and methylenetetrahydrofolate reductase gene (MTHFR). Other likely inherited causes are an increase in the expression levels of the factors VIII, 1× or XI, or fibrinogen genes (Seligsohn et al., New Eng J Med 344(16):1222-1231, 2001). Deficiencies of natural anticoagulants antithrombin, protein C and protein S are strong risk factors for DVT; however, the variants causing these deficiencies are rare, and explain only about 1% of all DVTs (Rosendaal et al., Lancet 1999; 353(9159):1167-1173). The factor V Leiden (FVL) and prothrombin G20210A genetic variants have been consistently found to be associated with DVT (Bertina et al., Nature 1994; 369(6475):64-67 and Poort et al., Blood 1996; 88(10):3698-3703) but still only explain a fraction of the DVT events (Rosendaal, Lancet 1999; 353(9159):1167-1173; Bertina et al., Nature 1994; 369(6475):64-67; Poort et al., Blood 1996; 88(10):3698-3703). Elevated plasma concentrations of coagulation factors (e.g., VIII, IX, X, and XI) have also been shown to be important risk factors for DVT (Kyrle et al., N Engl J Med. 2000; 343:457-462; van Hylckama Vlieg et al., Blood. 2000; 95:3678-3682; de Visser et al., Thromb Haemost. 2001; 85:1011-1017; and Meijers et al., N Engl J Med. 2000; 342:696-701, respectively).


About one-third of patients with symptomatic VT manifest pulmonary embolism (PE), whereas two-thirds manifest deep vein thrombosis (DVT) (White, Circulation 107(23 Suppl 1):I4-8 Review, 2003). DVT is an acute VT in a deep vein, usually in the thigh, legs, or pelvis, and it is a serious and potentially fatal disorder that can arise as a complication for hospital patients, but may also affect otherwise healthy people (Lensing et al., Lancet 353:479-485, 1999). Large blood clots in VT may interfere with blood circulation and impede normal blood flow. In some instances, blood clots may break off and travel to distant major organs such as the brain, heart or lungs as in PE and result in fatality. There is evidence to suggest that patients with a first episode of VT be treated with anticoagulant agents (Kearon et al., New Engl J Med 340:901-907, 1999).


VT is a chronic disease with episodic recurrence; about 30% of patients develop recurrence within 10 years after a first occurrence of VT (Heit et al., Arch Intern Med. 2000; 160: 761-768; Heit et al., Thromb Haemost 2001; 86(1):452-463; and Schulman et al., J Thromb Haemost. 2006; 4: 732-742). Recurrence of VT may be referred to herein as recurrent VT. The hazard of recurrence varies with the time since the incident event and is highest within the first 6 to 12 months. Although anticoagulation is effective in preventing recurrence, the duration of anticoagulation does not affect the risk of recurrence once primary therapy for the incident event is stopped (Schulman et al., J Thromb Haemost. 2006; 4: 732-742 and van Dongen et al., Arch Intern Med. 2003; 163: 1285-1293). Independent predictors of recurrence include male gender (McRae et al., Lancet. 2006; 368: 371-378), increasing patient age and body mass index, neurological disease with leg paresis, and active cancer (Cushman et al., Am J Med. 2004; 117: 19-25; Heit et al., Arch Intern Med. 2000; 160: 761-768; Schulman et al., J Thromb Haemost. 2006; 4: 732-742; and Baglin et al., Lancet. 2003; 362: 523-526). Additional predictors include “idiopathic” venous thrombosis (Baglin et al., Lancet. 2003; 362: 523-526), a lupus anticoagulant or antiphospholipid antibody (Kearon et al., N Engl J Med. 1999; 340: 901-907 and Schulman et al., Am J Med. 1998; 104: 332-338), antithrombin, protein C or protein S deficiency (van den Belt et al., Arch Intern Med. 1997; 157: 227-232), and possibly persistently increased plasma fibrin D-dimer (Palareti et al., N Engl J Med. 2006; 355: 1780-1789) and residual venous thrombosis (Prandoni et al., Ann Intern Med. 2002; 137: 955-960).


VT and cancer can be coincident. According to clinical data prospectively collected on the population of Olmsted County, Minnesota, since 1966, the annual incidence of a first episode of DVT or PE in the general population is 117 of 100,000. Cancer alone was associated with a 4.1-fold risk of thrombosis, whereas chemotherapy increased the risk 6.5-fold. Combining these estimates yields an approximate annual incidence of VT in cancer patients of 1 in 200 cancer patients (Lee et al., Circulation. 2003; 107:I-17-I-21). Extrinsic factors such as surgery, hormonal therapy, chemotherapy, and long-term use of central venous catheters increase the cancer-associated prethrombotic state. Post-operative thrombosis occurs more frequently in patients with cancer as compared to non-neoplastic patients (Rarh et al., Blood coagulation and fibrinolysis 1992; 3:451).


Thus, there is an urgent need for novel genetic markers that are predictive of predisposition to VT, particularly for individuals who are unrecognized as having a predisposition to developing the disease based on conventional risk factors. Such genetic markers may enable screening of VT in much larger populations compared with the populations that can currently be evaluated by using existing risk factors and biomarkers. The availability of a genetic test may allow, for example, appropriate preventive treatments for acute venous thrombotic events to be provided for high risk individuals (such preventive treatments may include, for example, anticoagulant agents). Moreover, the discovery of genetic markers associated with VT may provide novel targets for therapeutic intervention or preventive treatments.


SNPs


The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor genetic sequences (Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)). A variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances. For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal. In many cases, both progenitor and variant forms survive and co-exist in a species population. The coexistence of multiple forms of a genetic sequence gives rise to genetic polymorphisms, including SNPs.


Approximately 90% of all genetic polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. The SNP position (interchangeably referred to herein as SNP, SNP site, SNP locus, SNP marker, or marker) is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). An individual may be homozygous or heterozygous for an allele at each SNP position. A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP is an amino acid coding sequence.


A SNP may arise from a substitution of one nucleotide for another at the polymorphic site. Substitutions can be transitions or transversions. A transition is the replacement of one purine nucleotide by another purine nucleotide, or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine, or vice versa. A SNP may also be a single base insertion or deletion variant referred to as an “indel” (Weber et al., “Human diallelic insertion/deletion polymorphisms,” Am J Hum Genet. 2002 October; 71(4):854-62).


A synonymous codon change, or silent mutation/SNP (terms such as “SNP,” “polymorphism,” “mutation,” “mutant,” “variation,” and “variant” are used herein interchangeably), is one that does not result in a change of amino acid due to the degeneracy of the genetic code. A substitution that changes a codon coding for one amino acid to a codon coding for a different amino acid (i.e., a non-synonymous codon change) is referred to as a missense mutation. A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein. A read-through mutation is another type of non-synonymous codon change that causes the destruction of a stop codon, thereby resulting in an extended polypeptide product. While SNPs can be bi-, tri-, or tetra-allelic, the vast majority of the SNPs are bi-allelic, and are thus often referred to as “bi-allelic markers,” or “di-allelic markers.”


As used herein, references to SNPs and SNP genotypes include individual SNPs and/or haplotypes, which are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs, and therefore may provide increased diagnostic accuracy in some cases (Stephens et al. Science 293, 489-493, 20 Jul. 2001).


Causative SNPs are those SNPs that produce alterations in gene expression or in the expression, structure, and/or function of a gene product, and therefore are most predictive of a possible clinical phenotype. One such class includes SNPs falling within regions of genes encoding a polypeptide product, i.e. cSNPs. These SNPs may result in an alteration of the amino acid sequence of the polypeptide product (i.e., non-synonymous codon changes) and give rise to the expression of a defective or other variant protein. Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product. Such variant products can result in a pathological condition, e.g., genetic disease. Examples of genes in which a SNP within a coding sequence causes a genetic disease include sickle cell anemia and cystic fibrosis.


Causative SNPs do not necessarily have to occur in coding regions; causative SNPs can occur in, for example, any genetic region that can ultimately affect the expression, structure, and/or activity of the protein encoded by a nucleic acid. Such genetic regions include, for example, those involved in transcription, such as SNPs in transcription factor binding domains, SNPs in promoter regions, in areas involved in transcript processing, such as SNPs at intron-exon boundaries that may cause defective splicing, or SNPs in mRNA processing signal sequences such as polyadenylation signal regions. Some SNPs that are not causative SNPs nevertheless are in close association with, and therefore segregate with, a disease-causing sequence. In this situation, the presence of a SNP correlates with the presence of, or predisposition to, or an increased risk in developing the disease. These SNPs, although not causative, are nonetheless also useful for diagnostics, disease predisposition screening, and other uses.


An association study of a SNP and a specific disorder involves determining the presence or frequency of the SNP allele in biological samples from individuals with the disorder of interest, such as VT, and comparing the information to that of controls (i.e., individuals who do not have the disorder; controls may be also referred to as “healthy” or “normal” individuals) who are preferably of similar age and race. The appropriate selection of patients and controls is important to the success of SNP association studies. Therefore, a pool of individuals with well-characterized phenotypes is extremely desirable.


A SNP may be screened in diseased tissue samples or any biological sample obtained from a diseased individual, and compared to control samples, and selected for its increased (or decreased) occurrence in a specific pathological condition, such as pathologies related to VT. Once a statistically significant association is established between one or more SNP(s) and a pathological condition (or other phenotype) of interest, then the region around the SNP can optionally be thoroughly screened to identify the causative genetic locus/sequence(s) (e.g., causative SNP/mutation, gene, regulatory region, etc.) that influences the pathological condition or phenotype. Association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families (linkage studies).


Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous. There is a continuing need to improve pharmaceutical agent design and therapy. In that regard, SNPs can be used to identify patients most suited to therapy with particular pharmaceutical agents (this is often termed “pharmacogenomics”). Similarly, SNPs can be used to exclude patients from certain treatment due to the patient's increased likelihood of developing toxic side effects or their likelihood of not responding to the treatment. Pharmacogenomics can also be used in pharmaceutical research to assist the drug development and selection process. (Linder et al. (1997), Clinical Chemistry, 43, 254; Marshall (1997), Nature Biotechnology, 15, 1249; International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et al. (1998), Nature Biotechnology, 16: 3).


SUMMARY OF THE INVENTION

The present invention relates to the identification of novel SNPs, unique combinations of such SNPs, and haplotypes of SNPs that are associated with VT. The polymorphisms disclosed herein are directly useful as targets for the design of diagnostic reagents and the development of therapeutic agents for use in the diagnosis and treatment of VT.


Based on the identification of SNPs associated with VT, the present invention also provides methods of detecting these variants as well as the design and preparation of detection reagents needed to accomplish this task. The invention specifically provides, for example, novel SNPs in genetic sequences involved in VT, isolated nucleic acid molecules (including, for example, DNA and RNA molecules) containing these SNPs, variant proteins encoded by nucleic acid molecules containing such SNPs, antibodies to the encoded variant proteins, computer-based and data storage systems containing the novel SNP information, methods of detecting these SNPs in a test sample, methods of identifying individuals who have an altered (i.e., increased or decreased) risk of developing VT based on the presence or absence of one or more particular nucleotides (alleles) at one or more SNP sites disclosed herein or the detection of one or more encoded variant products (e.g., variant mRNA transcripts or variant proteins), methods of identifying individuals who are more or less likely to respond to a treatment (or more or less likely to experience undesirable side effects from a treatment, etc.), methods of screening for compounds useful in the treatment of a disorder associated with a variant gene/protein, compounds identified by these methods, methods of treating disorders mediated by a variant gene/protein, methods of using the novel SNPs of the present invention for human identification, etc.


In Tables 1-2, the present invention provides gene information, references to the identification of transcript sequences (SEQ ID NOS: 1-125), encoded amino acid sequences (SEQ ID NOS: 126-250), genomic sequences (SEQ ID NOS: 404-601), transcript-based context sequences (SEQ ID NOS: 251-403) and genomic-based context sequences (SEQ ID NOS: 602-1587) that contain the SNPs of the present invention, and extensive SNP information that includes observed alleles, allele frequencies, populations/ethnic groups in which alleles have been observed, information about the type of SNP and corresponding functional effect, and, for cSNPs, information about the encoded polypeptide product. The actual transcript sequences (SEQ ID NOS: 1-125), amino acid sequences (SEQ ID NOS: 126-250), genomic sequences (SEQ ID NOS: 404-601), transcript-based SNP context sequences (SEQ ID NOS: 251-403), and genomic-based SNP context sequences (SEQ ID NOS: 602-1587, as well as SEQ ID NOS: 2557-2580), together with primer sequences (SEQ ID NOS: 1588-2556) are provided in the Sequence Listing.


In one embodiment of the invention, applicants teach a method for identifying an individual who has an altered risk for developing VT, comprising detecting a single nucleotide polymorphism (SNP) in, or a SNP that is in linkage disequilibrium (LD) with, any one of the nucleotide sequences of SEQ ID NOS: 1-125, SEQ ID NOS: 126-250, SEQ ID NOS: 251-403, and SEQ ID NOS: 404-601 in said individual's nucleic acids, wherein the SNP is as specified in Table 1 and Table 2, respectively, and the presence of the SNP is correlated with an altered risk for VT in said individual. In a specific embodiment of the present invention, SNPs that occur naturally in the human genome are provided as isolated nucleic acid molecules. These SNPs are associated with VT, such that they can have a variety of uses in the diagnosis and/or treatment of VT and related pathologies. In an alternative embodiment, a nucleic acid of the invention is an amplified polynucleotide, which is produced by amplification of a SNP-containing nucleic acid template. In another embodiment, the invention provides for a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein.


In yet another embodiment of the invention, a reagent for detecting a SNP in the context of its naturally-occurring flanking nucleotide sequences (which can be, e.g., either DNA or mRNA) is provided. In particular, such a reagent may be in the form of, for example, a hybridization probe or an amplification primer that is useful in the specific detection of a SNP of interest. In an alternative embodiment, a protein detection reagent is used to detect a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein. A preferred embodiment of a protein detection reagent is an antibody or an antigen-reactive antibody fragment.


Various embodiments of the invention also provide kits comprising SNP detection reagents, and methods for detecting the SNPs disclosed herein by employing detection reagents. In a specific embodiment, the present invention provides for a method of identifying an individual having an increased or decreased risk of developing VT by detecting the presence or absence of one or more SNP alleles disclosed herein. In another embodiment, a method for diagnosis of VT by detecting the presence or absence of one or more SNP alleles disclosed herein is provided.


The nucleic acid molecules of the invention can be inserted in an expression vector, such as to produce a variant protein in a host cell. Thus, the present invention also provides for a vector comprising a SNP-containing nucleic acid molecule, genetically-engineered host cells containing the vector, and methods for expressing a recombinant variant protein using such host cells. In another specific embodiment, the host cells, SNP-containing nucleic acid molecules, and/or variant proteins can be used as targets in a method for screening and identifying therapeutic agents or pharmaceutical compounds useful in the treatment of VT.


An aspect of this invention is a method for treating VT in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1-2, which method comprises administering to said human subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disease, such as by inhibiting (or stimulating) the activity of the gene, transcript, and/or encoded protein identified in Tables 1-2.


Certain embodiments of the invention provide methods for reducing risk of VT (either a first VT or recurrent VT) in a human who has been identified as having an increased risk for VT due to the presence or absence of a SNP disclosed herein, in which the methods comprise administering to the human an effective amount of a therapeutic agent to reduce the risk for VT. In certain embodiments, the methods include testing nucleic acid from said human for the presence or absence of the SNP. In certain embodiments, the therapeutic agent is at least one of an anticoagulant agent and an antiplatelet agent.


Certain embodiments of the invention provide methods for determining whether a human should be administered a therapeutic agent for reducing their risk for VT (which can be either a first VT or a recurrent VT) based on the presence or absence of a SNP disclosed herein. In certain embodiments, the therapeutic agent is at least one of an anticoagulant agent and an antiplatelet agent.


Examples of anticoagulant agents include, but are not limited to, coumarines (vitamin K antagonists) such as warfarin (coumadin), acenocoumarol, phenprocoumon, and phenindione; heparin and derivative substances such as low molecular weight heparin; factor Xa inhibitors such as Fondaparinux, Idraparinux, and other synthetic pentasaccharide inhibitors of factor Xa; and thrombin inhibitors such as argatroban, lepirudin, bivalirudin, and dabigatran. Examples of antiplatelet agents include, but are not limited to, cyclooxygenase inhibitors such as aspirin, and adenosine diphosphate (ADP) receptor inhibitors such as clopidogrel (Plavix) and prasugrel (Effient).


Certain embodiments of the invention provide methods for conducting a clinical trial of a therapeutic agent in which a human is selected for inclusion in the clinical trial and/or assigned to a particular group (e.g., an “arm” or “cohort” of the trial) within a clinical trial based on the presence or absence of a SNP disclosed herein. In certain embodiments, the therapeutic agent is at least one of an anticoagulant agent and an antiplatelet agent.


Another aspect of this invention is a method for identifying an agent useful in therapeutically or prophylactically treating VT in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1-2, which method comprises contacting the gene, transcript, or encoded protein with a candidate agent under conditions suitable to allow formation of a binding complex between the gene, transcript, or encoded protein and the candidate agent and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.


Another aspect of this invention is a method for treating VT in a human subject, which method comprises:


(i) determining that said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1-2, and


(ii) administering to said subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disease such as anticoagulant or antiplatelet agents.


Many other uses and advantages of the present invention will be apparent to those skilled in the art upon review of the detailed description of the preferred embodiments herein. Solely for clarity of discussion, the invention is described in the sections below by way of non-limiting examples.


Description of the Text (ASCII) Files Submitted Electronically Via EFS-Web

The following three text (ASCII) files are submitted electronically via EFS-Web as part of the instant application:


1) File SEQLIST_CD000023.txt provides the Sequence Listing. The Sequence Listing provides the transcript sequences (SEQ ID NOS: 1-125) and protein sequences (SEQ ID NOS: 126-250) as referred to in Table 1, and genomic sequences (SEQ ID NOS: 404-601) as referred to in Table 2, for each VT-associated gene or genomic region (for intergenic SNPs) that contains one or more SNPs of the present invention. Also provided in the Sequence Listing are context sequences flanking each SNP, including both transcript-based context sequences as referred to in Table 1 (SEQ ID NOS: 251-403) and genomic-based context sequences as referred to in Table 2 (SEQ ID NOS: 602-1587). In addition, the Sequence Listing provides the primer sequences from Table 3 (SEQ ID NOS: 1588-2556), which are oligonucleotides that have been synthesized and used in the laboratory to assay the SNPs disclosed in Tables 5-13 during the course of association studies to verify the association of these SNPs with VT. The context sequences generally provide 100 bp upstream (5′) and 100 bp downstream (3′) of each SNP, with the SNP in the middle of the context sequence, for a total of 200 bp of context sequence surrounding each SNP. The Sequence Listing also provides SEQ ID NOS: 2557-2580, which are exemplary genomic context sequences for certain SNPs presented in Table 8 and Table 17.


File SEQLIST_CD000023.txt is 24,327 KB in size, and was created on Mar. 12, 2009.


2) File TABLE l_CD000023.txt provides Table 1. File Table l_CD000023.txt is 175 KB in size, and was created on Mar. 11, 2009.


3) File TABLE2—CD000023.txt provides Table 2. File Table2_CD000023.txt is 739 KB in size, and was created on Mar. 11, 2009.


These three files are hereby incorporated by reference pursuant to 37 CFR 1.77(b)(4).


Description of Table 1 and Table 2


Table 1 and Table 2 (both of which are ASCII text files submitted electronically via EFS-Web) disclose the SNP and associated gene/transcript/protein information of the present invention. For each gene, Table 1 provides a header containing gene, transcript and protein information, followed by a transcript and protein sequence identifier (SEQ ID), and then SNP information regarding each SNP found in that gene/transcript including the transcript context sequence. For each gene in Table 2, a header is provided that contains gene and genomic information, followed by a genomic sequence identifier (SEQ ID) and then SNP information regarding each SNP found in that gene, including the genomic context sequence.


Note that SNP markers may be included in both Table 1 and Table 2; Table 1 presents the SNPs relative to their transcript sequences and encoded protein sequences, whereas Table 2 presents the SNPs relative to their genomic sequences. In some instances Table 2 may also include, after the last gene sequence, genomic sequences of one or more intergenic regions, as well as SNP context sequences and other SNP information for any SNPs that lie within these intergenic regions. Additionally, in either Table 1 or 2 a “Related Interrogated SNP” may be listed following a SNP which is determined to be in LD with that interrogated SNP according to the given Power value. SNPs can readily be cross-referenced between all Tables based on their Celera hCV (or, in some instances, hDV) identification numbers, and to the Sequence Listing based on their corresponding SEQ ID NOS. The gene/transcript/protein information includes:


a gene number (1 through n, where n=the total number of genes in the Table)

    • a Celera hCG and UID internal identification numbers for the gene
    • a Celera hCT and UID internal identification numbers for the transcript (Table 1 only)
    • a public Genbank accession number (e.g., RefSeq NM number) for the transcript (Table 1 only)
    • a Celera hCP and UID internal identification numbers for the protein encoded by the hCT transcript (Table 1 only)
    • a public Genbank accession number (e.g., RefSeq NP number) for the protein (Table 1 only)
    • an art-known gene symbol
    • an art-known gene/protein name
    • Celera genomic axis position (indicating start nucleotide position-stop nucleotide position)
    • the chromosome number of the chromosome on which the gene is located
    • an OVTM (Online Mendelian Inheritance in Man; Johns Hopkins University/NCBI) public reference number for obtaining further information regarding the medical significance of each gene
    • alternative gene/protein name(s) and/or symbol(s) in the OVTEM entry


Note that, due to the presence of alternative splice forms, multiple transcript/protein entries may be provided for a single gene entry in Table 1; i.e., for a single Gene Number, multiple entries may be provided in series that differ in their transcript/protein information and sequences.


Following the gene/transcript/protein information is a transcript context sequence and (Table 1), or a genomic context sequence (Table 2), for each SNP within that gene.


After the last gene sequence, Table 2 may include additional genomic sequences of intergenic regions (in such instances, these sequences are identified as “Intergenic region:” followed by a numerical identification number), as well as SNP context sequences and other SNP information for any SNPs that lie within each intergenic region (such SNPs are identified as “INTERGENIC” for SNP type).


Note that the transcript, protein, and transcript-based SNP context sequences are all provided in the Sequence Listing. The transcript-based SNP context sequences are provided in both Table 1 and also in the Sequence Listing. The genomic and genomic-based SNP context sequences are provided in the Sequence Listing. The genomic-based SNP context sequences are provided in both Table 2 and in the Sequence Listing. SEQ ID NOS are indicated in Table 1 for the transcript-based context sequences (SEQ ID NOS: 251-403); SEQ ID NOS are indicated in Table 2 for the genomic-based context sequences (SEQ ID NOS: 602-1587).


The SNP information includes:

    • context sequence (taken from the transcript sequence in Table 1, the genomic sequence in Table 2) with the SNP represented by its IUB code, including 100 bp upstream (5′) of the SNP position plus 100 bp downstream (3′) of the SNP position (the transcript-based SNP context sequences in Table 1 are provided in the Sequence Listing as SEQ ID NOS: 251-403; the genomic-based SNP context sequences in Table 2 are provided in the Sequence Listing as SEQ ID NOS: 602-1587).
    • Celera hCV internal identification number for the SNP (in some instances, an “hDV” number is given instead of an “hCV” number).
    • The corresponding public identification number for the SNP, the RS number.
    • SNP position (position of the SNP within the given transcript sequence (Table 1) or within the given genomic sequence (Table 2)).
    • “Related Interrogated SNP” is as the interrogated SNP with which the listed SNP is in LD at the given value of Power.
    • SNP source (may include any combination of one or more of the following five codes, depending on which internal sequencing projects and/or public databases the SNP has been observed in: “Applera”=SNP observed during the re-sequencing of genes and regulatory regions of 39 individuals, “Celera”=SNP observed during shotgun sequencing and assembly of the Celera human genome sequence, “Celera Diagnostics”=SNP observed during re-sequencing of nucleic acid samples from individuals who have a disease, “dbSNP”=SNP observed in the dbSNP public database, “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP observed in the Human Gene Mutation Database (HGMD) public database, “HapMap”=SNP observed in the International HapMap Project public database, “CSNP”=SNP observed in an internal Applied Biosystems (Foster City, Calif.) database of coding SNPS (cSNPs)). Note that multiple “Applera” source entries for a single SNP indicate that the same SNP was covered by multiple overlapping amplification products and the re-sequencing results (e.g., observed allele counts) from each of these amplification products is being provided.


For the following SNPs provided in Table 1 and/or Table 2, the SNP source falls into one of the following three categories: 1) SNPs for which the SNP source is only “Applera” and none other, 2) SNPs for which the SNP source is only “Celera Diagnostics” and none other, and 3) SNPs for which the SNP source is both “Applera” and “Celera Diagnostics” but none other (the hCV identification number and SEQ ID NO for the SNP's genomic context sequence in Table 2 are indicated): hCV22275299 (SEQ ID NO:482), hCV25615822 (SEQ ID NO:639), hCV25651109 (SEQ ID NO:840), hCV25951678 (SEQ ID NO:1013), and hCV25615822 (SEQ ID NO:1375). These SNPs have not been observed in any of the public databases (dbSNP, HGBASE, and HGMD), and were also not observed during shotgun sequencing and assembly of the Celera human genome sequence (i.e., “Celera” SNP source).

    • Population/allele/allele count information in the format of [population1(first_allele,count|second_allele,count)population2(first_allele,count|second_allele,count) total (first_allele,total count|second_allele,total count)]. The information in this field includes populations/ethnic groups in which particular SNP alleles have been observed (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and “afr”=African-American, “jpn”=Japanese, “ind”=Indian, “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor, “no_pop”=no population information available), identified SNP alleles, and observed allele counts (within each population group and total allele counts), where available [“−” in the allele field represents a deletion allele of an insertion/deletion (“indel”) polymorphism (in which case the corresponding insertion allele, which may be comprised of one or more nucleotides, is indicated in the allele field on the opposite side of the “|”); “−” in the count field indicates that allele count information is not available]. For certain SNPs from the public dbSNP database, population/ethnic information is indicated as follows (this population information is publicly available in dbSNP): “HISP1”=human individual DNA (anonymized samples) from 23 individuals of self-described HISPANIC heritage; “PAC1”=human individual DNA (anonymized samples) from 24 individuals of self-described PACIFIC RIM heritage; “CAUC1”=human individual DNA (anonymized samples) from 31 individuals of self-described CAUCASIAN heritage; “AFR1”=human individual DNA (anonymized samples) from 24 individuals of self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human individual DNA (anonymized samples) from 102 individuals of self-described heritage; “PA130299515”; “SC12_A”=SANGER 12 DNAs of Asian origin from Corielle cell repositories, 6 of which are male and 6 female; “SC12_C”=SANGER 12 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library. Six male and 6 female; “SC12_AA”=SANGER 12 DNAs of African-American origin from Corielle cell repositories 6 of which are male and 6 female; “SC95_C”=SANGER 95 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library; and “SC12_CA”=Caucasians—12 DNAs from Corielle cell repositories that are from the CEPH/UTAH library.


Note that for SNPs of “Applera” SNP source, genes/regulatory regions of 39 individuals (20 Caucasians and 19 African Americans) were re-sequenced and, since each SNP position is represented by two chromosomes in each individual (with the exception of SNPs on X and Y chromosomes in males, for which each SNP position is represented by a single chromosome), up to 78 chromosomes were genotyped for each SNP position. Thus, the sum of the African-American (“afr”) allele counts is up to 38, the sum of the Caucasian allele counts (“cau”) is up to 40, and the total sum of all allele counts is up to 78.


Note that semicolons separate population/allele/count information corresponding to each indicated SNP source; i.e., if four SNP sources are indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” then population/allele/count information is provided in four groups which are separated by semicolons and listed in the same order as the listing of SNP sources, with each population/allele/count information group corresponding to the respective SNP source based on order; thus, in this example, the first population/allele/count information group would correspond to the first listed SNP source (Celera) and the third population/allele/count information group separated by semicolons would correspond to the third listed SNP source (HGBASE); if population/allele/count information is not available for any particular SNP source, then a pair of semicolons is still inserted as a place-holder in order to maintain correspondence between the list of SNP sources and the corresponding listing of population/allele/count information.

    • SNP type (e.g., location within gene/transcript and/or predicted functional effect) [“VTES-SENSE MUTATION”=SNP causes a change in the encoded amino acid (i.e., a non-synonymous coding SNP); “SILENT MUTATION”=SNP does not cause a change in the encoded amino acid (i.e., a synonymous coding SNP); “STOP CODON MUTATION”=SNP is located in a stop codon; “NONSENSE MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a 3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative 3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located in an acceptor splice site (3′ intron boundary); “CODING REGION”=SNP is located in a protein-coding region of the transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is located in an intron; “hmCS”=SNP is located in a human-mouse conserved segment; “TFBS”=SNP is located in a transcription factor binding site; “UNKNOWN”=SNP type is not defined; “INTERGENIC”=SNP is intergenic, i.e., outside of any gene boundary].
    • Protein coding information (Table 1 only), where relevant, in the format of [protein SEQ ID NO: #, amino acid position, (amino acid-1, codonl) (amino acid-2, codon2)]. The information in this field includes SEQ ID NO of the encoded protein sequence, position of the amino acid residue within the protein identified by the SEQ ID NO that is encoded by the codon containing the SNP, amino acids (represented by one-letter amino acid codes) that are encoded by the alternative SNP alleles (in the case of stop codons, “X” is used for the one-letter amino acid code), and alternative codons containing the alternative SNP nucleotides which encode the amino acid residues (thus, for example, for missense mutation-type SNPs, at least two different amino acids and at least two different codons are generally indicated; for silent mutation-type SNPs, one amino acid and at least two different codons are generally indicated, etc.). In instances where the SNP is located outside of a protein-coding region (e.g., in a UTR region), “None” is indicated following the protein SEQ ID NO.


DESCRIPTION OF TABLE 3

Table 3 provides sequences (SEQ ID NOS: 1588-2556) of oligonucleotides that have been synthesized and used in the laboratory to assay the SNPs disclosed in Tables 5-13 during the course of association studies to verify the association of these SNPs with VT. The experiments that were conducted using these primers are explained in detail in Example 1, below.


Table 3 provides the following:

    • the column labeled “Marker” lists the Celera identifier hCV number for each SNP marker.
    • the column labeled “Alleles” designates the two alternative alleles at the SNP site identified by the hCV identification number that are targeted by the allele-specific oligonucleotides.
    • allele-specific oligonucleotides with their respective SEQ ID numbers are shown in the next two columns, “Sequence A (allele-specific primer)” and “Sequence B (allele-specific primer).” These two primers were used in conjunction with a common primer in each PCR assay to genotype DNA samples for each SNP marker. Note that alleles may be presented in Table 3 based on a different orientation (i.e., the reverse complement) relative to how the same alleles are presented in Tables 1 and 2.
    • common oligonucleotides with their respective SEQ ID numbers are shown in the column, “Sequence C (common primer).” Each common primer was used in conjunction with the two allele-specific primers to genotype DNA samples for each SNP marker.


All sequences are given in the 5′ to 3′ direction.


Description of Table 4


Table 4 provides a list of the sample LD SNPs that are related to and derived from an interrogated SNP. These LD SNPs are provided as an example of the groups of SNPs which can also serve as markers for disease association based on their being in LD with the interrogated SNP. The criteria and process of selecting such LD SNPs, including the calculation of the r2 value and the r2 threshold value, are described in Example Ten, below.


In Table 4, the column labeled “Interrogated SNP” presents each marker as identified by its unique identifier, the hCV number. The column labeled “Interrogated rs” presents the publicly known identifier rs number for the corresponding hCV number. The column labeled “LD SNP” presents the hCV numbers of the LD SNPs that are derived from their corresponding interrogated SNPs. The column labeled “LD SNP rs” presents the publicly known rs number for the corresponding hCV number. The column labeled “Power (T)” presents the level of power where the r2 threshold is set. For example, when power is set at 51%, the threshold r2 value calculated therefrom is the minimum r2 that an LD SNP must have in reference to an interrogated SNP, in order for the LD SNP to be classified as a marker capable of being associated with a disease phenotype at greater than 51% probability. The column labeled “Threshold r72” presents the minimum value of r2 that an LD SNP must meet in reference to an interrogated SNP in order to qualify as an LD SNP. The column labeled “r2” presents the actual r2 value of the LD SNP in reference to the interrogated SNP to which it is related.


DESCRIPTION OF OTHER TABLES

Tables 3-4, 20-23, and 25-27 are provided following the Examples section (before the claims) of the instant specification. Tables 1-2 are provided as separate ASCII text files. Tables 1-4 are described above. Tables 5-19, 24, and 28-29 are provided within the Examples section of the instant specification below and are described there. Thus, this section describes Tables 20-23 and 25-27.


Table 20 provides unadjusted additive and genotypic association with DVT for 149 SNPs that were tested in both MEGA-1 and LETS, and were associated with DVT in both of these sample sets (p-value cutoff <=0.05 in MEGA-1 and p-value cutoff <=0.1 in LETS, in at least one model).


Table 21 provides unadjusted association of 92 SNPs with DVT in LETS (p<=0.05) that have not yet been tested in the MEGA-1 sample set.


Table 22 provides unadjusted association of 9 SNPs with DVT in MEGA-1 (p<=0.05) that have not yet been tested in the LETS sample set.


Table 23 provides age- and sex-adjusted association with DVT for 41 SNPs that were tested in the three sample sets LETS, MEGA-1, and MEGA-2.


See Example Five below regarding Tables 20-23. Table 25 provides age- and sex-adjusted association with isolated pulmonary embolism (PE) for 52 SNPs in MEGA-1 and MEGA-2 combined (p-value cutoff <=0.05). See Example Seven below.


Table 26 provides age- and sex-adjusted association with cancer-related DVT for 31 SNPs in MEGA-1 and MEGA-2 combined (p-value cutoff <=0.05). The SNPs provided in Table 26 had a p-value cutoff <=0.05 when comparing individuals (cases) in the MEGA-1 and MEGA-2 studies who had both cancer (of any type) and DVT compared with individuals (controls) who had neither cancer nor DVT. See Example Eight below.


Table 27 provides additive association with DVT for 123 SNPs in LETS (p-value cutoff <=0.1 in LETS). Linkage disequilibrium data from Hapmap is also provided for each SNP. The SNPs in Table 27 are based on fine-mapping/linkage disequilibrium analysis around the following target genes and SNPs (as indicated in Table 27): gene AKT3 (SNP hCV233148), gene SERPINC1 (SNP hCV16180170), gene RGS7 (SNP hCV916107), gene NR1I2 (SNP hCV263841), gene FGG (SNP hCV11503469), gene CYP4V2 (SNP hCV25990131), gene GP6 (SNP hCV8717873), and gene F9 (SNP hCV596331). See Example Nine below.


The following abbreviations may be used throughout the tables: “cnt”=count, “frq”=frequency, “dom”=dominant, “rec”=recessive, “gen”=genotypic, “add”=additive, “annot”=annotation (description), “genot”=genotype, and “Control RAF”=risk allele frequency in controls.


Throughout the tables, “HR” or “HRR” refers to the hazard ratio, “OR” refers to the odds ratio, terms such as “90% CI” or “95% CI” refer to the 90% or 95% confidence interval (respectively) for the hazard ratio or odds ratio, and terms such as “OR951” and “OR95u” refer to the lower and upper 95% confidence intervals (respectively) for the odds ratio (“CI”/“confidence interval” and “CL”/“confidence limit” may be used herein interchangeably). Hazard ratios (“HR” or “HRR”) or odds ratios (OR) that are greater than one indicate that a given allele (or combination of alleles such as a haplotype or diplotype) is a risk allele (which may also be referred to as a susceptibility allele), whereas hazard ratios or odds ratios that are less than one indicate that a given allele is a non-risk allele (which may also be referred to as a protective allele). For a given risk allele, the other alternative allele at the SNP position (which can be derived from the information provided in Tables 1-2, for example) may be considered a non-risk allele. For a given non-risk allele, the other alternative allele at the SNP position may be considered a risk allele.


Thus, with respect to disease risk (e.g., VT), if the risk estimate (odds ratio or hazard ratio) for a particular allele at a SNP position is greater than one, this indicates that an individual with this particular allele has a higher risk for the disease than an individual who has the other allele at the SNP position. In contrast, if the risk estimate (odds ratio or hazard ratio) for a particular allele is less than one, this indicates that an individual with this particular allele has a reduced risk for the disease compared with an individual who has the other allele at the SNP position.





DESCRIPTION OF THE FIGURES


FIG. 1 shows a flowchart of the approach used to identify SNPs associated with DVT. On the left, the “IN” box indicates the number of SNPs genotyped in each stage. On the right, the “OUT” box indicates the number of SNPs associated with DVT in each stage (P<0.05). To conserve MEGA-2 DNA in Stage 4, SNPs were genotyped using multiplexed oligo ligation assays, and assays for only 9 of the 18 Stage 3 SNPs were available in multiplex format at the time of this study.



FIG. 2 shows the meta-analysis of Factor IX Malmö with DVT in women and men.





DETAILED DESCRIPTION OF THE INVENTION

The present invention provides SNPs associated with VT, nucleic acid molecules containing SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The VT-associated SNPs disclosed herein are useful for diagnosing, screening for, and evaluating predisposition to VT and related pathologies in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic agents.


A large number of SNPs have been identified from re-sequencing DNA from 39 individuals, and they are indicated as “Applera” SNP source in Tables 1-2. Their allele frequencies observed in each of the Caucasian and African-American ethnic groups are provided. Additional SNPs included herein were previously identified during shotgun sequencing and assembly of the human genome, and they are indicated as “Celera” SNP source in Tables 1-2. Furthermore, the information provided in Table 1-2, particularly the allele frequency information obtained from 39 individuals and the identification of the precise position of each SNP within each gene/transcript, allows haplotypes (i.e., groups of SNPs that are co-inherited) to be readily inferred. The present invention encompasses SNP haplotypes, as well as individual SNPs.


Thus, the present invention provides individual SNPs associated with VT, as well as combinations of SNPs and haplotypes in genetic regions associated with VT, polymorphic/variant transcript sequences (SEQ ID NOS: 1-125) and genomic sequences (SEQ ID NOS: 404-601) containing SNPs, encoded amino acid sequences (SEQ ID NOS: 126-250), and both transcript-based SNP context sequences (SEQ ID NOS: 251-403) and genomic-based SNP context sequences (SEQ ID NOS: 602-1587) (transcript sequences, protein sequences, and transcript-based SNP context sequences are provided in Table 1 and the Sequence Listing; genomic sequences and genomic-based SNP context sequences are provided in Table 2 and the Sequence Listing), methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing VT, methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as VT, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment strategy, methods of treating a disorder associated with a variant gene/protein (i.e., therapeutic methods), methods of determining if an individual is likely to respond to a specific treatment and methods of using the SNPs of the present invention for human identification.


The present invention provides novel SNPs associated with VT, as well as SNPs that were previously known in the art, but were not previously known to be associated with VT. Accordingly, the present invention provides novel compositions and methods based on the novel SNPs disclosed herein, and also provides novel methods of using the known, but previously unassociated, SNPs in methods relating to VT (e.g., for diagnosing VT, etc.). In Tables 1-2, known SNPs are identified based on the public database in which they have been observed, which is indicated as one or more of the following SNP types: “dbSNP”=SNP observed in dbSNP, “HGBASE”=SNP observed in HGBASE, and “HGMD”=SNP observed in the Human Gene Mutation Database (HGMD). Novel SNPs for which the SNP source is only “Applera” and none other, i.e., those that have not been observed in any public databases and which were also not observed during shotgun sequencing and assembly of the Celera human genome sequence (i.e., “Celera” SNP source), are also noted in the tables.


Particular SNP alleles of the present invention can be associated with either an increased risk of having or developing VT, or a decreased risk of having or developing VT. SNP alleles that are associated with a decreased risk of having or developing VT may be referred to as “protective” alleles, and SNP alleles that are associated with an increased risk of having or developing VT may be referred to as “susceptibility” alleles, “risk” alleles, or “risk factors”. Thus, whereas certain SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of an increased risk of having or developing VT (i.e., a susceptibility allele), other SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of a decreased risk of having or developing VT (i.e., a protective allele). Similarly, particular SNP alleles of the present invention can be associated with either an increased or decreased likelihood of responding to a particular treatment or therapeutic compound, or an increased or decreased likelihood of experiencing toxic effects from a particular treatment or therapeutic compound. The term “altered” may be used herein to encompass either of these two possibilities (e.g., an increased or a decreased risk/likelihood).


Those skilled in the art will readily recognize that nucleic acid molecules may be double-stranded molecules and that reference to a particular site on one strand refers, as well, to the corresponding site on a complementary strand. In defining a SNP position, SNP allele, or nucleotide sequence, reference to an adenine, a thymine (uridine), a cytosine, or a guanine at a particular site on one strand of a nucleic acid molecule also defines the thymine (uridine), adenine, guanine, or cytosine (respectively) at the corresponding site on a complementary strand of the nucleic acid molecule. Thus, reference may be made to either strand in order to refer to a particular SNP position, SNP allele, or nucleotide sequence. Probes and primers, may be designed to hybridize to either strand and SNP genotyping methods disclosed herein may generally target either strand. Throughout the specification, in identifying a SNP position, reference is generally made to the protein-encoding strand, only for the purpose of convenience.


References to variant peptides, polypeptides, or proteins of the present invention include peptides, polypeptides, proteins, or fragments thereof, that contain at least one amino acid residue that differs from the corresponding amino acid sequence of the art-known peptide/polypeptide/protein (the art-known protein may be interchangeably referred to as the “wild-type,” “reference,” or “normal” protein). Such variant peptides/polypeptides/proteins can result from a codon change caused by a nonsynonymous nucleotide substitution at a protein-coding SNP position (i.e., a missense mutation) disclosed by the present invention. Variant peptides/polypeptides/proteins of the present invention can also result from a nonsense mutation, i.e., a SNP that creates a premature stop codon, a SNP that generates a read-through mutation by abolishing a stop codon, or due to any SNP disclosed by the present invention that otherwise alters the structure, function/activity, or expression of a protein, such as a SNP in a regulatory region (e.g. a promoter or enhancer) or a SNP that leads to alternative or defective splicing, such as a SNP in an intron or a SNP at an exon/intron boundary. As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably.


As used herein, an “allele” may refer to a nucleotide at a SNP position (wherein at least two alternative nucleotides exist in the population at the SNP position, in accordance with the inherent definition of a SNP) or may refer to an amino acid residue that is encoded by the codon which contains the SNP position (where the alternative nucleotides that are present in the population at the SNP position form alternative codons that encode different amino acid residues). An “allele” may also be referred to herein as a “variant”. Also, an amino acid residue that is encoded by a codon containing a particular SNP may simply be referred to as being encoded by the SNP.


A phrase such as “as represented by”, “as shown by”, “as symbolized by”, or “as designated by” may be used herein to refer to a SNP within a sequence (e.g., a polynucleotide context sequence surrounding a SNP), such as in the context of “a polymorphism as represented by position 101 of SEQ ID NO:X or its complement”. Typically, the sequence surrounding a SNP may be recited when referring to a SNP, however the sequence is not intended as a structural limitation beyond the specific SNP position itself. Rather, the sequence is recited merely as a way of referring to the SNP (in this example, “SEQ ID NO:X or its complement” is recited in order to refer to the SNP located at position 101 of SEQ ID NO:X, but SEQ ID NO:X or its complement is not intended as a structural limitation beyond the specific SNP position itself). A SNP is a variation at a single nucleotide position and therefore it is customary to refer to context sequence (e.g., SEQ ID NO:X in this example) surrounding a particular SNP position in order to uniquely identify and refer to the SNP. Alternatively, a SNP can be referred to by a unique identification number such as a public “rs” identification number or an internal “hCV” identification number, such as provided herein for each SNP (e.g., in Tables 1-2).


With respect to an individual's risk for a disease (e.g., based on the presence or absence of one or more SNPs disclosed herein in the individual's nucleic acid), terms such as “assigning” or “designating” may be used herein to characterize the individual's risk for the disease.


As used herein, the term “benefit” (with respect to a preventive or therapeutic drug treatment) is defined as achieving a reduced risk for a disease that the drug is intended to treat or prevent (e.g., VT) by administrating the drug treatment, compared with the risk for the disease in the absence of receiving the drug treatment (or receiving a placebo in lieu of the drug treatment) for the same genotype. The term “benefit” may be used herein interchangeably with terms such as “respond positively” or “positively respond”.


As used herein, the terms “drug” and “therapeutic agent” are used interchangeably, and may include, but are not limited to, small molecule compounds, biologics (e.g., antibodies, proteins, protein fragments, fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g., antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc., which may be used for therapeutic and/or preventive treatment of a disease (e.g., VT).


The various methods described herein, such as correlating the presence or absence of a polymorphism with an altered (e.g., increased or decreased) risk (or no altered risk) for VT, can be carried out by automated methods such as by using a computer (or other apparatus/devices such as biomedical devices, laboratory instrumentation, or other apparatus/devices having a computer processor) programmed to carry out any of the methods described herein. For example, computer software (which may be interchangeably referred to herein as a computer program) can perform the step of correlating the presence or absence of a polymorphism in an individual with an altered (e.g., increased or decreased) risk (or no altered risk) for VT for the individual. Computer software can also perform the step of correlating the presence or absence of a polymorphism in an individual with the predicted response of the individual to a therapeutic agent or other type of treatment. Accordingly, certain embodiments of the invention provide a computer (or other apparatus/device) programmed to carry out any of the methods described herein.


Reports, Programmed Computers, Business Methods, and Systems The results of a test (e.g., an individual's risk for VT, or an individual's predicted drug responsiveness, based on assaying one or more SNPs disclosed herein, and/or an individual's allele(s)/genotype at one or more SNPs disclosed herein, etc.), and/or any other information pertaining to a test, may be referred to herein as a “report”. A tangible report can optionally be generated as part of a testing process (which may be interchangeably referred to herein as “reporting”, or as “providing” a report, “producing” a report, or “generating” a report).


Examples of tangible reports may include, but are not limited to, reports in paper (such as computer-generated printouts of test results) or equivalent formats and reports stored on computer readable medium (such as a CD, USB flash drive or other removable storage device, computer hard drive, or computer network server, etc.). Reports, particularly those stored on computer readable medium, can be part of a database, which may optionally be accessible via the internet (such as a database of patient records or genetic information stored on a computer network server, which may be a “secure database” that has security features that limit access to the report, such as to allow only the patient and the patient's medical practioners to view the report while preventing other unauthorized individuals from viewing the report, for example). In addition to, or as an alternative to, generating a tangible report, reports can also be displayed on a computer screen (or the display of another electronic device or instrument).


A report can include, for example, an individual's risk for VT, or may just include the allele(s)/genotype that an individual carries at one or more SNPs disclosed herein, which may optionally be linked to information regarding the significance of having the allele(s)/genotype at the SNP (for example, a report on computer readable medium such as a network server may include hyperlink(s) to one or more journal publications or websites that describe the medical/biological implications, such as increased or decreased disease risk, for individuals having a certain allele/genotype at the SNP). Thus, for example, the report can include disease risk or other medical/biological significance (e.g., drug responsiveness, etc.) as well as optionally also including the allele/genotype information, or the report may just include allele/genotype information without including disease risk or other medical/biological significance (such that an individual viewing the report can use the allele/genotype information to determine the associated disease risk or other medical/biological significance from a source outside of the report itself, such as from a medical practioner, publication, website, etc., which may optionally be linked to the report such as by a hyperlink).


A report can further be “transmitted” or “communicated” (these terms may be used herein interchangeably), such as to the individual who was tested, a medical practitioner (e.g., a doctor, nurse, clinical laboratory practitioner, genetic counselor, etc.), a healthcare organization, a clinical laboratory, and/or any other party or requester intended to view or possess the report. The act of “transmitting” or “communicating” a report can be by any means known in the art, based on the format of the report. Furthermore, “transmitting” or “communicating” a report can include delivering a report (“pushing”) and/or retrieving (“pulling”) a report. For example, reports can be transmitted/communicated by various means, including being physically transferred between parties (such as for reports in paper format) such as by being physically delivered from one party to another, or by being transmitted electronically or in signal form (e.g., via e-mail or over the internet, by facsimile, and/or by any wired or wireless communication methods known in the art) such as by being retrieved from a database stored on a computer network server, etc.


In certain exemplary embodiments, the invention provides computers (or other apparatus/devices such as biomedical devices or laboratory instrumentation) programmed to carry out the methods described herein. For example, in certain embodiments, the invention provides a computer programmed to receive (i.e., as input) the identity (e.g., the allele(s) or genotype at a SNP) of one or more SNPs disclosed herein and provide (i.e., as output) the disease risk (e.g., an individual's risk for VT) or other result (e.g., disease diagnosis or prognosis, drug responsiveness, etc.) based on the identity of the SNP(s). Such output (e.g., communication of disease risk, disease diagnosis or prognosis, drug responsiveness, etc.) may be, for example, in the form of a report on computer readable medium, printed in paper form, and/or displayed on a computer screen or other display.


In various exemplary embodiments, the invention further provides methods of doing business (with respect to methods of doing business, the terms “individual” and “customer” are used herein interchangeably). For example, exemplary methods of doing business can comprise assaying one or more SNPs disclosed herein and providing a report that includes, for example, a customer's risk for VT (based on which allele(s)/genotype is present at the assayed SNP(s)) and/or that includes the allele(s)/genotype at the assayed SNP(s) which may optionally be linked to information (e.g., journal publications, websites, etc.) pertaining to disease risk or other biological/medical significance such as by means of a hyperlink (the report may be provided, for example, on a computer network server or other computer readable medium that is internet-accessible, and the report may be included in a secure database that allows the customer to access their report while preventing other unauthorized individuals from viewing the report), and optionally transmitting the report. Customers (or another party who is associated with the customer, such as the customer's doctor, for example) can request/order (e.g., purchase) the test online via the internet (or by phone, mail order, at an outlet/store, etc.), for example, and a kit can be sent/delivered (or otherwise provided) to the customer (or another party on behalf of the customer, such as the customer's doctor, for example) for collection of a biological sample from the customer (e.g., a buccal swab for collecting buccal cells), and the customer (or a party who collects the customer's biological sample) can submit their biological samples for assaying (e.g., to a laboratory or party associated with the laboratory such as a party that accepts the customer samples on behalf of the laboratory, a party for whom the laboratory is under the control of (e.g., the laboratory carries out the assays by request of the party or under a contract with the party, for example), and/or a party that receives at least a portion of the customer's payment for the test). The report (e.g., results of the assay including, for example, the customer's disease risk and/or allele(s)/genotype at the assayed SNP(s)) may be provided to the customer by, for example, the laboratory that assays the SNP(s) or a party associated with the laboratory (e.g., a party that receives at least a portion of the customer's payment for the assay, or a party that requests the laboratory to carry out the assays or that contracts with the laboratory for the assays to be carried out) or a doctor or other medical practitioner who is associated with (e.g., employed by or having a consulting or contracting arrangement with) the laboratory or with a party associated with the laboratory, or the report may be provided to a third party (e.g., a doctor, genetic counselor, hospital, etc.) which optionally provides the report to the customer. In further embodiments, the customer may be a doctor or other medical practitioner, or a hospital, laboratory, medical insurance organization, or other medical organization that requests/orders (e.g., purchases) tests for the purposes of having other individuals (e.g., their patients or customers) assayed for one or more SNPs disclosed herein and optionally obtaining a report of the assay results.


In certain exemplary methods of doing business, kits for collecting a biological sample from a customer (e.g., a buccal swab for collecting buccal cells) are provided (e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy, general merchandise store, or any other desirable outlet), online via the internet, by mail order, etc., whereby customers can obtain (e.g., purchase) the kits, collect their own biological samples, and submit (e.g., send/deliver via mail) their samples to a laboratory which assays the samples for one or more SNPs disclosed herein (such as to determine the customer's risk for VT) and optionally provides a report to the customer (of the customer's disease risk based on their SNP genotype(s), for example) or provides the results of the assay to another party (e.g., a doctor, genetic counselor, hospital, etc.) which optionally provides a report to the customer (of the customer's disease risk based on their SNP genotype(s), for example).


Certain further embodiments of the invention provide a system for determining an individual's DVT risk, or whether an individual will benefit from a drug treatment (or other therapy) in reducing DVT risk. Certain exemplary systems comprise an integrated “loop” in which an individual (or their medical practitioner) requests a determination of such individual's VT risk (or drug response, etc.), this determination is carried out by testing a sample from the individual, and then the results of this determination are provided back to the requestor. For example, in certain systems, a sample (e.g., blood or buccal cells) is obtained from an individual for testing (the sample may be obtained by the individual or, for example, by a medical practitioner), the sample is submitted to a laboratory (or other facility) for testing (e.g., determining the genotype of one or more SNPs disclosed herein), and then the results of the testing are sent to the patient (which optionally can be done by first sending the results to an intermediary, such as a medical practioner, who then provides or otherwise conveys the results to the individual and/or acts on the results), thereby forming an integrated loop system for determining an individual's DVT risk (or drug response, etc.). The portions of the system in which the results are transmitted (e.g., between any of a testing facility, a medical practitioner, and/or the individual) can be carried out by way of electronic or signal transmission (e.g., by computer such as via e-mail or the internet, by providing the results on a website or computer network server which may optionally be a secure database, by phone or fax, or by any other wired or wireless transmission methods known in the art). Optionally, the system can further include a risk reduction component (i.e., a disease management system) as part of the integrated loop (for an example of a disease management system, see U.S. Pat. No. 6,770,029, “Disease management system and method including correlation assessment”). For example, the results of the test can be used to reduce the risk of the disease in the individual who was tested, such as by implementing a preventive therapy regimen (e.g., administration of a drug regimen such as an anticoagulant and/or antiplatelet agent for reducing DVT risk), modifying the individual's diet, increasing exercise, reducing stress, and/or implementing any other physiological or behavioral modifications in the individual with the goal of reducing disease risk. For reducing DVT risk, this may include any means used in the art for improving cardiovascular health. Thus, in exemplary embodiments, the system is controlled by the individual and/or their medical practioner in that the individual and/or their medical practioner requests the test, receives the test results back, and (optionally) acts on the test results to reduce the individual's disease risk, such as by implementing a disease management component.


Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of the present invention that is associated with VT, including the transcript sequences (SEQ ID NOS: 1-125), genomic sequences (SEQ ID NOS: 404-601), and protein sequences (SEQ ID NOS: 126-250) of the encoded gene products (with the SNPs indicated by IUB codes in the nucleic acid sequences). In addition, Tables 1 and 2 include SNP context sequences, which generally include 100 nucleotide upstream (5′) plus 100 nucleotides downstream (3′) of each SNP position (SEQ ID NOS: 251-403 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS: 602-1587 correspond to genomic-based context sequences disclosed in Table 2), the alternative nucleotides (alleles) at each SNP position, and additional information about the variant where relevant, such as SNP type (coding, missense, splice site, UTR, etc.), human populations in which the SNP was observed, observed allele frequencies, information about the encoded protein, etc.


Isolated Nucleic Acid Molecules


The present invention provides isolated nucleic acid molecules that contain one or more SNPs disclosed Table 1 and/or Table 2. Isolated nucleic acid molecules containing one or more SNPs disclosed in at least one of Tables 1-2 may be interchangeably referred to throughout the present text as “SNP-containing nucleic acid molecules”. Isolated nucleic acid molecules may optionally encode a full-length variant protein or fragment thereof. The isolated nucleic acid molecules of the present invention also include probes and primers (which are described in greater detail below in the section entitled “SNP Detection Reagents”), which may be used for assaying the disclosed SNPs, and isolated full-length genes, transcripts, cDNA molecules, and fragments thereof, which may be used for such purposes as expressing an encoded protein.


As used herein, an “isolated nucleic acid molecule” generally is one that contains a SNP of the present invention or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule containing a SNP of the present invention, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered “isolated”. Nucleic acid molecules present in non-human transgenic animals, which do not naturally occur in the animal, are also considered “isolated”. For example, recombinant DNA molecules contained in a vector are considered “isolated”. Further examples of “isolated” DNA molecules include recombinant DNA molecules maintained in heterologous host cells, and purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated SNP-containing DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.


Generally, an isolated SNP-containing nucleic acid molecule comprises one or more SNP positions disclosed by the present invention with flanking nucleotide sequences on either side of the SNP positions. A flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences. Preferably the flanking sequence is up to about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side of a SNP position, or as long as the full-length gene or entire protein-coding sequence (or any portion thereof such as an exon), especially if the SNP-containing nucleic acid molecule is to be used to produce a protein or protein fragment.


For full-length genes and entire protein-coding sequences, a SNP flanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2 KB, 1 KB on either side of the SNP. Furthermore, in such instances, the isolated nucleic acid molecule comprises exonic sequences (including protein-coding and/or non-coding exonic sequences), but may also include intronic sequences. Thus, any protein coding sequence may be either contiguous or separated by introns. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences and is of appropriate length such that it can be subjected to the specific manipulations or uses described herein such as recombinant protein expression, preparation of probes and primers for assaying the SNP position, and other uses specific to the SNP-containing nucleic acid sequences.


An isolated SNP-containing nucleic acid molecule can comprise, for example, a full-length gene or transcript, such as a gene isolated from genomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, or an mRNA transcript molecule. Polymorphic transcript sequences are referred to in Table 1 and provided in the Sequence Listing (SEQ ID NOS: 1-125), and polymorphic genomic sequences are referred to in Table 2 and provided in the Sequence Listing (SEQ ID NOS: 404-601). Furthermore, fragments of such full-length genes and transcripts that contain one or more SNPs disclosed herein are also encompassed by the present invention, and such fragments may be used, for example, to express any part of a protein, such as a particular functional domain or an antigenic epitope.


Thus, the present invention also encompasses fragments of the nucleic acid sequences as disclosed in Tables 1-2 (transcript sequences are referred to in Table 1 as SEQ ID NOS: 1-125, genomic sequences are referred to in Table 2 as SEQ ID NOS: 404-601, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NO: 251-403, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NO: 602-1587) and their complements. The actual sequences referred to in the tables are provided in the Sequence Listing. A fragment typically comprises a contiguous nucleotide sequence at least about 8 or more nucleotides, more preferably at least about 12 or more nucleotides, and even more preferably at least about 16 or more nucleotides. Further, a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 (or any other number in-between) nucleotides in length. The length of the fragment will be based on its intended use. For example, the fragment can encode epitope-bearing regions of a variant peptide or regions of a variant peptide that differ from the normal/wild-type protein, or can be useful as a polynucleotide probe or primer. Such fragments can be isolated using the nucleotide sequences provided in Table 1 and/or Table 2 for the synthesis of a polynucleotide probe. A labeled probe can then be used, for example, to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in amplification reactions, such as for purposes of assaying one or more SNPs sites or for cloning specific regions of a gene.


An isolated nucleic acid molecule of the present invention further encompasses a SNP-containing polynucleotide that is the product of any one of a variety of nucleic acid amplification methods, which are used to increase the copy numbers of a polynucleotide of interest in a nucleic acid sample. Such amplification methods are well known in the art, and they include but are not limited to, polymerase chain reaction (PCR) (U.S. Pat. Nos. 4,683,195; and 4,683,202; PCR Technology: Principles and Applications for DNA Amplification, ed. H. A. Erlich, Freeman Press, NY, N.Y., 1992), ligase chain reaction (LCR) (Wu and Wallace, Genomics 4:560, 1989; Landegren et al., Science 241:1077, 1988), strand displacement amplification (SDA) (U.S. Pat. Nos. 5,270,184; and 5,422,252), transcription-mediated amplification (TMA) (U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat. No. 6,027,923), and the like, and isothermal amplification methods such as nucleic acid sequence based amplification (NASBA), and self-sustained sequence replication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87: 1874, 1990). Based on such methodologies, a person skilled in the art can readily design primers in any suitable regions 5′ and 3′ to a SNP disclosed herein. Such primers may be used to amplify DNA of any length so long that it contains the SNP of interest in its sequence.


As used herein, an “amplified polynucleotide” of the invention is a SNP-containing nucleic acid molecule whose amount has been increased at least two fold by any nucleic acid amplification method performed in vitro as compared to its starting amount in a test sample. In other preferred embodiments, an amplified polynucleotide is the result of at least ten fold, fifty fold, one hundred fold, one thousand fold, or even ten thousand fold increase as compared to its starting amount in a test sample. In a typical PCR amplification, a polynucleotide of interest is often amplified at least fifty thousand fold in amount over the unamplified genomic DNA, but the precise amount of amplification needed for an assay depends on the sensitivity of the subsequent detection method used.


Generally, an amplified polynucleotide is at least about 16 nucleotides in length. More typically, an amplified polynucleotide is at least about 20 nucleotides in length. In a preferred embodiment of the invention, an amplified polynucleotide is at least about 30 nucleotides in length. In a more preferred embodiment of the invention, an amplified polynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides in length. In yet another preferred embodiment of the invention, an amplified polynucleotide is at least about 100, 200, 300, 400, or 500 nucleotides in length. While the total length of an amplified polynucleotide of the invention can be as long as an exon, an intron or the entire gene where the SNP of interest resides, an amplified product is typically up to about 1,000 nucleotides in length (although certain amplification methods may generate amplified products greater than 1000 nucleotides in length). More preferably, an amplified polynucleotide is not greater than about 600-700 nucleotides in length. It is understood that irrespective of the length of an amplified polynucleotide, a SNP of interest may be located anywhere along its sequence.


In a specific embodiment of the invention, the amplified product is at least about 201 nucleotides in length, comprises one of the transcript-based context sequences or the genomic-based context sequences shown in Tables 1-2. Such a product may have additional sequences on its 5′ end or 3′ end or both. In another embodiment, the amplified product is about 101 nucleotides in length, and it contains a SNP disclosed herein. Preferably, the SNP is located at the middle of the amplified product (e.g., at position 101 in an amplified product that is 201 nucleotides in length, or at position 51 in an amplified product that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplified product (however, as indicated above, the SNP of interest may be located anywhere along the length of the amplified product).


The present invention provides isolated nucleic acid molecules that comprise, consist of, or consist essentially of one or more polynucleotide sequences that contain one or more SNPs disclosed herein, complements thereof, and SNP-containing fragments thereof.


Accordingly, the present invention provides nucleic acid molecules that consist of any of the nucleotide sequences shown in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS: 1-125, genomic sequences are referred to in Table 2 as SEQ ID NOS: 404-601, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NO: 251-403, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NO: 602-1587), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS: 126-250). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.


The present invention further provides nucleic acid molecules that consist essentially of any of the nucleotide sequences referred to in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-125, genomic sequences are referred to in Table 2 as SEQ ID NOS: 404-601, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NO: 251-403, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NO: 602-1587), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS: 126-250). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleotide residues in the final nucleic acid molecule.


The present invention further provides nucleic acid molecules that comprise any of the nucleotide sequences shown in Table 1 and/or Table 2 or a SNP-containing fragment thereof (transcript sequences are referred to in Table 1 as SEQ ID NOS: 1-125, genomic sequences are referred to in Table 2 as SEQ ID NOS: 404-601, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NO: 251-403, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NO: 602-1587), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS: 126-250). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleotide residues, such as residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have one to a few additional nucleotides or can comprise many more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made and isolated is provided below, and such techniques are well known to those of ordinary skill in the art (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, NY).


The isolated nucleic acid molecules can encode mature proteins plus additional amino or carboxyl-terminal amino acids or both, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life, or facilitate manipulation of a protein for assay or production. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.


Thus, the isolated nucleic acid molecules include, but are not limited to, nucleic acid molecules having a sequence encoding a peptide alone, a sequence encoding a mature peptide and additional coding sequences such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence), a sequence encoding a mature peptide with or without additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5′ and 3′ sequences such as transcribed but untranslated sequences that play a role in, for example, transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding, and/or stability of mRNA. In addition, the nucleic acid molecules may be fused to heterologous marker sequences encoding, for example, a peptide that facilitates purification.


Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA, which may be obtained, for example, by molecular cloning or produced by chemical synthetic techniques or by a combination thereof (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, NY). Furthermore, isolated nucleic acid molecules, particularly SNP detection reagents such as probes and primers, can also be partially or completely in the form of one or more types of nucleic acid analogs, such as peptide nucleic acid (PNA) (U.S. Pat. Nos. 5,539,082; 5,527,675; 5,623,049; 5,714,331). The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the complementary non-coding strand (anti-sense strand). DNA, RNA, or PNA segments can be assembled, for example, from fragments of the human genome (in the case of DNA or RNA) or single nucleotides, short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic nucleic acid molecule. Nucleic acid molecules can be readily synthesized using the sequences provided herein as a reference; oligonucleotide and PNA oligomer synthesis techniques are well known in the art (see, e.g., Corey, “Peptide nucleic acids: expanding the scope of nucleic acid recognition”, Trends Biotechnol. 1997 June; 15(6):224-9, and Hyrup et al., “Peptide nucleic acids (PNA): synthesis, properties and potential applications”, Bioorg Med. Chem. 1996 January; 4(1):5-23). Furthermore, large-scale automated oligonucleotide/PNA synthesis (including synthesis on an array or bead surface or other solid support) can readily be accomplished using commercially available nucleic acid synthesizers, such as the Applied Biosystems (Foster City, Calif.) 3900 High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid Synthesis System, and the sequence information provided herein.


The present invention encompasses nucleic acid analogs that contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art. Such nucleic acid analogs are useful, for example, as detection reagents (e.g., primers/probes) for detecting one or more SNPs identified in Table 1 and/or Table 2. Furthermore, kits/systems (such as beads, arrays, etc.) that include these analogs are also encompassed by the present invention. For example, PNA oligomers that are based on the polymorphic sequences of the present invention are specifically contemplated. PNA oligomers are analogs of DNA in which the phosphate backbone is replaced with a peptide-like backbone (Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters, 4: 1081-1082 (1994), Petersen et al., Bioorganic & Medicinal Chemistry Letters, 6: 793-796 (1996), Kumar et al., Organic Letters 3(9): 1269-1272 (2001), WO96/04000). PNA hybridizes to complementary RNA or DNA with higher affinity and specificity than conventional oligonucleotides and oligonucleotide analogs. The properties of PNA enable novel molecular biology and biochemistry applications unachievable with traditional oligonucleotides and peptides.


Additional examples of nucleic acid modifications that improve the binding properties and/or stability of a nucleic acid include the use of base analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263) and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, references herein to nucleic acid molecules, SNP-containing nucleic acid molecules, SNP detection reagents (e.g., probes and primers), oligonucleotides/polynucleotides include PNA oligomers and other nucleic acid analogs. Other examples of nucleic acid analogs and alternative/modified nucleic acid chemistries known in the art are described in Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y. (2002).


The present invention further provides nucleic acid molecules that encode fragments of the variant polypeptides disclosed herein as well as nucleic acid molecules that encode obvious variants of such variant polypeptides. Such nucleic acid molecules may be naturally occurring, such as paralogs (different locus) and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Non-naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, the variants can contain nucleotide substitutions, deletions, inversions and insertions (in addition to the SNPs disclosed in Tables 1-2). Variation can occur in either or both the coding and non-coding regions. The variations can produce conservative and/or non-conservative amino acid substitutions.


Further variants of the nucleic acid molecules disclosed in Tables 1-2, such as naturally occurring allelic variants (as well as orthologs and paralogs) and synthetic variants produced by mutagenesis techniques, can be identified and/or produced using methods well known in the art. Such further variants can comprise a nucleotide sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence disclosed in Table 1 and/or Table 2 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Further, variants can comprise a nucleotide sequence that encodes a polypeptide that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a polypeptide sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Thus, an aspect of the present invention that is specifically contemplated are isolated nucleic acid molecules that have a certain degree of sequence variation compared with the sequences shown in Tables 1-2, but that contain a novel SNP allele disclosed herein. In other words, as long as an isolated nucleic acid molecule contains a novel SNP allele disclosed herein, other portions of the nucleic acid molecule that flank the novel SNP allele can vary to some degree from the specific transcript, genomic, and context sequences referred to and shown in Tables 1-2, and can encode a polypeptide that varies to some degree from the specific polypeptide sequences referred to in Table 1.


To determine the percent identity of two amino acid sequences or two nucleotide sequences of two molecules that share sequence homology, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.


The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. (Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (J. Mol. Biol. (48):444-453 (1970)) which has been incorporated into the GAP program in the GCG software package, using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.


In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (Devereux, J., et al., Nucleic Acids Res. 12(1):387 (1984)), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.


The nucleotide and amino acid sequences of the present invention can further be used as a “query sequence” to perform a search against sequence databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (J. Mol. Biol. 215:403-10 (1990)). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res. 25(17):3389-3402 (1997)). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. In addition to BLAST, examples of other search and sequence comparison programs used in the art include, but are not limited to, FASTA (Pearson, Methods Mol. Biol. 25, 365-389 (1994)) and KERR (Dufresne et al., Nat Biotechnol 2002 December; 20(12):1269-71). For further information regarding bioinformatics techniques, see Current Protocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.


The present invention further provides non-coding fragments of the nucleic acid molecules disclosed in Table 1 and/or Table 2. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, intronic sequences, 5′ untranslated regions (UTRs), 3′ untranslated regions, gene modulating sequences and gene termination sequences. Such fragments are useful, for example, in controlling heterologous gene expression and in developing screens to identify gene-modulating agents.


SNP Detection Reagents


In a specific aspect of the present invention, the SNPs disclosed in Table 1 and/or Table 2, and their associated transcript sequences (referred to in Table 1 as SEQ ID NOS: 1-125), genomic sequences (referred to in Table 2 as SEQ ID NOS: 404-601), and context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS: 251-403; genomic-based context sequences are provided in Table 2 as SEQ ID NOS: 602-1587), can be used for the design of SNP detection reagents. The actual sequences referred to in the tables are provided in the Sequence Listing. As used herein, a “SNP detection reagent” is a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined). Typically, such detection reagent hybridizes to a target SNP-containing nucleic acid molecule by complementary base-pairing in a sequence specific manner, and discriminates the target variant sequence from other nucleic acid sequences such as an art-known form in a test sample. An example of a detection reagent is a probe that hybridizes to a target nucleic acid containing one or more of the SNPs referred to in Table 1 and/or Table 2. In a preferred embodiment, such a probe can differentiate between nucleic acids having a particular nucleotide (allele) at a target SNP position from other nucleic acids that have a different nucleotide at the same target SNP position. In addition, a detection reagent may hybridize to a specific region 5′ and/or 3′ to a SNP position, particularly a region corresponding to the context sequences referred to in Table 1 and/or Table 2 (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS: 251-403; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS: 602-1587). Another example of a detection reagent is a primer that acts as an initiation point of nucleotide extension along a complementary strand of a target polynucleotide. The SNP sequence information provided herein is also useful for designing primers, e.g. allele-specific primers, to amplify (e.g., using PCR) any SNP of the present invention.


In one preferred embodiment of the invention, a SNP detection reagent is an isolated or synthetic DNA or RNA polynucleotide probe or primer or PNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizes to a segment of a target nucleic acid molecule containing a SNP identified in Table 1 and/or Table 2. A detection reagent in the form of a polynucleotide may optionally contain modified base analogs, intercalators or minor groove binders. Multiple detection reagents such as probes may be, for example, affixed to a solid support (e.g., arrays or beads) or supplied in solution (e.g., probe/primer sets for enzymatic reactions such as PCR, RT-PCR, TaqMan assays, or primer-extension reactions) to form a SNP detection kit.


A probe or primer typically is a substantially purified oligonucleotide or PNA oligomer. Such oligonucleotide typically comprises a region of complementary nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50, 55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) or more consecutive nucleotides in a target nucleic acid molecule. Depending on the particular assay, the consecutive nucleotides can either include the target SNP position, or be a specific region in close enough proximity 5′ and/or 3′ to the SNP position to carry out the desired assay.


Other preferred primer and probe sequences can readily be determined using the transcript sequences (SEQ ID NOS: 1-125), genomic sequences (SEQ ID NOS: 404-601), and SNP context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS: 251-403; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS: 602-1587) disclosed in the Sequence Listing and in Tables 1-2. The actual sequences referred to in the tables are provided in the Sequence Listing. It will be apparent to one of skill in the art that such primers and probes are directly useful as reagents for genotyping the SNPs of the present invention, and can be incorporated into any kit/system format.


In order to produce a probe or primer specific for a target SNP-containing sequence, the gene/transcript and/or context sequence surrounding the SNP of interest is typically examined using a computer algorithm that starts at the 5′ or at the 3′ end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene/SNP context sequence, have a GC content within a range suitable for hybridization, lack predicted secondary structure that may interfere with hybridization, and/or possess other desired characteristics or that lack other undesired characteristics.


A primer or probe of the present invention is typically at least about 8 nucleotides in length. In one embodiment of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred embodiment, a primer or a probe is at least about 12 nucleotides in length. In a more preferred embodiment, a primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length. While the maximal length of a probe can be as long as the target sequence to be detected, depending on the type of assay in which it is employed, it is typically less than about 50, 60, 65, or 70 nucleotides in length. In the case of a primer, it is typically less than about 30 nucleotides in length. In a specific preferred embodiment of the invention, a primer or a probe is within the length of about 18 and about 28 nucleotides. However, in other embodiments, such as nucleic acid arrays and other embodiments in which probes are affixed to a substrate, the probes can be longer, such as on the order of 30-70, 75, 80, 90, 100, or more nucleotides in length (see the section below entitled “SNP Detection Kits and Systems”).


For analyzing SNPs, it may be appropriate to use oligonucleotides specific for alternative SNP alleles. Such oligonucleotides that detect single nucleotide variations in target sequences may be referred to by such terms as “allele-specific oligonucleotides”, “allele-specific probes”, or “allele-specific primers”. The design and use of allele-specific probes for analyzing polymorphisms is described in, e.g., Mutation Detection A Practical Approach, ed. Cotton et al. Oxford University Press, 1998; Saiki et al., Nature 324, 163-166 (1986); Dattagupta, EP235,726; and Saiki, WO 89/11548.


While the design of each allele-specific primer or probe depends on variables such as the precise composition of the nucleotide sequences flanking a SNP position in a target nucleic acid molecule, and the length of the primer or probe, another factor in the use of primers and probes is the stringency of the condition under which the hybridization between the probe or primer and the target sequence is performed. Higher stringency conditions utilize buffers with lower ionic strength and/or a higher reaction temperature, and tend to require a more perfect match between probe/primer and a target sequence in order to form a stable duplex. If the stringency is too high, however, hybridization may not occur at all. In contrast, lower stringency conditions utilize buffers with higher ionic strength and/or a lower reaction temperature, and permit the formation of stable duplexes with more mismatched bases between a probe/primer and a target sequence. By way of example and not limitation, exemplary conditions for high stringency hybridization conditions using an allele-specific probe are as follows: prehybridization with a solution containing 5× standard saline phosphate EDTA (SSPE), 0.5% NaDodSO4 (SDS) at 55° C., and incubating probe with target nucleic acid molecules in the same solution at the same temperature, followed by washing with a solution containing 2×SSPE, and 0.1% SDS at 55° C. or room temperature.


Moderate stringency hybridization conditions may be used for allele-specific primer extension reactions with a solution containing, e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may be carried out at an elevated temperature such as 60° C. In another embodiment, a moderately stringent hybridization condition suitable for oligonucleotide ligation assay (OLA) reactions wherein two probes are ligated if they are completely complementary to the target sequence may utilize a solution of about 100 mM KCl at a temperature of 46° C.


In a hybridization-based assay, allele-specific probes can be designed that hybridize to a segment of target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms (e.g., alternative SNP alleles/nucleotides) in the respective DNA segments from the two individuals. Hybridization conditions should be sufficiently stringent that there is a significant detectable difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles or significantly more strongly to one allele. While a probe may be designed to hybridize to a target sequence that contains a SNP site such that the SNP site aligns anywhere along the sequence of the probe, the probe is preferably designed to hybridize to a segment of the target sequence such that the SNP site aligns with a central position of the probe (e.g., a position within the probe that is at least three nucleotides from either end of the probe). This design of probe generally achieves good discrimination in hybridization between different allelic forms.


In another embodiment, a probe or primer may be designed to hybridize to a segment of target DNA such that the SNP aligns with either the 5′ most end or the 3′ most end of the probe or primer. In a specific preferred embodiment that is particularly suitable for use in a oligonucleotide ligation assay (U.S. Pat. No. 4,988,617), the 3′ most nucleotide of the probe aligns with the SNP position in the target sequence.


Oligonucleotide probes and primers may be prepared by methods well known in the art. Chemical synthetic methods include, but are limited to, the phosphotriester method described by Narang et al., 1979, Methods in Enzymology 68:90; the phosphodiester method described by Brown et al., 1979, Methods in Enzymology 68:109, the diethylphosphoamidate method described by Beaucage et al., 1981, Tetrahedron Letters 22:1859; and the solid support method described in U.S. Pat. No. 4,458,066.


Allele-specific probes are often used in pairs (or, less commonly, in sets of 3 or 4, such as if a SNP position is known to have 3 or 4 alleles, respectively, or to assay both strands of a nucleic acid molecule for a target SNP allele), and such pairs may be identical except for a one nucleotide mismatch that represents the allelic variants at the SNP position. Commonly, one member of a pair perfectly matches a reference form of a target sequence that has a more common SNP allele (i.e., the allele that is more frequent in the target population) and the other member of the pair perfectly matches a form of the target sequence that has a less common SNP allele (i.e., the allele that is rarer in the target population). In the case of an array, multiple pairs of probes can be immobilized on the same support for simultaneous analysis of multiple different polymorphisms.


In one type of PCR-based assay, an allele-specific primer hybridizes to a region on a target nucleic acid molecule that overlaps a SNP position and only primes amplification of an allelic form to which the primer exhibits perfect complementarity (Gibbs, 1989, Nucleic Acid Res. 17 2427-2448). Typically, the primer's 3′-most nucleotide is aligned with and complementary to the SNP position of the target nucleic acid molecule. This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers, producing a detectable product that indicates which allelic form is present in the test sample. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification or substantially reduces amplification efficiency, so that either no detectable product is formed or it is formed in lower amounts or at a slower pace. The method generally works most effectively when the mismatch is at the 3′-most position of the oligonucleotide (i.e., the 3′-most position of the oligonucleotide aligns with the target SNP position) because this position is most destabilizing to elongation from the primer (see, e.g., WO 93/22456). This PCR-based assay can be utilized as part of the TaqMan assay, described below.


In a specific embodiment of the invention, a primer of the invention contains a sequence substantially complementary to a segment of a target SNP-containing nucleic acid molecule except that the primer has a mismatched nucleotide in one of the three nucleotide positions at the 3′-most end of the primer, such that the mismatched nucleotide does not base pair with a particular allele at the SNP site. In a preferred embodiment, the mismatched nucleotide in the primer is the second from the last nucleotide at the 3′-most position of the primer. In a more preferred embodiment, the mismatched nucleotide in the primer is the last nucleotide at the 3′-most position of the primer.


In another embodiment of the invention, a SNP detection reagent of the invention is labeled with a fluorogenic reporter dye that emits a detectable signal. While the preferred reporter dye is a fluorescent dye, any reporter dye that can be attached to a detection reagent such as an oligonucleotide probe or primer is suitable for use in the invention. Such dyes include, but are not limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and Texas Red.


In yet another embodiment of the invention, the detection reagent may be further labeled with a quencher dye such as Tamra, especially when the reagent is used as a self-quenching probe such as a TaqMan (U.S. Pat. Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos. 5,118,801 and 5,312,728), or other stemless or linear beacon probe (Livak et al., 1995, PCR Method Appl. 4:357-362; Tyagi et al., 1996, Nature Biotechnology 14: 303-308; Nazarenko et al., 1997, Nucl. Acids Res. 25:2516-2521; U.S. Pat. Nos. 5,866,336 and 6,117,635).


The detection reagents of the invention may also contain other labels, including but not limited to, biotin for streptavidin binding, hapten for antibody binding, and oligonucleotide for binding to another complementary oligonucleotide such as pairs of zipcodes.


The present invention also contemplates reagents that do not contain (or that are complementary to) a SNP nucleotide identified herein but that are used to assay one or more SNPs disclosed herein. For example, primers that flank, but do not hybridize directly to a target SNP position provided herein are useful in primer extension reactions in which the primers hybridize to a region adjacent to the target SNP position (i.e., within one or more nucleotides from the target SNP site). During the primer extension reaction, a primer is typically not able to extend past a target SNP site if a particular nucleotide (allele) is present at that target SNP site, and the primer extension product can be detected in order to determine which SNP allele is present at the target SNP site. For example, particular ddNTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension product which includes a ddNTP at the 3′-most end of the primer extension product, and in which the ddNTP is a nucleotide of a SNP disclosed herein, is a composition that is specifically contemplated by the present invention). Thus, reagents that bind to a nucleic acid molecule in a region adjacent to a SNP site and that are used for assaying the SNP site, even though the bound sequences do not necessarily include the SNP site itself, are also contemplated by the present invention.


SNP Detection Kits and Systems


A person skilled in the art will recognize that, based on the SNP and associated sequence information disclosed herein, detection reagents can be developed and used to assay any SNP of the present invention individually or in combination, and such detection reagents can be readily incorporated into one of the established kit or system formats which are well known in the art. The terms “kits” and “systems”, as used herein in the context of SNP detection reagents, are intended to refer to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, etc.). Accordingly, the present invention further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g., TaqMan probe/primer sets), arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the present invention. The kits/systems can optionally include various electronic hardware components; for example, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip” systems) provided by various manufacturers typically comprise hardware components. Other kits/systems (e.g., probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with, optionally, other biochemical reagents) packaged in one or more containers.


In some embodiments, a SNP detection kit typically contains one or more detection reagents and other components (e.g., a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger-type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like) necessary to carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule. A kit may further contain means for determining the amount of a target nucleic acid, and means for comparing the amount with a standard, and can comprise instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest. In one embodiment of the present invention, kits are provided which contain the necessary reagents to carry out one or more assays to detect one or more SNPs disclosed herein. In a preferred embodiment of the present invention, SNP detection kits/systems are in the form of nucleic acid arrays, or compartmentalized kits, including microfluidic/lab-on-a-chip systems.


SNP detection kits/systems may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele-specific probes may be included in the kit/system to simultaneously assay large numbers of SNPs, at least one of which is a SNP of the present invention. In some kits/systems, the allele-specific probes are immobilized to a substrate such as an array or bead. For example, the same substrate can comprise allele-specific probes for detecting at least 1; 10; 100; 1000; 10,000; 100,000 (or any other number in-between) or substantially all of the SNPs shown in Table 1 and/or Table 2.


The terms “arrays,” “microarrays,” and “DNA chips” are used herein interchangeably to refer to an array of distinct polynucleotides affixed to a substrate, such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support. The polynucleotides can be synthesized directly on the substrate, or synthesized separate from the substrate and then affixed to the substrate. In one embodiment, the microarray is prepared and used according to the methods described in U.S. Pat. No. 5,837,832, Chee et al., PCT application WO95/11995 (Chee et al.), Lockhart, D. J. et al. (1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et al. (1996; Proc. Natl. Acad. Sci. 93: 10614-10619), all of which are incorporated herein in their entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al., U.S. Pat. No. 5,807,522.


Nucleic acid arrays are reviewed in the following references: Zammatteo et al., “New chips for molecular biology and diagnostics”, Biotechnol Annu Rev. 2002; 8:85-101; Sosnowski et al., “Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications”, Psychiatr Genet. 2002 December; 12(4):181-92; Heller, “DNA microarray technology: devices, systems, and applications”, Annu Rev Biomed Eng. 2002; 4:129-53. Epub 2002 Mar. 22; Kolchinsky et al., “Analysis of SNPs and other genomic variations using gel-based chips”, Hum Mutat. 2002 April; 19(4):343-60; and McGall et al., “High-density genechip oligonucleotide probe arrays”, Adv Biochem Eng Biotechnol. 2002; 77:21-42.


Any number of probes, such as allele-specific probes, may be implemented in an array, and each probe or pair of probes can hybridize to a different SNP position. In the case of polynucleotide probes, they can be synthesized at designated areas (or synthesized separately and then affixed to designated areas) on a substrate using a light-directed chemical process. Each DNA chip can contain, for example, thousands to millions of individual synthetic polynucleotide probes arranged in a grid-like pattern and miniaturized (e.g., to the size of a dime). Preferably, probes are attached to a solid support in an ordered, addressable array.


A microarray can be composed of a large number of unique, single-stranded polynucleotides, usually either synthetic antisense polynucleotides or fragments of cDNAs, fixed to a solid support. Typical polynucleotides are preferably about 6-60 nucleotides in length, more preferably about 15-30 nucleotides in length, and most preferably about 18-25 nucleotides in length. For certain types of microarrays or other detection kits/systems, it may be preferable to use oligonucleotides that are only about 7-20 nucleotides in length. In other types of arrays, such as arrays used in conjunction with chemiluminescent detection technology, preferred probe lengths can be, for example, about 15-80 nucleotides in length, preferably about 50-70 nucleotides in length, more preferably about 55-65 nucleotides in length, and most preferably about 60 nucleotides in length. The microarray or detection kit can contain polynucleotides that cover the known 5′ or 3′ sequence of a gene/transcript or target SNP site, sequential polynucleotides that cover the full-length sequence of a gene/transcript; or unique polynucleotides selected from particular areas along the length of a target gene/transcript sequence, particularly areas corresponding to one or more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides used in the microarray or detection kit can be specific to a SNP or SNPs of interest (e.g., specific to a particular SNP allele at a target SNP site, or specific to particular SNP alleles at multiple different SNP sites), or specific to a polymorphic gene/transcript or genes/transcripts of interest.


Hybridization assays based on polynucleotide arrays rely on the differences in hybridization stability of the probes to perfectly matched and mismatched target sequence variants. For SNP genotyping, it is generally preferable that stringency conditions used in hybridization assays are high enough such that nucleic acid molecules that differ from one another at as little as a single SNP position can be differentiated (e.g., typical SNP hybridization assays are designed so that hybridization will occur only if one particular nucleotide is present at a SNP position, but will not occur if an alternative nucleotide is present at that SNP position). Such high stringency conditions may be preferable when using, for example, nucleic acid arrays of allele-specific probes for SNP detection. Such high stringency conditions are described in the preceding section, and are well known to those skilled in the art and can be found in, for example, Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6.


In other embodiments, the arrays are used in conjunction with chemiluminescent detection technology. The following patents and patent applications, which are all hereby incorporated by reference, provide additional information pertaining to chemiluminescent detection: U.S. patent application Ser. Nos. 10/620,332 and 10/620,333 describe chemiluminescent approaches for microarray detection; U.S. Pat. Nos. 6,124,478, 6,107,024, 5,994,073, 5,981,768, 5,871,938, 5,843,681, 5,800,999, and 5773628 describe methods and compositions of dioxetane for performing chemiluminescent detection; and U.S. published application US2002/0110828 discloses methods and compositions for microarray controls.


In one embodiment of the invention, a nucleic acid array can comprise an array of probes of about 15-25 nucleotides in length. In further embodiments, a nucleic acid array can comprise any number of probes, in which at least one probe is capable of detecting one or more SNPs disclosed in Table 1 and/or Table 2, and/or at least one probe comprises a fragment of one of the sequences selected from the group consisting of those disclosed in Table 1, Table 2, the Sequence Listing, and sequences complementary thereto, said fragment comprising at least about 8 consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, more preferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or more consecutive nucleotides (or any other number in-between) and containing (or being complementary to) a novel SNP allele disclosed in Table 1 and/or Table 2. In some embodiments, the nucleotide complementary to the SNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of the probe, more preferably at the center of said probe.


A polynucleotide probe can be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application WO95/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a “gridded” array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other number which lends itself to the efficient use of commercially available instrumentation.


Using such arrays or other kits/systems, the present invention provides methods of identifying the SNPs disclosed herein in a test sample. Such methods typically involve incubating a test sample of nucleic acids with an array comprising one or more probes corresponding to at least one SNP position of the present invention, and assaying for binding of a nucleic acid from the test sample with one or more of the probes. Conditions for incubating a SNP detection reagent (or a kit/system that employs one or more such SNP detection reagents) with a test sample vary. Incubation conditions depend on such factors as the format employed in the assay, the detection methods employed, and the type and nature of the detection reagents used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification and array assay formats can readily be adapted to detect the SNPs disclosed herein.


A SNP detection kit/system of the present invention may include components that are used to prepare nucleic acids from a test sample for the subsequent amplification and/or detection of a SNP-containing nucleic acid molecule. Such sample preparation components can be used to produce nucleic acid extracts (including DNA and/or RNA), proteins or membrane extracts from any bodily fluids (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cells (especially nucleated cells), biopsies, buccal swabs or tissue specimens. The test samples used in the above-described methods will vary based on such factors as the assay format, nature of the detection method, and the specific tissues, cells or extracts used as the test sample to be assayed. Methods of preparing nucleic acids, proteins, and cell extracts are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized. Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, and examples are Qiagen's BioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparation system, and Roche Molecular Systems' COBAS AmpliPrep System.


Another form of kit contemplated by the present invention is a compartmentalized kit. A compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include, for example, small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allow one to efficiently transfer reagents from one compartment to another compartment such that the test samples and reagents are not cross-contaminated, or from one container to another vessel not included in the kit, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another or to another vessel. Such containers may include, for example, one or more containers which will accept the test sample, one or more containers which contain at least one probe or other SNP detection reagent for detecting one or more SNPs of the present invention, one or more containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and one or more containers which contain the reagents used to reveal the presence of the bound probe or other SNP detection reagents. The kit can optionally further comprise compartments and/or reagents for, for example, nucleic acid amplification or other enzymatic reactions such as primer extension reactions, hybridization, ligation, electrophoresis (preferably capillary electrophoresis), mass spectrometry, and/or laser-induced fluorescent detection. The kit may also include instructions for using the kit. Exemplary compartmentalized kits include microfluidic devices known in the art (see, e.g., Weigl et al., “Lab-on-a-chip for drug development”, Adv Drug Deliv Rev. 2003 Feb. 24; 55(3):349-77). In such microfluidic devices, the containers may be referred to as, for example, microfluidic “compartments”, “chambers”, or “channels”.


Microfluidic devices, which may also be referred to as “lab-on-a-chip” systems, biomedical micro-electro-mechanical systems (bioMEMs), or multicomponent integrated systems, are exemplary kits/systems of the present invention for analyzing SNPs. Such systems miniaturize and compartmentalize processes such as probe/target hybridization, nucleic acid amplification, and capillary electrophoresis reactions in a single functional device. Such microfluidic devices typically utilize detection reagents in at least one aspect of the system, and such detection reagents may be used to detect one or more SNPs of the present invention. One example of a microfluidic system is disclosed in U.S. Pat. No. 5,589,136, which describes the integration of PCR amplification and capillary electrophoresis in chips. Exemplary microfluidic systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples may be controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip to create functional microscopic valves and pumps with no moving parts. Varying the voltage can be used as a means to control the liquid flow at intersections between the micro-machined channels and to change the liquid flow rate for pumping across different sections of the microchip. See, for example, U.S. Pat. Nos. 6,153,073, Dubrow et al., and 6,156,181, Parce et al.


For genotyping SNPs, an exemplary microfluidic system may integrate, for example, nucleic acid amplification, primer extension, capillary electrophoresis, and a detection method such as laser induced fluorescence detection. In a first step of an exemplary process for using such an exemplary system, nucleic acid samples are amplified, preferably by PCR. Then, the amplification products are subjected to automated primer extension reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide primers to carry out primer extension reactions which hybridize just upstream of the targeted SNP. Once the extension at the 3′ end is completed, the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis. The separation medium used in capillary electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or dextran. The incorporated ddNTPs in the single nucleotide primer extension products are identified by laser-induced fluorescence detection. Such an exemplary microchip can be used to process, for example, at least 96 to 384 samples, or more, in parallel.


Uses of Nucleic Acid Molecules


The nucleic acid molecules of the present invention have a variety of uses, especially in the diagnosis and treatment of VT. For example, the nucleic acid molecules are useful as hybridization probes, such as for genotyping SNPs in messenger RNA, transcript, cDNA, genomic DNA, amplified DNA or other nucleic acid molecules, and for isolating full-length cDNA and genomic clones encoding the variant peptides disclosed in Table 1 as well as their orthologs.


A probe can hybridize to any nucleotide sequence along the entire length of a nucleic acid molecule referred to in Table 1 and/or Table 2. Preferably, a probe of the present invention hybridizes to a region of a target sequence that encompasses a SNP position indicated in Table 1 and/or Table 2. More preferably, a probe hybridizes to a SNP-containing target sequence in a sequence-specific manner such that it distinguishes the target sequence from other nucleotide sequences which vary from the target sequence only by which nucleotide is present at the SNP site. Such a probe is particularly useful for detecting the presence of a SNP-containing nucleic acid in a test sample, or for determining which nucleotide (allele) is present at a particular SNP site (i.e., genotyping the SNP site).


A nucleic acid hybridization probe may be used for determining the presence, level, form, and/or distribution of nucleic acid expression. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes specific for the SNPs described herein can be used to assess the presence, expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in gene expression relative to normal levels. In vitro techniques for detection of mRNA include, for example, Northern blot hybridizations and in situ hybridizations. In vitro techniques for detecting DNA include Southern blot hybridizations and in situ hybridizations (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.).


Probes can be used as part of a diagnostic test kit for identifying cells or tissues in which a variant protein is expressed, such as by measuring the level of a variant protein-encoding nucleic acid (e.g., mRNA) in a sample of cells from a subject or determining if a polynucleotide contains a SNP of interest.


Thus, the nucleic acid molecules of the invention can be used as hybridization probes to detect the SNPs disclosed herein, thereby determining whether an individual with the polymorphisms is at risk for VT or has developed early stage VT. Detection of a SNP associated with a disease phenotype provides a diagnostic tool for an active disease and/or genetic predisposition to the disease.


Furthermore, the nucleic acid molecules of the invention are therefore useful for detecting a gene (gene information is disclosed in Table 2, for example) which contains a SNP disclosed herein and/or products of such genes, such as expressed mRNA transcript molecules (transcript information is disclosed in Table 1, for example), and are thus useful for detecting gene expression. The nucleic acid molecules can optionally be implemented in, for example, an array or kit format for use in detecting gene expression.


The nucleic acid molecules of the invention are also useful as primers to amplify any given region of a nucleic acid molecule, particularly a region containing a SNP identified in Table 1 and/or Table 2.


The nucleic acid molecules of the invention are also useful for constructing recombinant vectors (described in greater detail below). Such vectors include expression vectors that express a portion of, or all of, any of the variant peptide sequences referred to in Table 1. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced SNPs.


The nucleic acid molecules of the invention are also useful for expressing antigenic portions of the variant proteins, particularly antigenic portions that contain a variant amino acid sequence (e.g., an amino acid substitution) caused by a SNP disclosed in Table 1 and/or Table 2.


The nucleic acid molecules of the invention are also useful for constructing vectors containing a gene regulatory region of the nucleic acid molecules of the present invention.


The nucleic acid molecules of the invention are also useful for designing ribozymes corresponding to all, or a part, of an mRNA molecule expressed from a SNP-containing nucleic acid molecule described herein.


The nucleic acid molecules of the invention are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and variant peptides.


The nucleic acid molecules of the invention are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and variant peptides. The production of recombinant cells and transgenic animals having nucleic acid molecules which contain the SNPs disclosed in Table 1 and/or Table 2 allow, for example, effective clinical design of treatment compounds and dosage regimens.


The nucleic acid molecules of the invention are also useful in assays for drug screening to identify compounds that, for example, modulate nucleic acid expression.


The nucleic acid molecules of the invention are also useful in gene therapy in patients whose cells have aberrant gene expression. Thus, recombinant cells, which include a patient's cells that have been engineered ex vivo and returned to the patient, can be introduced into an individual where the recombinant cells produce the desired protein to treat the individual.


SNP Genotyping Methods


The process of determining which specific nucleotide (i.e., allele) is present at each of one or more SNP positions, such as a SNP position in a nucleic acid molecule disclosed in Table 1 and/or Table 2, is referred to as SNP genotyping. The present invention provides methods of SNP genotyping, such as for use in screening for VT or related pathologies, or determining predisposition thereto, or determining responsiveness to a form of treatment, or in genome mapping or SNP association analysis, etc.


Nucleic acid samples can be genotyped to determine which allele(s) is/are present at any given genetic region (e.g., SNP position) of interest by methods well known in the art. The neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format. Exemplary SNP genotyping methods are described in Chen et al., “Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput”, Pharmacogenomics J. 2003; 3(2):77-96; Kwok et al., “Detection of single nucleotide polymorphisms”, Curr Issues Mol. Biol. 2003 April; 5(2):43-60; Shi, “Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes”, Am J Pharmacogenomics. 2002; 2(3):197-205; and Kwok, “Methods for genotyping single nucleotide polymorphisms”, Annu Rev Genomics Hum Genet. 2001; 2:235-58. Exemplary techniques for high-throughput SNP genotyping are described in Marnellos, “High-throughput SNP analysis for genetic association studies”, Curr Opin Drug Discov Devel. 2003 May; 6(3):317-21. Common SNP genotyping methods include, but are not limited to, TaqMan assays, molecular beacon assays, nucleic acid arrays, allele-specific primer extension, allele-specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, pyrosequencing, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length polymorphism, single base extension-tag assays, and the Invader assay. Such methods may be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.


Various methods for detecting polymorphisms include, but are not limited to, methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al., Meth. Enzymol. 217:286-295 (1992)), comparison of the electrophoretic mobility of variant and wild type nucleic acid molecules (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat. Res. 285:125-144 (1993); and Hayashi et al., Genet. Anal. Tech. Appl. 9:73-79 (1992)), and assaying the movement of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturant using denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequence variations at specific locations can also be assessed by nuclease protection assays such as RNase and S1 protection or chemical cleavage methods.


In a preferred embodiment, SNP genotyping is performed using the TaqMan assay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos. 5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of a specific amplified product during PCR. The TaqMan assay utilizes an oligonucleotide probe labeled with a fluorescent reporter dye and a quencher dye. The reporter dye is excited by irradiation at an appropriate wavelength, it transfers energy to the quencher dye in the same probe via a process called fluorescence resonance energy transfer (FRET). When attached to the probe, the excited reporter dye does not emit a signal. The proximity of the quencher dye to the reporter dye in the intact probe maintains a reduced fluorescence for the reporter. The reporter dye and quencher dye may be at the 5′ most and the 3′ most ends, respectively, or vice versa. Alternatively, the reporter dye may be at the 5′ or 3′ most end while the quencher dye is attached to an internal nucleotide, or vice versa. In yet another embodiment, both the reporter and the quencher may be attached to internal nucleotides at a distance from each other such that fluorescence of the reporter is reduced.


During PCR, the 5′ nuclease activity of DNA polymerase cleaves the probe, thereby separating the reporter dye and the quencher dye and resulting in increased fluorescence of the reporter. Accumulation of PCR product is detected directly by monitoring the increase in fluorescence of the reporter dye. The DNA polymerase cleaves the probe between the reporter dye and the quencher dye only if the probe hybridizes to the target SNP-containing template which is amplified during PCR, and the probe is designed to hybridize to the target SNP site only if a particular SNP allele is present.


Preferred TaqMan primer and probe sequences can readily be determined using the SNP and associated nucleic acid sequence information provided herein. A number of computer programs, such as Primer Express (Applied Biosystems, Foster City, Calif.), can be used to rapidly obtain optimal primer/probe sets. It will be apparent to one of skill in the art that such primers and probes for detecting the SNPs of the present invention are useful in diagnostic assays for VT and related pathologies, and can be readily incorporated into a kit format. The present invention also includes modifications of the Taqman assay well known in the art such as the use of Molecular Beacon probes (U.S. Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat. Nos. 5,866,336 and 6,117,635).


Another preferred method for genotyping the SNPs of the present invention is the use of two oligonucleotide probes in an OLA (see, e.g., U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to a segment of a target nucleic acid with its 3′ most end aligned with the SNP site. A second probe hybridizes to an adjacent segment of the target nucleic acid molecule directly 3′ to the first probe. The two juxtaposed probes hybridize to the target nucleic acid molecule, and are ligated in the presence of a linking agent such as a ligase if there is perfect complementarity between the 3′ most nucleotide of the first probe with the SNP site. If there is a mismatch, ligation would not occur. After the reaction, the ligated probes are separated from the target nucleic acid molecule, and detected as indicators of the presence of a SNP.


The following patents, patent applications, and published international patent applications, which are all hereby incorporated by reference, provide additional information pertaining to techniques for carrying out various types of OLA: U.S. Pat. Nos. 6,027,889, 6,268,148, 5,494,810, 5,830,711, and 6054564 describe OLA strategies for performing SNP detection; WO 97/31256 and WO 00/56927 describe OLA strategies for performing SNP detection using universal arrays, wherein a zipcode sequence can be introduced into one of the hybridization probes, and the resulting product, or amplified product, hybridized to a universal zip code array; U.S. application US01/17329 (and 09/584,905) describes OLA (or LDR) followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are determined by electrophoretic or universal zipcode array readout; U.S. applications 60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods and software for multiplexed SNP detection using OLA followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are hybridized with a zipchute reagent, and the identity of the SNP determined from electrophoretic readout of the zipchute. In some embodiments, OLA is carried out prior to PCR (or another method of nucleic acid amplification). In other embodiments, PCR (or another method of nucleic acid amplification) is carried out prior to OLA.


Another method for SNP genotyping is based on mass spectrometry. Mass spectrometry takes advantage of the unique mass of each of the four nucleotides of DNA. SNPs can be unambiguously genotyped by mass spectrometry by measuring the differences in the mass of nucleic acids having alternative SNP alleles. MALDI-TOF (Matrix Assisted Laser Desorption Ionization—Time of Flight) mass spectrometry technology is preferred for extremely precise determinations of molecular mass, such as SNPs. Numerous approaches to SNP analysis have been developed based on mass spectrometry. Preferred mass spectrometry-based methods of SNP genotyping include primer extension assays, which can also be utilized in combination with other approaches, such as traditional gel-based formats and microarrays.


Typically, the primer extension assay involves designing and annealing a primer to a template PCR amplicon upstream (5′) from a target SNP position. A mix of dideoxynucleotide triphosphates (ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to a reaction mixture containing template (e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR), primer, and DNA polymerase. Extension of the primer terminates at the first position in the template where a nucleotide complementary to one of the ddNTPs in the mix occurs. The primer can be either immediately adjacent (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide next to the target SNP site) or two or more nucleotides removed from the SNP position. If the primer is several nucleotides removed from the target SNP position, the only limitation is that the template sequence between the 3′ end of the primer and the SNP position cannot contain a nucleotide of the same type as the one to be detected, or this will cause premature termination of the extension primer. Alternatively, if all four ddNTPs alone, with no dNTPs, are added to the reaction mixture, the primer will always be extended by only one nucleotide, corresponding to the target SNP position. In this instance, primers are designed to bind one nucleotide upstream from the SNP position (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide that is immediately adjacent to the target SNP site on the 5′ side of the target SNP site). Extension by only one nucleotide is preferable, as it minimizes the overall mass of the extended primer, thereby increasing the resolution of mass differences between alternative SNP nucleotides. Furthermore, mass-tagged ddNTPs can be employed in the primer extension reactions in place of unmodified ddNTPs. This increases the mass difference between primers extended with these ddNTPs, thereby providing increased sensitivity and accuracy, and is particularly useful for typing heterozygous base positions. Mass-tagging also alleviates the need for intensive sample-preparation procedures and decreases the necessary resolving power of the mass spectrometer.


The extended primers can then be purified and analyzed by MALDI-TOF mass spectrometry to determine the identity of the nucleotide present at the target SNP position. In one method of analysis, the products from the primer extension reaction are combined with light absorbing crystals that form a matrix. The matrix is then hit with an energy source such as a laser to ionize and desorb the nucleic acid molecules into the gas-phase. The ionized molecules are then ejected into a flight tube and accelerated down the tube towards a detector. The time between the ionization event, such as a laser pulse, and collision of the molecule with the detector is the time of flight of that molecule. The time of flight is precisely correlated with the mass-to-charge ratio (m/z) of the ionized molecule. Ions with smaller m/z travel down the tube faster than ions with larger m/z and therefore the lighter ions reach the detector before the heavier ions. The time-of-flight is then converted into a corresponding, and highly precise, m/z. In this manner, SNPs can be identified based on the slight differences in mass, and the corresponding time of flight differences, inherent in nucleic acid molecules having different nucleotides at a single base position. For further information regarding the use of primer extension assays in conjunction with MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise et al., “A standard protocol for single nucleotide primer extension in the human genome using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry”, Rapid Commun Mass Spectrom. 2003; 17(11):1195-202.


The following references provide further information describing mass spectrometry-based methods for SNP genotyping: Bocker, “SNP and mutation discovery using base-specific cleavage and MALDI-TOF mass spectrometry”, Bioinformatics. 2003 July; 19 Suppl 1:144-153; Storm et al., “MALDI-TOF mass spectrometry-based SNP genotyping”, Methods Mol Biol. 2003; 212:241-62; Jurinke et al., “The use of Mass ARRAY technology for high throughput genotyping”, Adv Biochem Eng Biotechnol. 2002; 77:57-74; and Jurinke et al., “Automated genotyping using the DNA MassArray technology”, Methods Mol Biol. 2002; 187:179-92.


SNPs can also be scored by direct DNA sequencing. A variety of automated sequencing procedures can be utilized ((1995) Biotechniques 19:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO94/16101; Cohen et al., Adv. Chromatogr. 36:127-162 (1996); and Griffin et al., Appl. Biochem. Biotechnol. 38:147-159 (1993)). The nucleic acid sequences of the present invention enable one of ordinary skill in the art to readily design sequencing primers for such automated sequencing procedures. Commercial instrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730×1 DNA Analyzers (Foster City, Calif.), is commonly used in the art for automated sequencing.


Other methods that can be used to genotype the SNPs of the present invention include single-strand conformational polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). SSCP identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al., Proc. Nat. Acad. Single-stranded PCR products can be generated by heating or otherwise denaturing double stranded PCR products. Single-stranded nucleic acids may refold or form secondary structures that are partially dependent on the base sequence. The different electrophoretic mobilities of single-stranded amplification products are related to base-sequence differences at SNP positions. DGGE differentiates SNP alleles based on the different sequence-dependent stabilities and melting properties inherent in polymorphic DNA and the corresponding differences in electrophoretic migration patterns in a denaturing gradient gel (Erlich, ed., PCR Technology, Principles and Applications for DNA Amplification, W.H. Freeman and Co, New York, 1992, Chapter 7).


Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be used to score SNPs based on the development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature. If the SNP affects a restriction enzyme cleavage site, the SNP can be identified by alterations in restriction enzyme digestion patterns, and the corresponding changes in nucleic acid fragment lengths determined by gel electrophoresis


SNP genotyping can include the steps of, for example, collecting a biological sample from a human subject (e.g., sample of tissues, cells, fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product (assays can be designed so that hybridization and/or amplification will only occur if a particular SNP allele is present or absent). In some assays, the size of the amplification product is detected and compared to the length of a control sample; for example, deletions and insertions can be detected by a change in size of the amplified product compared to a normal genotype.


SNP genotyping is useful for numerous practical applications, as described below. Examples of such applications include, but are not limited to, SNP-disease association analysis, disease predisposition screening, disease diagnosis, disease prognosis, disease progression monitoring, determining therapeutic strategies based on an individual's genotype (“pharmacogenomics”), developing therapeutic agents based on SNP genotypes associated with a disease or likelihood of responding to a drug, stratifying a patient population for clinical trial for a treatment regimen, predicting the likelihood that an individual will experience toxic side effects from a therapeutic agent, and human identification applications such as forensics.


Analysis of Genetic Association Between SNPs and Phenotypic Traits


SNP genotyping for disease diagnosis, disease predisposition screening, disease prognosis, determining drug responsiveness (pharmacogenomics), drug toxicity screening, and other uses described herein, typically relies on initially establishing a genetic association between one or more specific SNPs and the particular phenotypic traits of interest.


Different study designs may be used for genetic association studies (Modern Epidemiology, Lippincott Williams & Wilkins (1998), 609-622). Observational studies are most frequently carried out in which the response of the patients is not interfered with. The first type of observational study identifies a sample of persons in whom the suspected cause of the disease is present and another sample of persons in whom the suspected cause is absent, and then the frequency of development of disease in the two samples is compared. These sampled populations are called cohorts, and the study is a prospective study. The other type of observational study is case-control or a retrospective study. In typical case-control studies, samples are collected from individuals with the phenotype of interest (cases) such as certain manifestations of a disease, and from individuals without the phenotype (controls) in a population (target population) that conclusions are to be drawn from. Then the possible causes of the disease are investigated retrospectively. As the time and costs of collecting samples in case-control studies are considerably less than those for prospective studies, case-control studies are the more commonly used study design in genetic association studies, at least during the exploration and discovery stage.


In both types of observational studies, there may be potential confounding factors that should be taken into consideration. Confounding factors are those that are associated with both the real cause(s) of the disease and the disease itself, and they include demographic information such as age, gender, ethnicity as well as environmental factors. When confounding factors are not matched in cases and controls in a study, and are not controlled properly, spurious association results can arise. If potential confounding factors are identified, they should be controlled for by analysis methods explained below.


In a genetic association study, the cause of interest to be tested is a certain allele or a SNP or a combination of alleles or a haplotype from several SNPs. Thus, tissue specimens (e.g., whole blood) from the sampled individuals may be collected and genomic DNA genotyped for the SNP(s) of interest. In addition to the phenotypic trait of interest, other information such as demographic (e.g., age, gender, ethnicity, etc.), clinical, and environmental information that may influence the outcome of the trait can be collected to further characterize and define the sample set. In many cases, these factors are known to be associated with diseases and/or SNP allele frequencies. There are likely gene-environment and/or gene-gene interactions as well. Analysis methods to address gene-environment and gene-gene interactions (for example, the effects of the presence of both susceptibility alleles at two different genes can be greater than the effects of the individual alleles at two genes combined) are discussed below.


After all the relevant phenotypic and genotypic information has been obtained, statistical analyses are carried out to determine if there is any significant correlation between the presence of an allele or a genotype with the phenotypic characteristics of an individual. Preferably, data inspection and cleaning are first performed before carrying out statistical tests for genetic association. Epidemiological and clinical data of the samples can be summarized by descriptive statistics with tables and graphs. Data validation is preferably performed to check for data completion, inconsistent entries, and outliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests if distributions are not normal) may then be used to check for significant differences between cases and controls for discrete and continuous variables, respectively. To ensure genotyping quality, Hardy-Weinberg disequilibrium tests can be performed on cases and controls separately. Significant deviation from Hardy-Weinberg equilibrium (HWE) in both cases and controls for individual markers can be indicative of genotyping errors. If HWE is violated in a majority of markers, it is indicative of population substructure that should be further investigated. Moreover, Hardy-Weinberg disequilibrium in cases only can indicate genetic association of the markers with the disease (Genetic Data Analysis, Weir B., Sinauer (1990)).


To test whether an allele of a single SNP is associated with the case or control status of a phenotypic trait, one skilled in the art can compare allele frequencies in cases and controls. Standard chi-squared tests and Fisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2 outcomes in the categorical trait of interest). To test whether genotypes of a SNP are associated, chi-squared tests can be carried out on a 3×2 table (3 genotypes×2 outcomes). Score tests are also carried out for genotypic association to contrast the three genotypic frequencies (major homozygotes, heterozygotes and minor homozygotes) in cases and controls, and to look for trends using 3 different modes of inheritance, namely dominant (with contrast coefficients 2, −1, −1), additive (with contrast coefficients 1, 0, −1) and recessive (with contrast coefficients 1, 1, −2). Odds ratios for minor versus major alleles, and odds ratios for heterozygote and homozygote variants versus the wild type genotypes are calculated with the desired confidence limits, usually 95%.


In order to control for confounders and to test for interaction and effect modifiers, stratified analyses may be performed using stratified factors that are likely to be confounding, including demographic information such as age, ethnicity, and gender, or an interacting element or effect modifier, such as a known major gene (e.g., APOE for Alzheimer's disease or HLA genes for autoimmune diseases), or environmental factors such as smoking in lung cancer. Stratified association tests may be carried out using Cochran-Mantel-Haenszel tests that take into account the ordinal nature of genotypes with 0, 1, and 2 variant alleles. Exact tests by StatXact may also be performed when computationally possible. Another way to adjust for confounding effects and test for interactions is to perform stepwise multiple logistic regression analysis using statistical packages such as SAS or R. Logistic regression is a model-building technique in which the best fitting and most parsimonious model is built to describe the relation between the dichotomous outcome (for instance, getting a certain disease or not) and a set of independent variables (for instance, genotypes of different associated genes, and the associated demographic and environmental factors). The most common model is one in which the logit transformation of the odds ratios is expressed as a linear combination of the variables (main effects) and their cross-product terms (interactions) (Applied Logistic Regression, Hosmer and Lemeshow, Wiley (2000)). To test whether a certain variable or interaction is significantly associated with the outcome, coefficients in the model are first estimated and then tested for statistical significance of their departure from zero.


In addition to performing association tests one marker at a time, haplotype association analysis may also be performed to study a number of markers that are closely linked together. Haplotype association tests can have better power than genotypic or allelic association tests when the tested markers are not the disease-causing mutations themselves but are in linkage disequilibrium with such mutations. The test will even be more powerful if the disease is indeed caused by a combination of alleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs that are very close to each other). In order to perform haplotype association effectively, marker-marker linkage disequilibrium measures, both D′ and r2, are typically calculated for the markers within a gene to elucidate the haplotype structure. Recent studies (Daly et al, Nature Genetics, 29, 232-235, 2001) in linkage disequilibrium indicate that SNPs within a gene are organized in block pattern, and a high degree of linkage disequilibrium exists within blocks and very little linkage disequilibrium exists between blocks. Haplotype association with the disease status can be performed using such blocks once they have been elucidated.


Haplotype association tests can be carried out in a similar fashion as the allelic and genotypic association tests. Each haplotype in a gene is analogous to an allele in a multi-allelic marker. One skilled in the art can either compare the haplotype frequencies in cases and controls or test genetic association with different pairs of haplotypes. It has been proposed (Schaid et al, Am. J. Hum. Genet., 70, 425-434, 2002) that score tests can be done on haplotypes using the program “haplo.score.” In that method, haplotypes are first inferred by EM algorithm and score tests are carried out with a generalized linear model (GLM) framework that allows the adjustment of other factors.


An important decision in the performance of genetic association tests is the determination of the significance level at which significant association can be declared when the P value of the tests reaches that level. In an exploratory analysis where positive hits will be followed up in subsequent confirmatory testing, an unadjusted P value <0.2 (a significance level on the lenient side), for example, may be used for generating hypotheses for significant association of a SNP with certain phenotypic characteristics of a disease. It is preferred that a p-value <0.05 (a significance level traditionally used in the art) is achieved in order for a SNP to be considered to have an association with a disease. It is more preferred that a p-value <0.01 (a significance level on the stringent side) is achieved for an association to be declared. When hits are followed up in confirmatory analyses in more samples of the same source or in different samples from different sources, adjustment for multiple testing will be performed as to avoid excess number of hits while maintaining the experiment-wide error rates at 0.05. While there are different methods to adjust for multiple testing to control for different kinds of error rates, a commonly used but rather conservative method is Bonferroni correction to control the experiment-wise or family-wise error rate (Multiple comparisons and multiple tests, Westfall et al, SAS Institute (1999)). Permutation tests to control for the false discovery rates, FDR, can be more powerful (Benjamini and Hochberg, Journal of the Royal Statistical Society, Series B 57, 1289-1300, 1995, Resampling-based Multiple Testing, Westfall and Young, Wiley (1993)). Such methods to control for multiplicity would be preferred when the tests are dependent and controlling for false discovery rates is sufficient as opposed to controlling for the experiment-wise error rates.


In replication studies using samples from different populations after statistically significant markers have been identified in the exploratory stage, meta-analyses can then be performed by combining evidence of different studies (Modern Epidemiology, Lippincott Williams & Wilkins, 1998, 643-673). If available, association results known in the art for the same SNPs can be included in the meta-analyses.


Since both genotyping and disease status classification can involve errors, sensitivity analyses may be performed to see how odds ratios and p-values would change upon various estimates on genotyping and disease classification error rates.


It has been well known that subpopulation-based sampling bias between cases and controls can lead to spurious results in case-control association studies (Ewens and Spielman, Am. J. Hum. Genet. 62, 450-458, 1995) when prevalence of the disease is associated with different subpopulation groups. Such bias can also lead to a loss of statistical power in genetic association studies. To detect population stratification, Pritchard and Rosenberg (Pritchard et al. Am. J. Hum. Gen. 1999, 65:220-228) suggested typing markers that are unlinked to the disease and using results of association tests on those markers to determine whether there is any population stratification. When stratification is detected, the genomic control (GC) method as proposed by Devlin and Roeder (Devlin et al. Biometrics 1999, 55:997-1004) can be used to adjust for the inflation of test statistics due to population stratification. GC method is robust to changes in population structure levels as well as being applicable to DNA pooling designs (Devlin et al. Genet. Epidem. 20001, 21:273-284).


While Pritchard's method recommended using 15-20 unlinked microsatellite markers, it suggested using more than 30 biallelic markers to get enough power to detect population stratification. For the GC method, it has been shown (Bacanu et al. Am. J. Hum. Genet. 2000, 66:1933-1944) that about 60-70 biallelic markers are sufficient to estimate the inflation factor for the test statistics due to population stratification. Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicated in a genome scan (Kehoe et al. Hum. Mol. Genet. 1999, 8:237-245).


Once individual risk factors, genetic or non-genetic, have been found for the predisposition to disease, the next step is to set up a classification/prediction scheme to predict the category (for instance, disease or no-disease) that an individual will be in depending on his genotypes of associated SNPs and other non-genetic risk factors. Logistic regression for discrete trait and linear regression for continuous trait are standard techniques for such tasks (Applied Regression Analysis, Draper and Smith, Wiley (1998)). Moreover, other techniques can also be used for setting up classification. Such techniques include, but are not limited to, MART, CART, neural network, and discriminant analyses that are suitable for use in comparing the performance of different methods (The Elements of Statistical Learning, Hastie, Tibshirani & Friedman, Springer (2002)).


Disease Diagnosis and Predisposition Screening


Information on association/correlation between genotypes and disease-related phenotypes can be exploited in several ways. For example, in the case of a highly statistically significant association between one or more SNPs with predisposition to a disease for which treatment is available, detection of such a genotype pattern in an individual may justify immediate administration of treatment, or at least the institution of regular monitoring of the individual. Detection of the susceptibility alleles associated with serious disease in a couple contemplating having children may also be valuable to the couple in their reproductive decisions. In the case of a weaker but still statistically significant association between a SNP and a human disease, immediate therapeutic intervention or monitoring may not be justified after detecting the susceptibility allele or SNP. Nevertheless, the subject can be motivated to begin simple life-style changes (e.g., diet, exercise) that can be accomplished at little or no cost to the individual but would confer potential benefits in reducing the risk of developing conditions for which that individual may have an increased risk by virtue of having the risk allele(s).


The SNPs of the invention may contribute to the development of VT in an individual in different ways. Some polymorphisms occur within a protein coding sequence and contribute to disease phenotype by affecting protein structure. Other polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on, for example, replication, transcription, and/or translation. A single SNP may affect more than one phenotypic trait. Likewise, a single phenotypic trait may be affected by multiple SNPs in different genes.


As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics” include, but are not limited to any of the following: detection of VT that an individual may presently have, predisposition/susceptibility screening (i.e., determining the increased risk of an individual in developing VT in the future, or determining whether an individual has a decreased risk of developing VT in the future), determining a particular type or subclass of VT in an individual known to have VT, confirming or reinforcing a previously made diagnosis of VT, pharmacogenomic evaluation of an individual to determine which therapeutic strategy that individual is most likely to positively respond to or to predict whether a patient is likely to respond to a particular treatment, predicting whether a patient is likely to experience toxic effects from a particular treatment or therapeutic compound, and evaluating the future prognosis of an individual having VT. Such diagnostic uses are based on the SNPs individually or in a unique combination or SNP haplotypes of the present invention.


Haplotypes are particularly useful in that, for example, fewer SNPs can be genotyped to determine if a particular genomic region harbors a locus that influences a particular phenotype, such as in linkage disequilibrium-based SNP association analysis.


Linkage disequilibrium (LD) refers to the co-inheritance of alleles (e.g., alternative nucleotides) at two or more different SNP sites at frequencies greater than would be expected from the separate frequencies of occurrence of each allele in a given population. The expected frequency of co-occurrence of two alleles that are inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur at expected frequencies are said to be in “linkage equilibrium.” In contrast, LD refers to any non-random genetic association between allele(s) at two or more different SNP sites, which is generally due to the physical proximity of the two loci along a chromosome. LD can occur when two or more SNPs sites are in close physical proximity to each other on a given chromosome and therefore alleles at these SNP sites will tend to remain unseparated for multiple generations with the consequence that a particular nucleotide (allele) at one SNP site will show a non-random association with a particular nucleotide (allele) at a different SNP site located nearby. Hence, genotyping one of the SNP sites will give almost the same information as genotyping the other SNP site that is in LD.


Various degrees of LD can be encountered between two or more SNPs with the result being that some SNPs are more closely associated (i.e., in stronger LD) than others. Furthermore, the physical distance over which LD extends along a chromosome differs between different regions of the genome, and therefore the degree of physical separation between two or more SNP sites necessary for LD to occur can differ between different regions of the genome.


For diagnostic purposes and similar uses, if a particular SNP site is found to be useful for diagnosing VT (e.g., has a significant statistical association with the condition and/or is recognized as a causative polymorphism for the condition), then the skilled artisan would recognize that other SNP sites which are in LD with this SNP site would also be useful for diagnosing the condition. Thus, polymorphisms (e.g., SNPs and/or haplotypes) that are not the actual disease-causing (causative) polymorphisms, but are in LD with such causative polymorphisms, are also useful. In such instances, the genotype of the polymorphism(s) that is/are in LD with the causative polymorphism is predictive of the genotype of the causative polymorphism and, consequently, predictive of the phenotype (e.g., VT) that is influenced by the causative SNP(s). Therefore, polymorphic markers that are in LD with causative polymorphisms are useful as diagnostic markers, and are particularly useful when the actual causative polymorphism(s) is/are unknown.


Examples of polymorphisms that can be in LD with one or more causative polymorphisms (and/or in LD with one or more polymorphisms that have a significant statistical association with a condition) and therefore useful for diagnosing the same condition that the causative/associated SNP(s) is used to diagnose, include other SNPs in the same gene, protein-coding, or mRNA transcript-coding region as the causative/associated SNP, other SNPs in the same exon or same intron as the causative/associated SNP, other SNPs in the same haplotype block as the causative/associated SNP, other SNPs in the same intergenic region as the causative/associated SNP, SNPs that are outside but near a gene (e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) that harbors a causative/associated SNP, etc. Such useful LD SNPs can be selected from among the SNPs disclosed in Tables 1-2, for example.


Linkage disequilibrium in the human genome is reviewed in: Wall et al., “Haplotype blocks and linkage disequilibrium in the human genome”, Nat Rev Genet. 2003 August; 4(8):587-97; Garner et al., “On selecting markers for association studies: patterns of linkage disequilibrium between two and three diallelic loci”, Genet Epidemiol. 2003 January; 24(1):57-67; Ardlie et al., “Patterns of linkage disequilibrium in the human genome”, Nat Rev Genet. 2002 April; 3(4):299-309 (erratum in Nat Rev Genet 2002 July; 3(7):566); and Remm et al., “High-density genotyping and linkage disequilibrium in the human genome using chromosome 22 as a model”; Curr Opin Chem Biol. 2002 February; 6(1):24-30; Haldane J B S (1919) The combination of linkage values, and the calculation of distances between the loci of linked factors. J Genet 8:299-309; Mendel, G. (1866) Versuche über Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereines in Brünn (Proceedings of the Natural History Society of Brünn]; Lewin B (1990) Genes IV. Oxford University Press, New York, USA; Hartl D L and Clark A G (1989) Principles of Population Genetics 2nd ed. Sinauer Associates, Inc. Sunderland, Mass., USA; Gillespie J H (2004) Population Genetics: A Concise Guide.2nd ed. Johns Hopkins University Press. USA; Lewontin R C (1964). The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 49:49-67; Hoel P G (1954) Introduction to Mathematical Statistics 2nd ed. John Wiley & Sons, Inc. New York, USA; Hudson R R (2001) Two-locus sampling distributions and their application. Genetics 159:1805-1817; Dempster A P, Laird N M, Rubin D B (1977) Maximum likelihood from incomplete data via the EM algorithm. J R Stat Soc 39:1-38; Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12(5):921-927; Tregouet D A, Escolano S, Tiret L, Mallet A, Golmard J L (2004) A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm. Ann Hum Genet. 68(Pt 2):165-177; Long A D and Langley C H (1999) The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Research 9:720-731; Agresti A (1990) Categorical Data Analysis. John Wiley & Sons, Inc. New York, USA; Lange K (1997) Mathematical and Statistical Methods for Genetic Analysis. Springer-Verlag New York, Inc. New York, USA; The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789-796; The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299-1320; Thorisson G A, Smith A V, Krishnan L, Stein L D (2005), The International HapMap Project Web Site. Genome Research 15:1591-1593; McVean G, Spencer C C A, Chaix R (2005) Perspectives on human genetic variation from the HapMap project. PLoS Genetics 1(4):413-418; Hirschhorn J N, Daly M J (2005) Genome-wide association studies for common diseases and complex traits. Nat Genet 6:95-108; Schrodi S J (2005) A probabilistic approach to large-scale association scans: a semi-Bayesian method to detect disease-predisposing alleles. SAGMB 4(1):31; Wang W Y S, Barratt B J, Clayton D G, Todd J A (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6:109-118. Pritchard J K, Przeworski M (2001) Linkage disequilibrium in humans: models and data. Am J Hum Genet 69:1-14.


As discussed above, one aspect of the present invention is the discovery that SNPs which are in certain LD distance with the interrogated SNP can also be used as valid markers for identifying an increased or decreased risks of having or developing VT. As used herein, the term “interrogated SNP” refers to SNPs that have been found to be associated with an increased or decreased risk of disease using genotyping results and analysis, or other appropriate experimental method as exemplified in the working examples described in this application. As used herein, the term “LD SNP” refers to a SNP that has been characterized as a SNP associating with an increased or decreased risk of diseases due to their being in LD with the “interrogated SNP” under the methods of calculation described in the application. Below, applicants describe the methods of calculation with which one of ordinary skilled in the art may determine if a particular SNP is in LD with an interrogated SNP. The parameter r2 is commonly used in the genetics art to characterize the extent of linkage disequilibrium between markers (Hudson, 2001). As used herein, the term “in LD with” refers to a particular SNP that is measured at above the threshold of a parameter such as r2 with an interrogated SNP.


The r2 value between any two or more SNPs can be obtained from databases such as the HapMap. For instance, if the r2 value between SNP1 and SNP2 is 0.8 (assuming 0.8 is used as a threshold), then these two SNPs are in LD with each other, thus leading one to conclude that if SNP1 is associated with a disease, then SNP2 will be associated with the disease as well.


It is now common place to directly observe genetic variants in a sample of chromosomes obtained from a population. Suppose one has genotype data at two genetic markers located on the same chromosome, for the markers A and B. Further suppose that two alleles segregate at each of these two markers such that alleles A1 and A2 can be found at marker A and alleles B1 and B2 at marker B. Also assume that these two markers are on a human autosome. If one is to examine a specific individual and find that they are heterozygous at both markers, such that their two-marker genotype is A1A2B1B2, then there are two possible configurations: the individual in question could have the alleles A1B1 on one chromosome and A2B2 on the remaining chromosome; alternatively, the individual could have alleles A1B2 on one chromosome and A2B1 on the other. The arrangement of alleles on a chromosome is called a haplotype. In this illustration, the individual could have haplotypes A1B1/A2B2 or A1B2/A2B1 (see Hartl and Clark (1989) for a more complete description). The concept of linkage equilibrium relates the frequency of haplotypes to the allele frequencies.


Assume that a sample of individuals is selected from a larger population. Considering the two markers described above, each having two alleles, there are four possible haplotypes: A1B1, A1B2, A2B1 and A2B2. Denote the frequencies of these four haplotypes with the following notation.






P
11=freq(A1B1)  (1)






P
12=freq(A1B2)  (2)






P
21=freq(A2B1)  (3)






P
22=freq(A2B2  (4)


The allele frequencies at the two markers are then the sum of different haplotype frequencies, it is straightforward to write down a similar set of equations relating single-marker allele frequencies to two-marker haplotype frequencies:






p
1=freq(A1)=P11+P12  (5)






p
2=freq(A2)=P21+P22  (6)






q
1=freq(B1)=P11+P21  (7)






q
2=freq(B2)=P12+P22  (8)


Note that the four haplotype frequencies and the allele frequencies at each marker must sum to a frequency of 1.






P
11
+P
12
+P
21
+P
22=1  (9)






p
1
±p
2=1  (10)






q
1
+q
2=1  (11)


If there is no correlation between the alleles at the two markers, one would expect that the frequency of the haplotypes would be approximately the product of the composite alleles. Therefore,






P
11
≈p
1
q
1  (12)






P
12
≈p
1
q
2  (13)






P
21
≈p
2
q
1  (14)






P
22
≈p
2
q
2  (15)


These approximating equations (12)-(15) represent the concept of linkage equilibrium where there is independent assortment between the two markers—the alleles at the two markers occur together at random. These are represented as approximations because linkage equilibrium and linkage disequilibrium are concepts typically thought of as properties of a sample of chromosomes; and as such they are susceptible to stochastic fluctuations due to the sampling process. Empirically, many pairs of genetic markers will be in linkage equilibrium, but certainly not all pairs.


Having established the concept of linkage equilibrium above, applicants can now describe the concept of linkage disequilibrium (LD), which is the deviation from linkage equilibrium. Since the frequency of the A1B1 haplotype is approximately the product of the allele frequencies for A1 and B1 under the assumption of linkage equilibrium as stated mathematically in (12), a simple measure for the amount of departure from linkage equilibrium is the difference in these two quantities, D,






D=P
11
−p
1
q
1  (16)


D=0 indicates perfect linkage equilibrium. Substantial departures from D=0 indicates LD in the sample of chromosomes examined. Many properties of D are discussed in Lewontin (1964) including the maximum and minimum values that D can take. Mathematically, using basic algebra, it can be shown that D can also be written solely in terms of haplotypes:






D=P
11
P
22
−P
12
P
21  (17)


If one transforms D by squaring it and subsequently dividing by the product of the allele frequencies of A1, A2, B1 and B2, the resulting quantity, called r2, is equivalent to the square of the Pearson's correlation coefficient commonly used in statistics (e.g. Hoel, 1954).










r
2

=


D
2



p
1



p
2



q
1



q
2







(
18
)







As with D, values of r2 close to 0 indicate linkage equilibrium between the two markers examined in the sample set. As values of r2 increase, the two markers are said to be in linkage disequilibrium. The range of values that r2 can take are from 0 to 1. r2=1 when there is a perfect correlation between the alleles at the two markers.


In addition, the quantities discussed above are sample-specific. And as such, it is necessary to formulate notation specific to the samples studied. In the approach discussed here, three types of samples are of primary interest: (i) a sample of chromosomes from individuals affected by a disease-related phenotype (cases), (ii) a sample of chromosomes obtained from individuals not affected by the disease-related phenotype (controls), and (iii) a standard sample set used for the construction of haplotypes and calculation pairwise linkage disequilibrium. For the allele frequencies used in the development of the method described below, an additional subscript will be added to denote either the case or control sample sets.






p
1,cs=freq(A1 in cases)  (19)






p
2,cs=freq(A2 in cases)  (20)






q
1,cs=freq(B1 in cases)  (21)






q
2,cs=freq(B2 in cases)  (22)





Similarly,






p
1,ct=freq(A1 in controls)  (23)






p
2,ct=freq(A2 in controls)  (24)






q
1,ct=freq(B1 in controls)  (25)






q
2,ct=freq(B2 in controls)  (26)


As a well-accepted sample set is necessary for robust linkage disequilibrium calculations, data obtained from the International HapMap project (The International HapMap Consortium 2003, 2005; Thorisson et al, 2005; McVean et al, 2005) can be used for the calculation of pairwise r2 values. Indeed, the samples genotyped for the International HapMap Project were selected to be representative examples from various human sub-populations with sufficient numbers of chromosomes examined to draw meaningful and robust conclusions from the patterns of genetic variation observed. The International HapMap project website (hapmap.org) contains a description of the project, methods utilized and samples examined. It is useful to examine empirical data to get a sense of the patterns present in such data.


Haplotype frequencies were explicit arguments in equation (18) above. However, knowing the 2-marker haplotype frequencies requires that phase to be determined for doubly heterozygous samples. When phase is unknown in the data examined, various algorithms can be used to infer phase from the genotype data. This issue was discussed earlier where the doubly heterozygous individual with a 2-SNP genotype of A1A2B1B2 could have one of two different sets of chromosomes: A1B1/A2B2 or A1B2/A2/B1. One such algorithm to estimate haplotype frequencies is the expectation-maximization (EM) algorithm first formalized by Dempster et al (1977). This algorithm is often used in genetics to infer haplotype frequencies from genotype data (e.g. Excoffier and Slatkin, 1995; Tregouet et al, 2004). It should be noted that for the two-SNP case explored here, EM algorithms have very little error provided that the allele frequencies and sample sizes are not too small. The impact on r2 values is typically negligible.


As correlated genetic markers share information, interrogation of SNP markers in LD with a disease-associated SNP marker can also have sufficient power to detect disease association (Long and Langley, 1999). The relationship between the power to directly find disease-associated alleles and the power to indirectly detect disease-association was investigated by Pritchard and Przeworski (2001). In a straight-forward derivation, it can be shown that the power to detect disease association indirectly at a marker locus in linkage disequilibrium with a disease-association locus is approximately the same as the power to detect disease-association directly at the disease-association locus if the sample size is increased by a factor of






1

r
2





(the reciprocal of equation 18) at the marker in comparison with the disease-association locus.


Therefore, if one calculated the power to detect disease-association indirectly with an experiment having N samples, then equivalent power to directly detect disease-association (at the actual disease-susceptibility locus) would necessitate an experiment using approximately r2N samples. This elementary relationship between power, sample size and linkage disequilibrium can be used to derive an r2 threshold value useful in determining whether or not genotyping markers in linkage disequilibrium with a SNP marker directly associated with disease status has enough power to indirectly detect disease-association.


To commence a derivation of the power to detect disease-associated markers through an indirect process, define the effective chromosomal sample size as










n
=


4


N
cs



N
ct




N
cs

+

N
ct




;




(
27
)







where Ncs and Nct are the numbers of diploid cases and controls, respectively. This is necessary to handle situations where the numbers of cases and controls are not equivalent. For equal case and control sample sizes, Ncs=Nct=N, the value of the effective number of chromosomes is simply n=2N—as expected. Let power be calculated for a significance level α (such that traditional P-values below α will be deemed statistically significant). Define the standard Gaussian distribution function as Φ(•). Mathematically,










Φ


(
x
)


=


1


2

π








-


x






-


θ
2

2










θ








(
28
)







Alternatively, the following error function notation (Erf) may also be used,










Φ


(
x
)


=


1
2



[

1
+

Erf


(

x

2


)



]






(
29
)







For example, Φ(1.644854)=0.95. The value of r2 may be derived to yield a pre-specified minimum amount of power to detect disease association though indirect interrogation. Noting that the LD SNP marker could be the one that is carrying the disease-association allele, therefore that this approach constitutes a lower-bound model where all indirect power results are expected to be at least as large as those interrogated.


Denote by β the error rate for not detecting truly disease-associated markers. Therefore, 1−β is the classical definition of statistical power. Substituting the Pritchard-Pzreworski result into the sample size, the power to detect disease association at a significance level of α is given by the approximation











1
-
β



Φ
[



|


q

1
,
cs


-

q

1
,
ct



|






q

1
,
cs




(

1
-

q

1
,
cs



)


+


q

1
,
ct




(

1
-

q

1
,
ct



)





r
2


n




-

z

1
-

α
2




]


;




(
30
)







where Zu is the inverse of the standard normal cumulative distribution evaluated at u (uε(0,1)). Zu−1(u), where Φ(Φ−1 (u))=Φ−1(Φ(u))=u. For example, setting α=0.05, and therefore 1−=α/2=0.975, Z0.975=1.95996 is obtained. Next, setting power equal to a threshold of a minimum power of T,









T
=

Φ
[



|


q

1
,
cs


-

q

1
,
ct



|






q

1
,
cs




(

1
-

q

1
,
cs



)


+


q

1
,
ct




(

1
-

q

1
,
ct



)





r
2


n




-

z

1
-

α
2




]





(
31
)







and solving for r2, the following threshold r2 is obtained:











r
T
2

=



[



q

1
,
cs




(

1
-

q

1
,
cs



)


+


q

1
,
ct




(

1
-

q

1
,
ct



)



]



n


(


q

1
,
cs


-

q

1
,
ct



)


2




[



Φ

-
1




(
T
)


+

Z

1
-

α
2




]









Or
,





(
32
)







r
T
2

=


(



Z
T

+

Z

1
-

α
2




n

)



[



q

1
,
cs


-


(

q

1
,
cs


)

2

+

q

1
,
ct


-


(

q

1
,
ct


)

2




(


q

1
,
cs


-

q

1
,
ct



)

2


]






(
33
)







Suppose that r2 is calculated between an interrogated SNP and a number of other SNPs with varying levels of LD with the interrogated SNP. The threshold value rT2 is the minimum value of linkage disequilibrium between the interrogated SNP and the potential LD SNPs such that the LD SNP still retains a power greater or equal to T for detecting disease-association. For example, suppose that SNP rs200 is genotyped in a case-control disease-association study and it is found to be associated with a disease phenotype. Further suppose that the minor allele frequency in 1,000 case chromosomes was found to be 16% in contrast with a minor allele frequency of 10% in 1,000 control chromosomes. Given those measurements one could have predicted, prior to the experiment, that the power to detect disease association at a significance level of 0.05 was quite high—approximately 98% using a test of allelic association. Applying equation (32) one can calculate a minimum value of r2 to indirectly assess disease association assuming that the minor allele at SNP rs200 is truly disease-predisposing for a threshold level of power. If one sets the threshold level of power to be 80%, then rT2=0.489 given the same significance level and chromosome numbers as above. Hence, any SNP with a pairwise r2 value with rs200 greater than 0.489 is expected to have greater than 80% power to detect the disease association. Further, this is assuming the conservative model where the LD SNP is disease-associated only through linkage disequilibrium with the interrogated SNP rs200.


The contribution or association of particular SNPs and/or SNP haplotypes with disease phenotypes, such as VT, enables the SNPs of the present invention to be used to develop superior diagnostic tests capable of identifying individuals who express a detectable trait, such as VT, as the result of a specific genotype, or individuals whose genotype places them at an increased or decreased risk of developing a detectable trait at a subsequent time as compared to individuals who do not have that genotype. As described herein, diagnostics may be based on a single SNP or a group of SNPs. Combined detection of a plurality of SNPs (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between, or more, of the SNPs provided in Table 1 and/or Table 2) typically increases the probability of an accurate diagnosis. For example, the presence of a single SNP known to correlate with VT might indicate a probability of 20% that an individual has or is at risk of developing VT, whereas detection of five SNPs, each of which correlates with VT, might indicate a probability of 80% that an individual has or is at risk of developing VT. To further increase the accuracy of diagnosis or predisposition screening, analysis of the SNPs of the present invention can be combined with that of other polymorphisms or other risk factors of VT, such as disease symptoms, pathological characteristics, family history, diet, environmental factors or lifestyle factors.


It will, of course, be understood by practitioners skilled in the treatment or diagnosis of VT that the present invention generally does not intend to provide an absolute identification of individuals who are at risk (or less at risk) of developing VT, and/or pathologies related to VT, but rather to indicate a certain increased (or decreased) degree or likelihood of developing the disease based on statistically significant association results. However, this information is extremely valuable as it can be used to, for example, initiate preventive treatments or to allow an individual carrying one or more significant SNPs or SNP haplotypes to foresee warning signs such as minor clinical symptoms, or to have regularly scheduled physical exams to monitor for appearance of a condition in order to identify and begin treatment of the condition at an early stage. Particularly with diseases that are extremely debilitating or fatal if not treated on time, the knowledge of a potential predisposition, even if this predisposition is not absolute, would likely contribute in a very significant manner to treatment efficacy.


The diagnostic techniques of the present invention may employ a variety of methodologies to determine whether a test subject has a SNP or a SNP pattern associated with an increased or decreased risk of developing a detectable trait or whether the individual suffers from a detectable trait as a result of a particular polymorphism/mutation, including, for example, methods which enable the analysis of individual chromosomes for haplotyping, family studies, single sperm DNA analysis, or somatic hybrids. The trait analyzed using the diagnostics of the invention may be any detectable trait that is commonly observed in pathologies and disorders related to VT.


Another aspect of the present invention relates to a method of determining whether an individual is at risk (or less at risk) of developing one or more traits or whether an individual expresses one or more traits as a consequence of possessing a particular trait-causing or trait-influencing allele. These methods generally involve obtaining a nucleic acid sample from an individual and assaying the nucleic acid sample to determine which nucleotide(s) is/are present at one or more SNP positions, wherein the assayed nucleotide(s) is/are indicative of an increased or decreased risk of developing the trait or indicative that the individual expresses the trait as a result of possessing a particular trait-causing or trait-influencing allele.


In another embodiment, the SNP detection reagents of the present invention are used to determine whether an individual has one or more SNP allele(s) affecting the level (e.g., the concentration of mRNA or protein in a sample, etc.) or pattern (e.g., the kinetics of expression, rate of decomposition, stability profile, Km, Vmax, etc.) of gene expression (collectively, the “gene response” of a cell or bodily fluid). Such a determination can be accomplished by screening for mRNA or protein expression (e.g., by using nucleic acid arrays, RT-PCR, TaqMan assays, or mass spectrometry), identifying genes having altered expression in an individual, genotyping SNPs disclosed in Table 1 and/or Table 2 that could affect the expression of the genes having altered expression (e.g., SNPs that are in and/or around the gene(s) having altered expression, SNPs in regulatory/control regions, SNPs in and/or around other genes that are involved in pathways that could affect the expression of the gene(s) having altered expression, or all SNPs could be genotyped), and correlating SNP genotypes with altered gene expression. In this manner, specific SNP alleles at particular SNP sites can be identified that affect gene expression.


Pharmacogenomics and Therapeutics/Drug Development


The present invention provides methods for assessing the pharmacogenomics of a subject harboring particular SNP alleles or haplotypes to a particular therapeutic agent or pharmaceutical compound, or to a class of such compounds. Pharmacogenomics deals with the roles which clinically significant hereditary variations (e.g., SNPs) play in the response to drugs due to altered drug disposition and/or abnormal action in affected persons. See, e.g., Roses, Nature 405, 857-865 (2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001); Eichelbaum, Clin. Exp. Pharmacol. Physiol. 23(10-11):983-985 (1996); and Linder, Clin. Chem. 43(2):254-266 (1997). The clinical outcomes of these variations can result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the SNP genotype of an individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. For example, SNPs in drug metabolizing enzymes can affect the activity of these enzymes, which in turn can affect both the intensity and duration of drug action, as well as drug metabolism and clearance.


The discovery of SNPs in drug metabolizing enzymes, drug transporters, proteins for pharmaceutical agents, and other drug targets has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. SNPs can be expressed in the phenotype of the extensive metabolizer and in the phenotype of the poor metabolizer. Accordingly, SNPs may lead to allelic variants of a protein in which one or more of the protein functions in one population are different from those in another population. SNPs and the encoded variant peptides thus provide targets to ascertain a genetic predisposition that can affect treatment modality. For example, in a ligand-based treatment, SNPs may give rise to amino terminal extracellular domains and/or other ligand-binding regions of a receptor that are more or less active in ligand binding, thereby affecting subsequent protein activation. Accordingly, ligand dosage would necessarily be modified to maximize the therapeutic effect within a given population containing particular SNP alleles or haplotypes.


As an alternative to genotyping, specific variant proteins containing variant amino acid sequences encoded by alternative SNP alleles could be identified. Thus, pharmacogenomic characterization of an individual permits the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic uses based on the individual's SNP genotype, thereby enhancing and optimizing the effectiveness of the therapy. Furthermore, the production of recombinant cells and transgenic animals containing particular SNPs/haplotypes allow effective clinical design and testing of treatment compounds and dosage regimens. For example, transgenic animals can be produced that differ only in specific SNP alleles in a gene that is orthologous to a human disease susceptibility gene.


Pharmacogenomic uses of the SNPs of the present invention provide several significant advantages for patient care, particularly in treating VT. Pharmacogenomic characterization of an individual, based on an individual's SNP genotype, can identify those individuals unlikely to respond to treatment with a particular medication and thereby allows physicians to avoid prescribing the ineffective medication to those individuals. On the other hand, SNP genotyping of an individual may enable physicians to select the appropriate medication and dosage regimen that will be most effective based on an individual's SNP genotype. This information increases a physician's confidence in prescribing medications and motivates patients to comply with their drug regimens. Furthermore, pharmacogenomics may identify patients predisposed to toxicity and adverse reactions to particular drugs or drug dosages. Adverse drug reactions lead to more than 100,000 avoidable deaths per year in the United States alone and therefore represent a significant cause of hospitalization and death, as well as a significant economic burden on the healthcare system (Pfost et. al., Trends in Biotechnology, Aug. 2000.). Thus, pharmacogenomics based on the SNPs disclosed herein has the potential to both save lives and reduce healthcare costs substantially.


Pharmacogenomics in general is discussed further in Rose et al., “Pharmacogenetic analysis of clinically relevant genetic polymorphisms”, Methods Mol Med. 2003; 85:225-37. Pharmacogenomics as it relates to Alzheimer's disease and other neurodegenerative disorders is discussed in Cacabelos, “Pharmacogenomics for the treatment of dementia”, Ann Med. 2002; 34(5):357-79, Maimone et al., “Pharmacogenomics of neurodegenerative diseases”, Eur J Pharmacol. 2001 Feb. 9; 413(1):11-29, and Poirier, “Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease”, Mol Diagn. 1999 December; 4(4):335-41. Pharmacogenomics as it relates to cardiovascular disorders is discussed in Siest et al., “Pharmacogenomics of drugs affecting the cardiovascular system”, Clin Chem Lab Med. 2003 April; 41(4):590-9, Mukherjee et al., “Pharmacogenomics in cardiovascular diseases”, Prog Cardiovasc Dis. 2002 May-June; 44(6):479-98, and Mooser et al., “Cardiovascular pharmacogenetics in the SNP era”, J Thromb Haemost. 2003 July; 1(7):1398-402. Pharmacogenomics as it relates to cancer is discussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, and the individual patient”, Cancer Invest. 2003; 21(4):630-40 and Watters et al., “Cancer pharmacogenomics: current and future applications”, Biochim Biophys Acta. 2003 Mar. 17; 1603(2):99-111.


The SNPs of the present invention also can be used to identify novel therapeutic targets for VT. For example, genes containing the disease-associated variants (“variant genes”) or their products, as well as genes or their products that are directly or indirectly regulated by or interacting with these variant genes or their products, can be targeted for the development of therapeutics that, for example, treat the disease or prevent or delay disease onset. The therapeutics may be composed of, for example, small molecules, proteins, protein fragments or peptides, antibodies, nucleic acids, or their derivatives or mimetics which modulate the functions or levels of the target genes or gene products.


The SNP-containing nucleic acid molecules disclosed herein, and their complementary nucleic acid molecules, may be used as antisense constructs to control gene expression in cells, tissues, and organisms. Antisense technology is well established in the art and extensively reviewed in Antisense Drug Technology: Principles, Strategies, and Applications, Crooke (ed.), Marcel Dekker, Inc.: New York (2001). An antisense nucleic acid molecule is generally designed to be complementary to a region of mRNA expressed by a gene so that the antisense molecule hybridizes to the mRNA and thereby blocks translation of mRNA into protein. Various classes of antisense oligonucleotides are used in the art, two of which are cleavers and blockers. Cleavers, by binding to target RNAs, activate intracellular nucleases (e.g., RNaseH or RNase L) that cleave the target RNA. Blockers, which also bind to target RNAs, inhibit protein translation through steric hindrance of ribosomes. Exemplary blockers include peptide nucleic acids, morpholinos, locked nucleic acids, and methylphosphonates (see, e.g., Thompson, Drug Discovery Today, 7 (17): 912-917 (2002)). Antisense oligonucleotides are directly useful as therapeutic agents, and are also useful for determining and validating gene function (e.g., in gene knock-out or knock-down experiments).


Antisense technology is further reviewed in: Layery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation”, Curr Opin Drug Discov Devel. 2003 July; 6(4):561-9; Stephens et al., “Antisense oligonucleotide therapy in cancer”, Curr Opin Mol Ther. 2003 April; 5(2):118-22; Kurreck, “Antisense technologies. Improvement through novel chemical modifications”, Eur J Biochem. 2003 April; 270(8):1628-44; Dias et al., “Antisense oligonucleotides: basic concepts and mechanisms”, Mol Cancer Ther. 2002 March; 1(5):347-55; Chen, “Clinical development of antisense oligonucleotides as anti-cancer therapeutics”, Methods Mol Med. 2003; 75:621-36; Wang et al., “Antisense anticancer oligonucleotide therapeutics”, Curr Cancer Drug Targets. 2001 November; 1(3):177-96; and Bennett, “Efficiency of antisense oligonucleotide drug discovery”, Antisense Nucleic Acid Drug Dev. 2002 June; 12(3):215-24.


The SNPs of the present invention are particularly useful for designing antisense reagents that are specific for particular nucleic acid variants. Based on the SNP information disclosed herein, antisense oligonucleotides can be produced that specifically target mRNA molecules that contain one or more particular SNP nucleotides. In this manner, expression of mRNA molecules that contain one or more undesired polymorphisms (e.g., SNP nucleotides that lead to a defective protein such as an amino acid substitution in a catalytic domain) can be inhibited or completely blocked. Thus, antisense oligonucleotides can be used to specifically bind a particular polymorphic form (e.g., a SNP allele that encodes a defective protein), thereby inhibiting translation of this form, but which do not bind an alternative polymorphic form (e.g., an alternative SNP nucleotide that encodes a protein having normal function).


Antisense molecules can be used to inactivate mRNA in order to inhibit gene expression and production of defective proteins. Accordingly, these molecules can be used to treat a disorder, such as VT, characterized by abnormal or undesired gene expression or expression of certain defective proteins. This technique can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible mRNA regions include, for example, protein-coding regions and particularly protein-coding regions corresponding to catalytic activities, substrate/ligand binding, or other functional activities of a protein.


The SNPs of the present invention are also useful for designing RNA interference reagents that specifically target nucleic acid molecules having particular SNP variants. RNA interference (RNAi), also referred to as gene silencing, is based on using double-stranded RNA (dsRNA) molecules to turn genes off. When introduced into a cell, dsRNAs are processed by the cell into short fragments (generally about 21, 22, or 23 nucleotides in length) known as small interfering RNAs (siRNAs) which the cell uses in a sequence-specific manner to recognize and destroy complementary RNAs (Thompson, Drug Discovery Today, 7 (17): 912-917 (2002)). Accordingly, an aspect of the present invention specifically contemplates isolated nucleic acid molecules that are about 18-26 nucleotides in length, preferably 19-25 nucleotides in length, and more preferably 20, 21, 22, or 23 nucleotides in length, and the use of these nucleic acid molecules for RNAi. Because RNAi molecules, including siRNAs, act in a sequence-specific manner, the SNPs of the present invention can be used to design RNAi reagents that recognize and destroy nucleic acid molecules having specific SNP alleles/nucleotides (such as deleterious alleles that lead to the production of defective proteins), while not affecting nucleic acid molecules having alternative SNP alleles (such as alleles that encode proteins having normal function). As with antisense reagents, RNAi reagents may be directly useful as therapeutic agents (e.g., for turning off defective, disease-causing genes), and are also useful for characterizing and validating gene function (e.g., in gene knock-out or knock-down experiments).


The following references provide a further review of RNAi: Reynolds et al., “Rational siRNA design for RNA interference”, Nat Biotechnol. 2004 March; 22(3):326-30. Epub 2004 Feb. 1; Chi et al., “Genomewide view of gene silencing by small interfering RNAs”, PNAS 100(11):6343-6346, 2003; Vickers et al., “Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents”, J. Biol. Chem. 278: 7108-7118, 2003; Agami, “RNAi and related mechanisms and their potential use for therapy”, Curr Opin Chem. Biol. 2002 December; 6(6):829-34; Layery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation”, Curr Opin Drug Discov Devel. 2003 July; 6(4):561-9; Shi, “Mammalian RNAi for the masses”, Trends Genet. 2003 January; 19(1):9-12), Shuey et al., “RNAi: gene-silencing in therapeutic intervention”, Drug Discovery Today 2002 October; 7(20):1040-1046; McManus et al., Nat Rev Genet 2002 October; 3(10):737-47; Xia et al., Nat Biotechnol 2002 October; 20(10):1006-10; Plasterk et al., Curr Opin Genet Dev 2000 October; 10(5):562-7; Bosher et al., Nat Cell Biol 2000 February; 2(2):E31-6; and Hunter, Curr Biol 1999 Jun. 17; 9(12):R440-2).


A subject suffering from a pathological condition, such as VT, ascribed to a SNP may be treated so as to correct the genetic defect (see Kren et al., Proc. Natl. Acad. Sci. USA 96:10349-10354 (1999)). Such a subject can be identified by any method that can detect the polymorphism in a biological sample drawn from the subject. Such a genetic defect may be permanently corrected by administering to such a subject a nucleic acid fragment incorporating a repair sequence that supplies the normal/wild-type nucleotide at the position of the SNP. This site-specific repair sequence can encompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The site-specific repair sequence is administered in an appropriate vehicle, such as a complex with polyethylenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus, or other pharmaceutical composition that promotes intracellular uptake of the administered nucleic acid. A genetic defect leading to an inborn pathology may then be overcome, as the chimeric oligonucleotides induce incorporation of the normal sequence into the subject's genome. Upon incorporation, the normal gene product is expressed, and the replacement is propagated, thereby engendering a permanent repair and therapeutic enhancement of the clinical condition of the subject.


In cases in which a cSNP results in a variant protein that is ascribed to be the cause of, or a contributing factor to, a pathological condition, a method of treating such a condition can include administering to a subject experiencing the pathology the wild-type/normal cognate of the variant protein. Once administered in an effective dosing regimen, the wild-type cognate provides complementation or remediation of the pathological condition.


The invention further provides a method for identifying a compound or agent that can be used to treat VT. The SNPs disclosed herein are useful as targets for the identification and/or development of therapeutic agents. A method for identifying a therapeutic agent or compound typically includes assaying the ability of the agent or compound to modulate the activity and/or expression of a SNP-containing nucleic acid or the encoded product and thus identifying an agent or a compound that can be used to treat a disorder characterized by undesired activity or expression of the SNP-containing nucleic acid or the encoded product. The assays can be performed in cell-based and cell-free systems. Cell-based assays can include cells naturally expressing the nucleic acid molecules of interest or recombinant cells genetically engineered to express certain nucleic acid molecules.


Variant gene expression in a VT patient can include, for example, either expression of a SNP-containing nucleic acid sequence (for instance, a gene that contains a SNP can be transcribed into an mRNA transcript molecule containing the SNP, which can in turn be translated into a variant protein) or altered expression of a normal/wild-type nucleic acid sequence due to one or more SNPs (for instance, a regulatory/control region can contain a SNP that affects the level or pattern of expression of a normal transcript).


Assays for variant gene expression can involve direct assays of nucleic acid levels (e.g., mRNA levels), expressed protein levels, or of collateral compounds involved in a signal pathway. Further, the expression of genes that are up- or down-regulated in response to the signal pathway can also be assayed. In this embodiment, the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.


Modulators of variant gene expression can be identified in a method wherein, for example, a cell is contacted with a candidate compound/agent and the expression of mRNA determined. The level of expression of mRNA in the presence of the candidate compound is compared to the level of expression of mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of variant gene expression based on this comparison and be used to treat a disorder such as VT that is characterized by variant gene expression (e.g., either expression of a SNP-containing nucleic acid or altered expression of a normal/wild-type nucleic acid molecule due to one or more SNPs that affect expression of the nucleic acid molecule) due to one or more SNPs of the present invention. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.


The invention further provides methods of treatment, with the SNP or associated nucleic acid domain (e.g., catalytic domain, ligand/substrate-binding domain, regulatory/control region, etc.) or gene, or the encoded mRNA transcript, as a target, using a compound identified through drug screening as a gene modulator to modulate variant nucleic acid expression. Modulation can include either up-regulation (i.e., activation or agonization) or down-regulation (i.e., suppression or antagonization) of nucleic acid expression.


Expression of mRNA transcripts and encoded proteins, either wild type or variant, may be altered in individuals with a particular SNP allele in a regulatory/control element, such as a promoter or transcription factor binding domain, that regulates expression. In this situation, methods of treatment and compounds can be identified, as discussed herein, that regulate or overcome the variant regulatory/control element, thereby generating normal, or healthy, expression levels of either the wild type or variant protein.


The SNP-containing nucleic acid molecules of the present invention are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of a variant gene, or encoded product, in clinical trials or in a treatment regimen. Thus, the gene expression pattern can serve as an indicator for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance, as well as an indicator for toxicities. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant. Similarly, if the level of nucleic acid expression falls below a desirable level, administration of the compound could be commensurately decreased.


In another aspect of the present invention, there is provided a pharmaceutical pack comprising a therapeutic agent (e.g., a small molecule drug, antibody, peptide, antisense or RNAi nucleic acid molecule, etc.) and a set of instructions for administration of the therapeutic agent to humans diagnostically tested for one or more SNPs or SNP haplotypes provided by the present invention.


The SNPs/haplotypes of the present invention are also useful for improving many different aspects of the drug development process. For instance, an aspect of the present invention includes selecting individuals for clinical trials based on their SNP genotype. For example, individuals with SNP genotypes that indicate that they are likely to positively respond to a drug can be included in the trials, whereas those individuals whose SNP genotypes indicate that they are less likely to or would not respond to the drug, or who are at risk for suffering toxic effects or other adverse reactions, can be excluded from the clinical trials. This not only can improve the safety of clinical trials, but also can enhance the chances that the trial will demonstrate statistically significant efficacy. Furthermore, the SNPs of the present invention may explain why certain previously developed drugs performed poorly in clinical trials and may help identify a subset of the population that would benefit from a drug that had previously performed poorly in clinical trials, thereby “rescuing” previously developed drugs, and enabling the drug to be made available to a particular VT patient population that can benefit from it.


SNPs have many important uses in drug discovery, screening, and development. A high probability exists that, for any gene/protein selected as a potential drug target, variants of that gene/protein will exist in a patient population. Thus, determining the impact of gene/protein variants on the selection and delivery of a therapeutic agent should be an integral aspect of the drug discovery and development process. (Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine, 2002 March; S30-S36).


Knowledge of variants (e.g., SNPs and any corresponding amino acid polymorphisms) of a particular therapeutic target (e.g., a gene, mRNA transcript, or protein) enables parallel screening of the variants in order to identify therapeutic candidates (e.g., small molecule compounds, antibodies, antisense or RNAi nucleic acid compounds, etc.) that demonstrate efficacy across variants (Rothberg, Nat Biotechnol 2001 March; 19(3):209-11). Such therapeutic candidates would be expected to show equal efficacy across a larger segment of the patient population, thereby leading to a larger potential market for the therapeutic candidate.


Furthermore, identifying variants of a potential therapeutic target enables the most common form of the target to be used for selection of therapeutic candidates, thereby helping to ensure that the experimental activity that is observed for the selected candidates reflects the real activity expected in the largest proportion of a patient population (Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine, 2002 March; S30-S36).


Additionally, screening therapeutic candidates against all known variants of a target can enable the early identification of potential toxicities and adverse reactions relating to particular variants. For example, variability in drug absorption, distribution, metabolism and excretion (ADME) caused by, for example, SNPs in therapeutic targets or drug metabolizing genes, can be identified, and this information can be utilized during the drug development process to minimize variability in drug disposition and develop therapeutic agents that are safer across a wider range of a patient population. The SNPs of the present invention, including the variant proteins and encoding polymorphic nucleic acid molecules provided in Tables 1-2, are useful in conjunction with a variety of toxicology methods established in the art, such as those set forth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.


Furthermore, therapeutic agents that target any art-known proteins (or nucleic acid molecules, either RNA or DNA) may cross-react with the variant proteins (or polymorphic nucleic acid molecules) disclosed in Table 1, thereby significantly affecting the pharmacokinetic properties of the drug. Consequently, the protein variants and the SNP-containing nucleic acid molecules disclosed in Tables 1-2 are useful in developing, screening, and evaluating therapeutic agents that target corresponding art-known protein forms (or nucleic acid molecules). Additionally, as discussed above, knowledge of all polymorphic forms of a particular drug target enables the design of therapeutic agents that are effective against most or all such polymorphic forms of the drug target.


Pharmaceutical Compositions and Administration Thereof


Any of the VT-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating VT and related pathologies, and the present disclosure enables therapeutic compounds (e.g., small molecules, antibodies, therapeutic proteins, RNAi and antisense molecules, etc.) to be developed that target (or are comprised of) any of these therapeutic targets.


In general, a therapeutic compound will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the therapeutic compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.


Therapeutically effective amounts of therapeutic compounds may range from, for example, approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as an example, for administration to a 70 kg person, the dosage range would most preferably be about 7 mg to 1.4 g per day.


In general, therapeutic compounds will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.


The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.


Pharmaceutical compositions are comprised of, in general, a therapeutic compound in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the therapeutic compound. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art.


Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.


Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.


Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).


The amount of the therapeutic compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of the therapeutic compound based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %.


Therapeutic compounds can be administered alone or in combination with other therapeutic compounds or in combination with one or more other active ingredient(s). For example, an inhibitor or stimulator of an VT-associated protein can be administered in combination with another agent that inhibits or stimulates the activity of the same or a different VT-associated protein to thereby counteract the affects of VT.


For further information regarding pharmacology, see Current Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.


Human Identification Applications


In addition to their diagnostic and therapeutic uses in VT and related pathologies, the SNPs provided by the present invention are also useful as human identification markers for such applications as forensics, paternity testing, and biometrics (see, e.g., Gill, “An assessment of the utility of single nucleotide polymorphisms (SNPs) for forensic purposes”, Int J Legal Med. 2001; 114(4-5):204-10). Genetic variations in the nucleic acid sequences between individuals can be used as genetic markers to identify individuals and to associate a biological sample with an individual. Determination of which nucleotides occupy a set of SNP positions in an individual identifies a set of SNP markers that distinguishes the individual. The more SNP positions that are analyzed, the lower the probability that the set of SNPs in one individual is the same as that in an unrelated individual. Preferably, if multiple sites are analyzed, the sites are unlinked (i.e., inherited independently). Thus, preferred sets of SNPs can be selected from among the SNPs disclosed herein, which may include SNPs on different chromosomes, SNPs on different chromosome arms, and/or SNPs that are dispersed over substantial distances along the same chromosome arm.


Furthermore, among the SNPs disclosed herein, preferred SNPs for use in certain forensic/human identification applications include SNPs located at degenerate codon positions (i.e., the third position in certain codons which can be one of two or more alternative nucleotides and still encode the same amino acid), since these SNPs do not affect the encoded protein. SNPs that do not affect the encoded protein are expected to be under less selective pressure and are therefore expected to be more polymorphic in a population, which is typically an advantage for forensic/human identification applications. However, for certain forensics/human identification applications, such as predicting phenotypic characteristics (e.g., inferring ancestry or inferring one or more physical characteristics of an individual) from a DNA sample, it may be desirable to utilize SNPs that affect the encoded protein.


For many of the SNPs disclosed in Tables 1-2 (which are identified as “Applera” SNP source), Tables 1-2 provide SNP allele frequencies obtained by re-sequencing the DNA of chromosomes from 39 individuals (Tables 1-2 also provide allele frequency information for “Celera” source SNPs and, where available, public SNPs from dbEST, HGBASE, and/or HGMD). The allele frequencies provided in Tables 1-2 enable these SNPs to be readily used for human identification applications. Although any SNP disclosed in Table 1 and/or Table 2 could be used for human identification, the closer that the frequency of the minor allele at a particular SNP site is to 50%, the greater the ability of that SNP to discriminate between different individuals in a population since it becomes increasingly likely that two randomly selected individuals would have different alleles at that SNP site. Using the SNP allele frequencies provided in Tables 1-2, one of ordinary skill in the art could readily select a subset of SNPs for which the frequency of the minor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables 1-2 provide allele frequencies based on the re-sequencing of the chromosomes from 39 individuals, a subset of SNPs could readily be selected for human identification in which the total allele count of the minor allele at a particular SNP site is, for example, at least 1, 2, 4, 8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other number in-between.


Furthermore, Tables 1-2 also provide population group (interchangeably referred to herein as ethnic or racial groups) information coupled with the extensive allele frequency information. For example, the group of 39 individuals whose DNA was re-sequenced was made-up of 20 Caucasians and 19 African-Americans. This population group information enables further refinement of SNP selection for human identification. For example, preferred SNPs for human identification can be selected from Tables 1-2 that have similar allele frequencies in both the Caucasian and African-American populations; thus, for example, SNPs can be selected that have equally high discriminatory power in both populations. Alternatively, SNPs can be selected for which there is a statistically significant difference in allele frequencies between the Caucasian and African-American populations (as an extreme example, a particular allele may be observed only in either the Caucasian or the African-American population group but not observed in the other population group); such SNPs are useful, for example, for predicting the race/ethnicity of an unknown perpetrator from a biological sample such as a hair or blood stain recovered at a crime scene. For a discussion of using SNPs to predict ancestry from a DNA sample, including statistical methods, see Frudakis et al., “A Classifier for the SNP-Based Inference of Ancestry,” Journal of Forensic Sciences 2003; 48(4):771-782.


SNPs have numerous advantages over other types of polymorphic markers, such as short tandem repeats (STRs). For example, SNPs can be easily scored and are amenable to automation, making SNPs the markers of choice for large-scale forensic databases. SNPs are found in much greater abundance throughout the genome than repeat polymorphisms. Population frequencies of two polymorphic forms can usually be determined with greater accuracy than those of multiple polymorphic forms at multi-allelic loci. SNPs are mutationaly more stable than repeat polymorphisms. SNPs are not susceptible to artefacts such as stutter bands that can hinder analysis. Stutter bands are frequently encountered when analyzing repeat polymorphisms, and are particularly troublesome when analyzing samples such as crime scene samples that may contain mixtures of DNA from multiple sources. Another significant advantage of SNP markers over STR markers is the much shorter length of nucleic acid needed to score a SNP. For example, STR markers are generally several hundred base pairs in length. A SNP, on the other hand, comprises a single nucleotide, and generally a short conserved region on either side of the SNP position for primer and/or probe binding. This makes SNPs more amenable to typing in highly degraded or aged biological samples that are frequently encountered in forensic casework in which DNA may be fragmented into short pieces.


SNPs also are not subject to microvariant and “off-ladder” alleles frequently encountered when analyzing STR loci. Microvariants are deletions or insertions within a repeat unit that change the size of the amplified DNA product so that the amplified product does not migrate at the same rate as reference alleles with normal sized repeat units. When separated by size, such as by electrophoresis on a polyacrylamide gel, microvariants do not align with a reference allelic ladder of standard sized repeat units, but rather migrate between the reference alleles. The reference allelic ladder is used for precise sizing of alleles for allele classification; therefore alleles that do not align with the reference allelic ladder lead to substantial analysis problems. Furthermore, when analyzing multi-allelic repeat polymorphisms, occasionally an allele is found that consists of more or less repeat units than has been previously seen in the population, or more or less repeat alleles than are included in a reference allelic ladder. These alleles will migrate outside the size range of known alleles in a reference allelic ladder, and therefore are referred to as “off-ladder” alleles. In extreme cases, the allele may contain so few or so many repeats that it migrates well out of the range of the reference allelic ladder. In this situation, the allele may not even be observed, or, with multiplex analysis, it may migrate within or close to the size range for another locus, further confounding analysis.


SNP analysis avoids the problems of microvariants and off-ladder alleles encountered in STR analysis. Importantly, microvariants and off-ladder alleles may provide significant problems, and may be completely missed, when using analysis methods such as oligonucleotide hybridization arrays, which utilize oligonucleotide probes specific for certain known alleles. Furthermore, off-ladder alleles and microvariants encountered with STR analysis, even when correctly typed, may lead to improper statistical analysis, since their frequencies in the population are generally unknown or poorly characterized, and therefore the statistical significance of a matching genotype may be questionable. All these advantages of SNP analysis are considerable in light of the consequences of most DNA identification cases, which may lead to life imprisonment for an individual, or re-association of remains to the family of a deceased individual.


DNA can be isolated from biological samples such as blood, bone, hair, saliva, or semen, and compared with the DNA from a reference source at particular SNP positions. Multiple SNP markers can be assayed simultaneously in order to increase the power of discrimination and the statistical significance of a matching genotype. For example, oligonucleotide arrays can be used to genotype a large number of SNPs simultaneously. The SNPs provided by the present invention can be assayed in combination with other polymorphic genetic markers, such as other SNPs known in the art or STRs, in order to identify an individual or to associate an individual with a particular biological sample.


Furthermore, the SNPs provided by the present invention can be genotyped for inclusion in a database of DNA genotypes, for example, a criminal DNA databank such as the FBI's Combined DNA Index System (CODIS) database. A genotype obtained from a biological sample of unknown source can then be queried against the database to find a matching genotype, with the SNPs of the present invention providing nucleotide positions at which to compare the known and unknown DNA sequences for identity. Accordingly, the present invention provides a database comprising novel SNPs or SNP alleles of the present invention (e.g., the database can comprise information indicating which alleles are possessed by individual members of a population at one or more novel SNP sites of the present invention), such as for use in forensics, biometrics, or other human identification applications. Such a database typically comprises a computer-based system in which the SNPs or SNP alleles of the present invention are recorded on a computer readable medium (see the section of the present specification entitled “Computer-Related Embodiments”).


The SNPs of the present invention can also be assayed for use in paternity testing. The object of paternity testing is usually to determine whether a male is the father of a child. In most cases, the mother of the child is known and thus, the mother's contribution to the child's genotype can be traced. Paternity testing investigates whether the part of the child's genotype not attributable to the mother is consistent with that of the putative father. Paternity testing can be performed by analyzing sets of polymorphisms in the putative father and the child, with the SNPs of the present invention providing nucleotide positions at which to compare the putative father's and child's DNA sequences for identity. If the set of polymorphisms in the child attributable to the father does not match the set of polymorphisms of the putative father, it can be concluded, barring experimental error, that the putative father is not the father of the child. If the set of polymorphisms in the child attributable to the father match the set of polymorphisms of the putative father, a statistical calculation can be performed to determine the probability of coincidental match, and a conclusion drawn as to the likelihood that the putative father is the true biological father of the child.


In addition to paternity testing, SNPs are also useful for other types of kinship testing, such as for verifying familial relationships for immigration purposes, or for cases in which an individual alleges to be related to a deceased individual in order to claim an inheritance from the deceased individual, etc. For further information regarding the utility of SNPs for paternity testing and other types of kinship testing, including methods for statistical analysis, see Krawczak, “Informativity assessment for biallelic single nucleotide polymorphisms”, Electrophoresis 1999 June; 20(8):1676-81.


The use of the SNPs of the present invention for human identification further extends to various authentication systems, commonly referred to as biometric systems, which typically convert physical characteristics of humans (or other organisms) into digital data. Biometric systems include various technological devices that measure such unique anatomical or physiological characteristics as finger, thumb, or palm prints; hand geometry; vein patterning on the back of the hand; blood vessel patterning of the retina and color and texture of the iris; facial characteristics; voice patterns; signature and typing dynamics; and DNA. Such physiological measurements can be used to verify identity and, for example, restrict or allow access based on the identification. Examples of applications for biometrics include physical area security, computer and network security, aircraft passenger check-in and boarding, financial transactions, medical records access, government benefit distribution, voting, law enforcement, passports, visas and immigration, prisons, various military applications, and for restricting access to expensive or dangerous items, such as automobiles or guns (see, for example, O'Connor, Stanford Technology Law Review and U.S. Pat. No. 6,119,096).


Groups of SNPs, particularly the SNPs provided by the present invention, can be typed to uniquely identify an individual for biometric applications such as those described above. Such SNP typing can readily be accomplished using, for example, DNA chips/arrays. Preferably, a minimally invasive means for obtaining a DNA sample is utilized. For example, PCR amplification enables sufficient quantities of DNA for analysis to be obtained from buccal swabs or fingerprints, which contain DNA-containing skin cells and oils that are naturally transferred during contact.


Further information regarding techniques for using SNPs in forensic/human identification applications can be found in, for example, Current Protocols in Human Genetics, John Wiley & Sons, N.Y. (2002), 14.1-14.7.


Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof


Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules


The present invention provides SNP-containing nucleic acid molecules, many of which encode proteins having variant amino acid sequences as compared to the art-known (i.e., wild-type) proteins. Amino acid sequences encoded by the polymorphic nucleic acid molecules of the present invention are referred to as SEQ ID NOS: 126-250 in Table 1 and provided in the Sequence Listing. These variants will generally be referred to herein as variant proteins/peptides/polypeptides, or polymorphic proteins/peptides/polypeptides of the present invention. The terms “protein,” “peptide,” and “polypeptide” are used herein interchangeably.


A variant protein of the present invention may be encoded by, for example, a nonsynonymous nucleotide substitution at any one of the cSNP positions disclosed herein. In addition, variant proteins may also include proteins whose expression, structure, and/or function is altered by a SNP disclosed herein, such as a SNP that creates or destroys a stop codon, a SNP that affects splicing, and a SNP in control/regulatory elements, e.g. promoters, enhancers, or transcription factor binding domains.


As used herein, a protein or peptide is said to be “isolated” or “purified” when it is substantially free of cellular material or chemical precursors or other chemicals. The variant proteins of the present invention can be purified to homogeneity or other lower degrees of purity. The level of purification will be based on the intended use. The key feature is that the preparation allows for the desired function of the variant protein, even if in the presence of considerable amounts of other components.


As used herein, “substantially free of cellular material” includes preparations of the variant protein having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the variant protein is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.


The language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.


An isolated variant protein may be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant host cells), or synthesized using known protein synthesis methods. For example, a nucleic acid molecule containing SNP(s) encoding the variant protein can be cloned into an expression vector, the expression vector introduced into a host cell, and the variant protein expressed in the host cell. The variant protein can then be isolated from the cells by any appropriate purification scheme using standard protein purification techniques. Examples of these techniques are described in detail below (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).


The present invention provides isolated variant proteins that comprise, consist of or consist essentially of amino acid sequences that contain one or more variant amino acids encoded by one or more codons that contain a SNP of the present invention.


Accordingly, the present invention provides variant proteins that consist of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists of an amino acid sequence when the amino acid sequence is the entire amino acid sequence of the protein.


The present invention further provides variant proteins that consist essentially of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues in the final protein.


The present invention further provides variant proteins that comprise amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein may contain only the variant amino acid sequence or have additional amino acid residues, such as a contiguous encoded sequence that is naturally associated with it or heterologous amino acid residues. Such a protein can have a few additional amino acid residues or can comprise many more additional amino acids. A brief description of how various types of these proteins can be made and isolated is provided below.


The variant proteins of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a variant protein operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the variant protein. “Operatively linked” indicates that the coding sequences for the variant protein and the heterologous protein are ligated in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the variant protein. In another embodiment, the fusion protein is encoded by a fusion polynucleotide that is synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see Ausubel et al., Current Protocols in Molecular Biology, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A variant protein-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the variant protein.


In many uses, the fusion protein does not affect the activity of the variant protein. The fusion protein can include, but is not limited to, enzymatic fusion proteins, for example, beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate their purification following recombinant expression. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Fusion proteins are further described in, for example, Terpe, “Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems”, Appl Microbiol Biotechnol. 2003 January; 60(5):523-33. Epub 2002 Nov. 7; Graddis et al., “Designing proteins that work using recombinant technologies”, Curr Pharm Biotechnol. 2002 December; 3(4):285-97; and Nilsson et al., “Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins”, Protein Expr Punf 1997 October; 11(1):1-16.


The present invention also relates to further obvious variants of the variant polypeptides of the present invention, such as naturally-occurring mature forms (e.g., alleleic variants), non-naturally occurring recombinantly-derived variants, and orthologs and paralogs of such proteins that share sequence homology. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry. It is understood, however, that variants exclude those known in the prior art before the present invention.


Further variants of the variant polypeptides disclosed in Table 1 can comprise an amino acid sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel amino acid residue (allele) disclosed in Table 1 (which is encoded by a novel SNP allele). Thus, an aspect of the present invention that is specifically contemplated are polypeptides that have a certain degree of sequence variation compared with the polypeptide sequences shown in Table 1, but that contain a novel amino acid residue (allele) encoded by a novel SNP allele disclosed herein. In other words, as long as a polypeptide contains a novel amino acid residue disclosed herein, other portions of the polypeptide that flank the novel amino acid residue can vary to some degree from the polypeptide sequences shown in Table 1.


Full-length pre-processed forms, as well as mature processed forms, of proteins that comprise one of the amino acid sequences disclosed herein can readily be identified as having complete sequence identity to one of the variant proteins of the present invention as well as being encoded by the same genetic locus as the variant proteins provided herein.


Orthologs of a variant peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of a variant peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from non-human mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs can be encoded by a nucleic acid sequence that hybridizes to a variant peptide-encoding nucleic acid molecule under moderate to stringent conditions depending on the degree of relatedness of the two organisms yielding the homologous proteins.


Variant proteins include, but are not limited to, proteins containing deletions, additions and substitutions in the amino acid sequence caused by the SNPs of the present invention. One class of substitutions is conserved amino acid substitutions in which a given amino acid in a polypeptide is substituted for another amino acid of like characteristics. Typical conservative substitutions are replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Be; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found in, for example, Bowie et al., Science 247:1306-1310 (1990).


Variant proteins can be fully functional or can lack function in one or more activities, e.g. ability to bind another molecule, ability to catalyze a substrate, ability to mediate signaling, etc. Fully functional variants typically contain only conservative variations or variations in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree. Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, truncations or extensions, or a substitution, insertion, inversion, or deletion of a critical residue or in a critical region.


Amino acids that are essential for function of a protein can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science 244:1081-1085 (1989)), particularly using the amino acid sequence and polymorphism information provided in Table 1. The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as enzyme activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992); de Vos et al. Science 255:306-312 (1992)).


Polypeptides can contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Accordingly, the variant proteins of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (e.g., polyethylene glycol), or in which additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.


Known protein modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.


Such protein modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as Proteins—Structure and Molecular Properties, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); Wold, F., Posttranslational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press, New York 1-12 (1983); Seifter et al., Meth. Enzymol. 182: 626-646 (1990); and Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992).


The present invention further provides fragments of the variant proteins in which the fragments contain one or more amino acid sequence variations (e.g., substitutions, or truncations or extensions due to creation or destruction of a stop codon) encoded by one or more SNPs disclosed herein. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that have been disclosed in the prior art before the present invention.


As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14, 16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or more contiguous amino acid residues from a variant protein, wherein at least one amino acid residue is affected by a SNP of the present invention, e.g., a variant amino acid residue encoded by a nonsynonymous nucleotide substitution at a cSNP position provided by the present invention. The variant amino acid encoded by a cSNP may occupy any residue position along the sequence of the fragment. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the variant protein or the ability to perform a function, e.g., act as an immunogen. Particularly important fragments are biologically active fragments. Such fragments will typically comprise a domain or motif of a variant protein of the present invention, e.g., active site, transmembrane domain, or ligand/substrate binding domain. Other fragments include, but are not limited to, domain or motif-containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known to those of skill in the art (e.g., PROSITE analysis) (Current Protocols in Protein Science, John Wiley & Sons, N.Y. (2002)).


Uses of Variant Proteins


The variant proteins of the present invention can be used in a variety of ways, including but not limited to, in assays to determine the biological activity of a variant protein, such as in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another type of immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the variant protein (or its binding partner) in biological fluids; as a marker for cells or tissues in which it is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); as a target for screening for a therapeutic agent; and as a direct therapeutic agent to be administered into a human subject. Any of the variant proteins disclosed herein may be developed into reagent grade or kit format for commercialization as research products. Methods for performing the uses listed above are well known to those skilled in the art (see, e.g., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Sambrook and Russell, 2000, and Methods in Enzymology: Guide to Molecular Cloning Techniques, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987).


In a specific embodiment of the invention, the methods of the present invention include detection of one or more variant proteins disclosed herein. Variant proteins are disclosed in Table 1 and in the Sequence Listing as SEQ ID NOS: 126-250. Detection of such proteins can be accomplished using, for example, antibodies, small molecule compounds, aptamers, ligands/substrates, other proteins or protein fragments, or other protein-binding agents. Preferably, protein detection agents are specific for a variant protein of the present invention and can therefore discriminate between a variant protein of the present invention and the wild-type protein or another variant form. This can generally be accomplished by, for example, selecting or designing detection agents that bind to the region of a protein that differs between the variant and wild-type protein, such as a region of a protein that contains one or more amino acid substitutions that is/are encoded by a non-synonymous cSNP of the present invention, or a region of a protein that follows a nonsense mutation-type SNP that creates a stop codon thereby leading to a shorter polypeptide, or a region of a protein that follows a read-through mutation-type SNP that destroys a stop codon thereby leading to a longer polypeptide in which a portion of the polypeptide is present in one version of the polypeptide but not the other.


In another specific aspect of the invention, the variant proteins of the present invention are used as targets for diagnosing VT or for determining predisposition to VT in a human. Accordingly, the invention provides methods for detecting the presence of, or levels of, one or more variant proteins of the present invention in a cell, tissue, or organism. Such methods typically involve contacting a test sample with an agent (e.g., an antibody, small molecule compound, or peptide) capable of interacting with the variant protein such that specific binding of the agent to the variant protein can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an array, for example, an antibody or aptamer array (arrays for protein detection may also be referred to as “protein chips”). The variant protein of interest can be isolated from a test sample and assayed for the presence of a variant amino acid sequence encoded by one or more SNPs disclosed by the present invention. The SNPs may cause changes to the protein and the corresponding protein function/activity, such as through non-synonymous substitutions in protein coding regions that can lead to amino acid substitutions, deletions, insertions, and/or rearrangements; formation or destruction of stop codons; or alteration of control elements such as promoters. SNPs may also cause inappropriate post-translational modifications.


One preferred agent for detecting a variant protein in a sample is an antibody capable of selectively binding to a variant form of the protein (antibodies are described in greater detail in the next section). Such samples include, for example, tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.


In vitro methods for detection of the variant proteins associated with VT that are disclosed herein and fragments thereof include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), Western blots, immunoprecipitations, immunofluorescence, and protein arrays/chips (e.g., arrays of antibodies or aptamers). For further information regarding immunoassays and related protein detection methods, see Current Protocols in Immunology, John Wiley & Sons, N.Y., and Hage, “Immunoassays”, Anal Chem. 1999 Jun. 15; 71(12):294R-304R.


Additional analytic methods of detecting amino acid variants include, but are not limited to, altered electrophoretic mobility, altered tryptic peptide digest, altered protein activity in cell-based or cell-free assay, alteration in ligand or antibody-binding pattern, altered isoelectric point, and direct amino acid sequencing.


Alternatively, variant proteins can be detected in vivo in a subject by introducing into the subject a labeled antibody (or other type of detection reagent) specific for a variant protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.


Other uses of the variant peptides of the present invention are based on the class or action of the protein. For example, proteins isolated from humans and their mammalian orthologs serve as targets for identifying agents (e.g., small molecule drugs or antibodies) for use in therapeutic applications, particularly for modulating a biological or pathological response in a cell or tissue that expresses the protein. Pharmaceutical agents can be developed that modulate protein activity.


As an alternative to modulating gene expression, therapeutic compounds can be developed that modulate protein function. For example, many SNPs disclosed herein affect the amino acid sequence of the encoded protein (e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Such alterations in the encoded amino acid sequence may affect protein function, particularly if such amino acid sequence variations occur in functional protein domains, such as catalytic domains, ATP-binding domains, or ligand/substrate binding domains. It is well established in the art that variant proteins having amino acid sequence variations in functional domains can cause or influence pathological conditions. In such instances, compounds (e.g., small molecule drugs or antibodies) can be developed that target the variant protein and modulate (e.g., up- or down-regulate) protein function/activity.


The therapeutic methods of the present invention further include methods that target one or more variant proteins of the present invention. Variant proteins can be targeted using, for example, small molecule compounds, antibodies, aptamers, ligands/substrates, other proteins, or other protein-binding agents. Additionally, the skilled artisan will recognize that the novel protein variants (and polymorphic nucleic acid molecules) disclosed in Table 1 may themselves be directly used as therapeutic agents by acting as competitive inhibitors of corresponding art-known proteins (or nucleic acid molecules such as mRNA molecules).


The variant proteins of the present invention are particularly useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can utilize cells that naturally express the protein, a biopsy specimen, or cell cultures. In one embodiment, cell-based assays involve recombinant host cells expressing the variant protein. Cell-free assays can be used to detect the ability of a compound to directly bind to a variant protein or to the corresponding SNP-containing nucleic acid fragment that encodes the variant protein.


A variant protein of the present invention, as well as appropriate fragments thereof, can be used in high-throughput screening assays to test candidate compounds for the ability to bind and/or modulate the activity of the variant protein. These candidate compounds can be further screened against a protein having normal function (e.g., a wild-type/non-variant protein) to further determine the effect of the compound on the protein activity. Furthermore, these compounds can be tested in animal or invertebrate systems to determine in vivo activity/effectiveness. Compounds can be identified that activate (agonists) or inactivate (antagonists) the variant protein, and different compounds can be identified that cause various degrees of activation or inactivation of the variant protein.


Further, the variant proteins can be used to screen a compound for the ability to stimulate or inhibit interaction between the variant protein and a target molecule that normally interacts with the protein. The target can be a ligand, a substrate or a binding partner that the protein normally interacts with (for example, epinephrine or norepinephrine). Such assays typically include the steps of combining the variant protein with a candidate compound under conditions that allow the variant protein, or fragment thereof, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the variant protein and the target, such as any of the associated effects of signal transduction.


Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab′)2, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).


One candidate compound is a soluble fragment of the variant protein that competes for ligand binding. Other candidate compounds include mutant proteins or appropriate fragments containing mutations that affect variant protein function and thus compete for ligand. Accordingly, a fragment that competes for ligand, for example with a higher affinity, or a fragment that binds ligand but does not allow release, is encompassed by the invention.


The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) variant protein activity. The assays typically involve an assay of events in the signal transduction pathway that indicate protein activity. Thus, the expression of genes that are up or down-regulated in response to the variant protein dependent signal cascade can be assayed. In one embodiment, the regulatory region of such genes can be operably linked to a marker that is easily detectable, such as luciferase. Alternatively, phosphorylation of the variant protein, or a variant protein target, could also be measured. Any of the biological or biochemical functions mediated by the variant protein can be used as an endpoint assay. These include all of the biochemical or biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art.


Binding and/or activating compounds can also be screened by using chimeric variant proteins in which an amino terminal extracellular domain or parts thereof, an entire transmembrane domain or subregions, and/or the carboxyl terminal intracellular domain or parts thereof, can be replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than that which is normally recognized by a variant protein. Accordingly, a different set of signal transduction components is available as an end-point assay for activation. This allows for assays to be performed in other than the specific host cell from which the variant protein is derived.


The variant proteins are also useful in competition binding assays in methods designed to discover compounds that interact with the variant protein. Thus, a compound can be exposed to a variant protein under conditions that allow the compound to bind or to otherwise interact with the variant protein. A binding partner, such as ligand, that normally interacts with the variant protein is also added to the mixture. If the test compound interacts with the variant protein or its binding partner, it decreases the amount of complex formed or activity from the variant protein. This type of assay is particularly useful in screening for compounds that interact with specific regions of the variant protein (Hodgson, Bio/technology, 1992, September 10(9), 973-80).


To perform cell-free drug screening assays, it is sometimes desirable to immobilize either the variant protein or a fragment thereof, or its target molecule, to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Any method for immobilizing proteins on matrices can be used in drug screening assays. In one embodiment, a fusion protein containing an added domain allows the protein to be bound to a matrix. For example, glutathione-S-transferase/125I fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g., 35S-labeled) and a candidate compound, such as a drug candidate, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads can be washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of bound material found in the bead fraction quantitated from the gel using standard electrophoretic techniques.


Either the variant protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Alternatively, antibodies reactive with the variant protein but which do not interfere with binding of the variant protein to its target molecule can be derivatized to the wells of the plate, and the variant protein trapped in the wells by antibody conjugation. Preparations of the target molecule and a candidate compound are incubated in the variant protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the protein target molecule, or which are reactive with variant protein and compete with the target molecule, and enzyme-linked assays that rely on detecting an enzymatic activity associated with the target molecule.


Modulators of variant protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the protein pathway, such as VT. These methods of treatment typically include the steps of administering the modulators of protein activity in a pharmaceutical composition to a subject in need of such treatment.


The variant proteins, or fragments thereof, disclosed herein can themselves be directly used to treat a disorder characterized by an absence of, inappropriate, or unwanted expression or activity of the variant protein. Accordingly, methods for treatment include the use of a variant protein disclosed herein or fragments thereof.


In yet another aspect of the invention, variant proteins can be used as “bait proteins” in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993) Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and Brent WO94/10300) to identify other proteins that bind to or interact with the variant protein and are involved in variant protein activity. Such variant protein-binding proteins are also likely to be involved in the propagation of signals by the variant proteins or variant protein targets as, for example, elements of a protein-mediated signaling pathway. Alternatively, such variant protein-binding proteins are inhibitors of the variant protein.


The two-hybrid system is based on the modular nature of most transcription factors, which typically consist of separable DNA-binding and activation domains. Briefly, the assay typically utilizes two different DNA constructs. In one construct, the gene that codes for a variant protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a variant protein-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected, and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein that interacts with the variant protein.


Antibodies Directed to Variant Proteins


The present invention also provides antibodies that selectively bind to the variant proteins disclosed herein and fragments thereof. Such antibodies may be used to quantitatively or qualitatively detect the variant proteins of the present invention. As used herein, an antibody selectively binds a target variant protein when it binds the variant protein and does not significantly bind to non-variant proteins, i.e., the antibody does not significantly bind to normal, wild-type, or art-known proteins that do not contain a variant amino acid sequence due to one or more SNPs of the present invention (variant amino acid sequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPs that create a stop codon, thereby causing a truncation of a polypeptide or SNPs that cause read-through mutations resulting in an extension of a polypeptide).


As used herein, an antibody is defined in terms consistent with that recognized in the art: they are multi-subunit proteins produced by an organism in response to an antigen challenge. The antibodies of the present invention include both monoclonal antibodies and polyclonal antibodies, as well as antigen-reactive proteolytic fragments of such antibodies, such as Fab, F(ab)′2, and Fv fragments. In addition, an antibody of the present invention further includes any of a variety of engineered antigen-binding molecules such as a chimeric antibody (U.S. Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851, 1984; Neuberger et al., Nature 312:604, 1984), a humanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089; and 5,565,332), a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544, 1989), a bispecific antibody with two binding specificities (Segal et al., J. Immunol. Methods 248:1, 2001; Carter, J. Immunol. Methods 248:7, 2001), a diabody, a triabody, and a tetrabody (Todorovska et al., J. Immunol. Methods, 248:47, 2001), as well as a Fab conjugate (dimer or trimer), and a minibody.


Many methods are known in the art for generating and/or identifying antibodies to a given target antigen (Harlow, Antibodies, Cold Spring Harbor Press, (1989)). In general, an isolated peptide (e.g., a variant protein of the present invention) is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit, hamster or mouse. Either a full-length protein, an antigenic peptide fragment (e.g., a peptide fragment containing a region that varies between a variant protein and a corresponding wild-type protein), or a fusion protein can be used. A protein used as an immunogen may be naturally-occurring, synthetic or recombinantly produced, and may be administered in combination with an adjuvant, including but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substance such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and the like.


Monoclonal antibodies can be produced by hybridoma technology (Kohler and Milstein, Nature, 256:495, 1975), which immortalizes cells secreting a specific monoclonal antibody. The immortalized cell lines can be created in vitro by fusing two different cell types, typically lymphocytes, and tumor cells. The hybridoma cells may be cultivated in vitro or in vivo. Additionally, fully human antibodies can be generated by transgenic animals (He et al., J. Immunol., 169:595, 2002). Fd phage and Fd phagemid technologies may be used to generate and select recombinant antibodies in vitro (Hoogenboom and Chames, Immunol. Today 21:371, 2000; Liu et al., J. Mol. Biol. 315:1063, 2002). The complementarity-determining regions of an antibody can be identified, and synthetic peptides corresponding to such regions may be used to mediate antigen binding (U.S. Pat. No. 5,637,677).


Antibodies are preferably prepared against regions or discrete fragments of a variant protein containing a variant amino acid sequence as compared to the corresponding wild-type protein (e.g., a region of a variant protein that includes an amino acid encoded by a nonsynonymous cSNP, a region affected by truncation caused by a nonsense SNP that creates a stop codon, or a region resulting from the destruction of a stop codon due to read-through mutation caused by a SNP). Furthermore, preferred regions will include those involved in function/activity and/or protein/binding partner interaction. Such fragments can be selected on a physical property, such as fragments corresponding to regions that are located on the surface of the protein, e.g., hydrophilic regions, or can be selected based on sequence uniqueness, or based on the position of the variant amino acid residue(s) encoded by the SNPs provided by the present invention. An antigenic fragment will typically comprise at least about 8-10 contiguous amino acid residues in which at least one of the amino acid residues is an amino acid affected by a SNP disclosed herein. The antigenic peptide can comprise, however, at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) or more amino acid residues, provided that at least one amino acid is affected by a SNP disclosed herein.


Detection of an antibody of the present invention can be facilitated by coupling (i.e., physically linking) the antibody or an antigen-reactive fragment thereof to a detectable substance. Detectable substances include, but are not limited to, various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 125I, 131I, 35S or 3H.


Antibodies, particularly the use of antibodies as therapeutic agents, are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,” Expert Rev Vaccines. 2003 February; 2(1):53-9; Ross et al., “Anticancer antibodies,” Am J Clin Pathol. 2003 April; 119(4):472-85; Goldenberg, “Advancing role of radiolabeled antibodies in the therapy of cancer,” Cancer Immunol Immunother. 2003 May; 52(5):281-96. Epub 2003 Mar. 11; Ross et al., “Antibody-based therapeutics in oncology,” Expert Rev Anticancer Ther. 2003 February; 3(1):107-21; Cao et al., “Bispecific antibody conjugates in therapeutics,” Adv Drug Deliv Rev. 2003 Feb. 10; 55(2):171-97; von Mehren et al., “Monoclonal antibody therapy for cancer,” Annu Rev Med. 2003; 54:343-69. Epub 2001 Dec. 3; Hudson et al., “Engineered antibodies,” Nat Med. 2003 January; 9(1):129-34; Brekke et al., “Therapeutic antibodies for human diseases at the dawn of the twenty-first century,” Nat Rev Drug Discov. 2003 January; 2(1):52-62 (Erratum in: Nat Rev Drug Discov. 2003 March; 2(3):240); Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol. 2002 December; 13(6):625-9; Andreakos et al., “Monoclonal antibodies in immune and inflammatory diseases,” Curr Opin Biotechnol. 2002 December; 13(6):615-20; Kellermann et al., “Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics,” Curr Opin Biotechnol. 2002 December; 13(6):593-7; Pini et al., “Phage display and colony filter screening for high-throughput selection of antibody libraries,” Comb Chem High Throughput Screen. 2002 November; 5(7):503-10; Batra et al., “Pharmacokinetics and biodistribution of genetically engineered antibodies,” Curr Opin Biotechnol. 2002 December; 13(6):603-8; and Tangri et al., “Rationally engineered proteins or antibodies with absent or reduced immunogenicity,” Curr Med Chem. 2002 December; 9(24):2191-9.


Uses of Antibodies


Antibodies can be used to isolate the variant proteins of the present invention from a natural cell source or from recombinant host cells by standard techniques, such as affinity chromatography or immunoprecipitation. In addition, antibodies are useful for detecting the presence of a variant protein of the present invention in cells or tissues to determine the pattern of expression of the variant protein among various tissues in an organism and over the course of normal development or disease progression. Further, antibodies can be used to detect variant protein in situ, in vitro, in a bodily fluid, or in a cell lysate or supernatant in order to evaluate the amount and pattern of expression. Also, antibodies can be used to assess abnormal tissue distribution, abnormal expression during development, or expression in an abnormal condition, such as VT. Additionally, antibody detection of circulating fragments of the full-length variant protein can be used to identify turnover.


Antibodies to the variant proteins of the present invention are also useful in pharmacogenomic analysis. Thus, antibodies against variant proteins encoded by alternative SNP alleles can be used to identify individuals that require modified treatment modalities.


Further, antibodies can be used to assess expression of the variant protein in disease states such as in active stages of the disease or in an individual with a predisposition to a disease related to the protein's function, particularly VT. Antibodies specific for a variant protein encoded by a SNP-containing nucleic acid molecule of the present invention can be used to assay for the presence of the variant protein, such as to screen for predisposition to VT as indicated by the presence of the variant protein.


Antibodies are also useful as diagnostic tools for evaluating the variant proteins in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays well known in the art.


Antibodies are also useful for tissue typing. Thus, where a specific variant protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.


Antibodies can also be used to assess aberrant subcellular localization of a variant protein in cells in various tissues. The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting the expression level or the presence of variant protein or aberrant tissue distribution or developmental expression of a variant protein, antibodies directed against the variant protein or relevant fragments can be used to monitor therapeutic efficacy.


The antibodies are also useful for inhibiting variant protein function, for example, by blocking the binding of a variant protein to a binding partner. These uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be used, for example, to block or competitively inhibit binding, thus modulating (agonizing or antagonizing) the activity of a variant protein. Antibodies can be prepared against specific variant protein fragments containing sites required for function or against an intact variant protein that is associated with a cell or cell membrane. For in vivo administration, an antibody may be linked with an additional therapeutic payload such as a radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent. Suitable cytotoxic agents include, but are not limited to, bacterial toxin such as diphtheria, and plant toxin such as ricin. The in vivo half-life of an antibody or a fragment thereof may be lengthened by pegylation through conjugation to polyethylene glycol (Leong et al., Cytokine 16:106, 2001).


The invention also encompasses kits for using antibodies, such as kits for detecting the presence of a variant protein in a test sample. An exemplary kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample; means for determining the amount, or presence/absence of variant protein in the sample; means for comparing the amount of variant protein in the sample with a standard; and instructions for use.


Vectors and Host Cells


The present invention also provides vectors containing the SNP-containing nucleic acid molecules described herein. The term “vector” refers to a vehicle, preferably a nucleic acid molecule, which can transport a SNP-containing nucleic acid molecule. When the vector is a nucleic acid molecule, the SNP-containing nucleic acid molecule can be covalently linked to the vector nucleic acid. Such vectors include, but are not limited to, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, or MAC.


A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the SNP-containing nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the SNP-containing nucleic acid molecules when the host cell replicates.


The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the SNP-containing nucleic acid molecules. The vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors).


Expression vectors typically contain cis-acting regulatory regions that are operably linked in the vector to the SNP-containing nucleic acid molecules such that transcription of the SNP-containing nucleic acid molecules is allowed in a host cell. The SNP-containing nucleic acid molecules can also be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the SNP-containing nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.


The regulatory sequences to which the SNP-containing nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.


In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.


In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region, a ribosome-binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. A person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors (see, e.g., Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).


A variety of expression vectors can be used to express a SNP-containing nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example, vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors can also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g., cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.


The regulatory sequence in a vector may provide constitutive expression in one or more host cells (e.g., tissue specific expression) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor, e.g., a hormone or other ligand. A variety of vectors that provide constitutive or inducible expression of a nucleic acid sequence in prokaryotic and eukaryotic host cells are well known to those of ordinary skill in the art.


A SNP-containing nucleic acid molecule can be inserted into the vector by methodology well-known in the art. Generally, the SNP-containing nucleic acid molecule that will ultimately be expressed is joined to an expression vector by cleaving the SNP-containing nucleic acid molecule and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.


The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial host cells include, but are not limited to, E. coli, Streptomyces, and Salmonella typhimurium. Eukaryotic host cells include, but are not limited to, yeast, insect cells such as Drosophila, animal cells such as COS and CHO cells, and plant cells.


As described herein, it may be desirable to express the variant peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the variant peptides. Fusion vectors can, for example, increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting, for example, as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired variant peptide can ultimately be separated from the fusion moiety. Proteolytic enzymes suitable for such use include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).


Recombinant protein expression can be maximized in a bacterial host by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein (Gottesman, S., Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990) 119-128). Alternatively, the sequence of the SNP-containing nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example, E. coli (Wada et al., Nucleic Acids Res. 20:2111-2118 (1992)).


The SNP-containing nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari, et al., EMBO J. 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943 (1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).


The SNP-containing nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., Mol. Cell. Biol. 3:2156-2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)).


In certain embodiments of the invention, the SNP-containing nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (Seed, B. Nature 329:840 (1987)) and pMT2PC (Kaufman et al., EMBO J. 6:187-195 (1987)).


The invention also encompasses vectors in which the SNP-containing nucleic acid molecules described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to the SNP-containing nucleic acid sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).


The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.


The recombinant host cells can be prepared by introducing the vector constructs described herein into the cells by techniques readily available to persons of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those described in Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).


Host cells can contain more than one vector. Thus, different SNP-containing nucleotide sequences can be introduced in different vectors into the same cell. Similarly, the SNP-containing nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the SNP-containing nucleic acid molecules, such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced, or joined to the nucleic acid molecule vector.


In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication can occur in host cells that provide functions that complement the defects.


Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be inserted in the same vector that contains the SNP-containing nucleic acid molecules described herein or may be in a separate vector. Markers include, for example, tetracycline or ampicillin-resistance genes for prokaryotic host cells, and dihydrofolate reductase or neomycin resistance genes for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait can be effective.


While the mature variant proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these variant proteins using RNA derived from the DNA constructs described herein.


Where secretion of the variant protein is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as G-protein-coupled receptors (GPCRs), appropriate secretion signals can be incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.


Where the variant protein is not secreted into the medium, the protein can be isolated from the host cell by standard disruption procedures, including freeze/thaw, sonication, mechanical disruption, use of lysing agents, and the like. The variant protein can then be recovered and purified by well-known purification methods including, for example, ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.


It is also understood that, depending upon the host cell in which recombinant production of the variant proteins described herein occurs, they can have various glycosylation patterns, or may be non-glycosylated, as when produced in bacteria. In addition, the variant proteins may include an initial modified methionine in some cases as a result of a host-mediated process.


For further information regarding vectors and host cells, see Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.


Uses of Vectors and Host Cells, and Transgenic Animals


Recombinant host cells that express the variant proteins described herein have a variety of uses. For example, the cells are useful for producing a variant protein that can be further purified into a preparation of desired amounts of the variant protein or fragments thereof. Thus, host cells containing expression vectors are useful for variant protein production.


Host cells are also useful for conducting cell-based assays involving the variant protein or variant protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a variant protein is useful for assaying compounds that stimulate or inhibit variant protein function. Such an ability of a compound to modulate variant protein function may not be apparent from assays of the compound on the native/wild-type protein, or from cell-free assays of the compound. Recombinant host cells are also useful for assaying functional alterations in the variant proteins as compared with a known function.


Genetically-engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a non-human mammal, for example, a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA containing a SNP of the present invention which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more of its cell types or tissues. Such animals are useful for studying the function of a variant protein in vivo, and identifying and evaluating modulators of variant protein activity. Other examples of transgenic animals include, but are not limited to, non-human primates, sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-human mammals such as cows and goats can be used to produce variant proteins which can be secreted in the animal's milk and then recovered.


A transgenic animal can be produced by introducing a SNP-containing nucleic acid molecule into the male pronuclei of a fertilized oocyte, e.g., by microinjection or retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any nucleic acid molecules that contain one or more SNPs of the present invention can potentially be introduced as a transgene into the genome of a non-human animal.


Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the variant protein in particular cells or tissues.


Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described in, for example, U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No. 4,873,191 by Wagner et al., and in Hogan, B., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes a non-human animal in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.


In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1 (Lakso et al. PNAS 89:6232-6236 (1992)). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae (O'Gorman et al. Science 251:1351-1355 (1991)). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are generally needed. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected variant protein and the other containing a transgene encoding a recombinase.


Clones of the non-human transgenic animals described herein can also be produced according to the methods described in, for example, Wilmut, I. et al. Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter Go phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell (e.g., a somatic cell) is isolated.


Transgenic animals containing recombinant cells that express the variant proteins described herein are useful for conducting the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could influence ligand or substrate binding, variant protein activation, signal transduction, or other processes or interactions, may not be evident from in vitro cell-free or cell-based assays. Thus, non-human transgenic animals of the present invention may be used to assay in vivo variant protein function as well as the activities of a therapeutic agent or compound that modulates variant protein function/activity or expression. Such animals are also suitable for assessing the effects of null mutations (i.e., mutations that substantially or completely eliminate one or more variant protein functions).


For further information regarding transgenic animals, see Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol. 2002 December; 13(6):625-9; Petters et al., “Transgenic animals as models for human disease,” Transgenic Res. 2000; 9(4-5):347-51; discussion 345-6; Wolf et al., “Use of transgenic animals in understanding molecular mechanisms of toxicity,” J Pharm Pharmacol. 1998 June; 50(6):567-74; Echelard, “Recombinant protein production in transgenic animals,” Curr Opin Biotechnol. 1996 October; 7(5):536-40; Houdebine, “Transgenic animal bioreactors,” Transgenic Res. 2000; 9(4-5):305-20; Pirity et al., “Embryonic stem cells, creating transgenic animals,” Methods Cell Biol. 1998; 57:279-93; and Robl et al., “Artificial chromosome vectors and expression of complex proteins in transgenic animals,” Theriogenology. 2003 Jan. 1; 59(1):107-13.


EXAMPLES

The following examples are offered to illustrate, but not to limit, the claimed invention.


Example One
SNPs Associated with Deep Vein Thrombosis

Introduction


To identify SNPs associated with DVT, 19,682 SNPs (which were primarily missense SNPs) were investigated for association with DVT in three large case-control studies.


Methods


Study Populations and Data Collection


The 3 studies (LETS, MEGA-1 and MEGA-2) in the present analysis are derived from 2 large population-based case-control studies: the Leiden Thrombophilia Study (LETS) and the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study) (Koster et al., Lancet 1993; 342(8886-8887):1503-1506 and Blom et al., JAMA 2005; 293(6):715-722). These studies were approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, The Netherlands. All participants gave informed consent to participate.


LETS Population


Collection and ascertainment of DVT events in LETS has been described previously (Koster et al., Lancet 1993; 342(8886-8887):1503-1506). Briefly, 474 consecutive patients, 70 years or younger, without a known malignancy were recruited between Jan. 1, 1988 and Dec. 30, 1992 from 3 anticoagulation clinics in The Netherlands. For each patient, an age- and sex-matched control participant without a history of DVT was enrolled. Participants completed a questionnaire on risk factors for DVT and provided a blood sample. No ethnicity information was collected. After exclusion of 52 participants due to inadequate sample, 443 cases and 453 controls remained in the analyses.


MEGA-1 and MEGA-2 Studies


Collection and ascertainment of DVT events in MEGA has been described previously (Blom et al., JAMA 2005; 293(6):715-722; van Stralen et al., Arch Intern Med 2008; 168(1):21-26). MEGA enrolled consecutive patients aged 18 to 70 years who presented with their first diagnosis of DVT or pulmonary embolism (PE) at any of 6 anticoagulation clinics in The Netherlands between Mar. 1, 1999 and May 31, 2004. Control subjects included partners of patients and random population control subjects frequency-matched on age and sex to the patient group. Participants completed a questionnaire on risk factors for DVT and provided a blood or buccal swab sample. The questionnaire included an item on parent birth country as a proxy for ethnicity.


For the present analyses, the MEGA study was split to form 2 case-control studies, based on recruitment date and sample availability (blood or buccal swab). Individuals with isolated pulmonary embolism or a history of malignant disorders were excluded in order to obtain a study population similar to the LETS population. The first subset of MEGA, “MEGA-1”, included 1398 cases and 1757 controls who had all donated blood samples. The remaining 1314 cases and 2877 controls, who donated either a blood sample or a buccal swab sample, were included in “MEGA-2”.


Baseline characteristics of the participants in the studies described above are presented in Table 5.


SNP Association Study


The 19,682 SNPs tested in this study are located in 10,887 genes and were selected because of their potential to affect gene function or expression (Shiffman et al., Am J Hum Genet. 2005; 77(4):596-605). Most SNPs (69%) are missense. Another 24% of the SNPs are located in transcription factor binding sites or in untranslated regions of mRNA, which could affect mRNA expression or stability. 91% of the SNPs studied have minor allele frequencies ≧5% in whites.


The design of the SNP association study is presented in FIG. 1. First, all 19,682 SNPs were tested in pooled DNA samples of LETS. SNPs that were associated with DVT (P≦0.05) were tested in pooled DNA samples of MEGA-1. SNPs that were associated in both LETS and MEGA-1 pools (P≦0.05) were confirmed by genotyping individual samples of LETS and MEGA-1. SNP genotypes consistently associated with DVT in LETS and MEGA-1 (P≦0.05) were genotyped in MEGA-2.


Allele Frequency and Genotype Determination


DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes, Invitrogen Corp, Carlsbad, Calif.) fluorescent dye. DNA pools, typically of 30-100 samples, were assembled based on case-control status, sex, age and factor V Leiden status. DNA pools were made by mixing equal volumes of standardized DNA solution from each individual sample. Each allele was amplified separately by PCR using 3 ng of pooled DNA. In the pooled stage, 6 case pools and 4 control pools were used for LETS, and 13 case pools and 18 control pools were used for MEGA-1. Allele frequencies in pooled DNA were determined by kinetic polymerase chain reaction (kPCR) (Germer et al., Genome Res 2000; 10(2):258-266). Duplicate kPCR assays were run for each allele and the amplification curves from these assays were used to calculate the allele frequencies of the SNP (Germer et al., Genome Res 2000; 10(2):258-266). Genotyping of individual DNA samples was similarly performed using 0.3 ng of DNA in kPCR assays or using multiplexed oligo ligation assays (OLA) (Shiffman et al., Arterioscler Thromb Vasc Biol 2008; 28(1):173-179). Genotyping accuracy of the multiplex methodology and kPCR has been assessed in 3 previous studies and the overall concordance of the genotype calls from these two methods was >99% (Shiffman et al., Am J Hum Genet 2005; 77(4):596-605; Iakoubova et al., Arterioscler Thromb Vasc Biol 2006; 26(12):2763-2768; and Shiffman et al., Arterioscler Thromb Vasc Biol 2006; 26(7):1613-1618). The SNPs associated with DVT in MEGA-2 were successfully genotyped in >95% of the subjects in LETS, MEGA-1 and MEGA-2.


Gene Variants and DVT Risk in the CYP4V2 Region


The rs13146272 SNP in the gene CYP4V2 was most strongly associated with DVT in the SNP association study. To investigate whether other SNPs in this region are associated with DVT, results from the HapMap Project were used to identify a region surrounding rs13146272 (chr 4:187, 297,249-187,467,731) (Nature 2005; 437(7063):1299-1320). This region contained 149 SNPs with allele frequencies >2% (HapMap NCBI build 36). Allele frequencies and linkage disequilibrium were calculated from the SNP genotypes in the HapMap CEPH population, which includes Utah residents with ancestry from northern and western Europe. 48 of these 149 SNPs were selected for genotyping, as surrogates for 142 of the 149 SNPs in this region that were either directly genotyped or in strong linkage disequilibrium (r2>0.8) with at least one of the 48 genotyped SNPs (the remaining 7 of the 149 SNPs were in low linkage disequilibrium with rs13146272 (r2<0.2) and therefore not likely to be the cause of the observed association). The 48 SNPs were chosen using pairwise tagging in Tagger (implemented in Haploview) (Barrett et al., Bioinformatics 2005; 21(2):263-265).


The 48 SNPs were initially investigated in LETS, and SNPs that were equally or more strongly associated with DVT than rs13146272 were investigated in MEGA-1.


Factor XI Assays


Factor XI antigen measurements in LETS were described previously (Meijers et al., N Engl J Med 2000; 342(10):696-701). In MEGA, factor XI levels were measured on a STA-R coagulation analyzer (Diagnostica Stago, Asnieres, France). STA CaCl2 solution was used as an activator, STA Unicalibrator was used as a reference standard and Preciclot plus I (normal factor XI range) was used as control plasma. The intra-assay coefficient of variation (CV) was 5.8% (10 assays). The inter-assay CV was 8.7% (48 assays).


Statistical Analysis


Deviations from Hardy-Weinberg expectations were assessed using an exact test in controls (Weir, Genetic Data Analysis II Sunderland: Sinauer Associates Inc 1996). For pooled DNA analysis, a Fisher's exact test was used to evaluate allele frequency differences between cases and controls. For the final set of SNPs presented in Table 6, logistic regression models were used to calculate the odds ratio (OR), 95% confidence interval (95% CI) and 2-sided P-value for the association of each SNP with DVT and to adjust for age and sex. For each SNP, the OR per genotype relative to non-carriers of the risk allele, and the risk allele OR from an additive model, were calculated. This risk allele OR can be interpreted as the risk increase per copy of the risk allele, and the corresponding P-value was used to decide whether the SNP was associated with DVT (P≦0.05). For SNPs on the X chromosome the analysis was conducted separately in men and women.


The OR (95% CI) for SNPs in the CYP4V2 region was estimated by logistic regression with adjustment for factor XI levels and other SNPs in the region. Differences in factor XI level between groups were tested with t-tests, and changes in factor XI level per allele were estimated by linear regression. Analyses were done with SAS version 9 and SPSS for Windows, 14.0.2 (SPSS Inc, Chicago, Ill.).


False Discovery Rate


Studies of thousands of SNPs can lead to false-positive associations. Therefore, 2 replications were performed after the initial discovery stage in LETS and the false discovery rate was calculated for the SNPs genotyped in MEGA-2. The false discovery rate estimates the expected fraction of false positives among a group of SNPs; and is a function of the P-values and the number of tests (Benjamini et al., Journal of the Royal Statistical Society 1995; (Serials B(57)):1289-1300). False discovery rates were estimated using the 2-sided, unadjusted P-value from the additive model. A false discovery rate of 0.10 was used as a criterion for further analysis (for a false discovery rate of 0.10, one would expect 10% of the SNPs in the group considered associated to be false positives).


Results


SNPs Associated with DVT in LETS and MEGA-1


In LETS19,682 SNPs were investigated by comparing the allele frequencies of patients and controls using pooled DNA samples (Germer et al., Genome Res 2000; 10(2):258-266). It was found that 1206 of these 19,682 SNPs were associated (P≦0.05) with DVT. These 1206 SNPs were then investigated in patients and controls from MEGA-1 using pooled DNA samples. SNPs that were associated with DVT in both LETS and MEGA-1 were confirmed by genotyping in both studies, and it was found that 18 SNPs were consistently (with the same risk allele) associated with DVT (P≦0.05) in both LETS and MEGA-1 (Table 6).


SNPs Associated with DVT in MEGA-2


Nine of these 18 SNPs were subsequently tested in MEGA-2 for association with DVT (Table 7); assays for the other 9 SNPs were not available at the time. The genotypes of these 9 SNPs did not deviate from Hardy-Weinberg equilibrium (P≦0.01) in the LETS and MEGA controls.


To account for the many tests, the false discovery rate was estimated for the SNPs tested in MEGA-2. In Table 6, factor V Leiden and the prothrombin G20210A mutation are presented for reference, but since these variants were not included in the SNP association study, their false discovery rate was not calculated. For the SNP in F9 (rs6048), only men were included because no association with DVT was observed in women in LETS and MEGA-1. It was found that 3 SNPs were again associated with DVT in MEGA-2 (P<0.05), with false discovery rates ≦0.10. These 3 SNPs were in the genes CYP4V2, SERPINC1 and GP6. The 4 SNPs with the next lowest P-values (ranging from 0.06 to 0.15) also had low false discovery rates (≦0.20). These SNPs were in the genes RGS7, NR1I2, NAT8B and F9. The risk allele frequencies for these 7 SNPs ranged from 10% to 82% among the controls. The OR for homozygous carriers, compared with homozygotes of the other allele, ranged from 1.19 to 1.49. The 2 SNPs most strongly associated with DVT were in CYP4V2 (rs13146272, P<0.001, false discovery rate 0.0006) and SERPINC1 (rs2227589, P<0.001, false discovery rate 0.004).


For the two SNPs on chromosome 1 (rs2227589 and rs670659), linkage disequilibrium with the factor V Leiden (FVL) variant was investigated. The SNP (rs2227589) in SERPINC1, which encodes antithrombin, is 4.37 megabases away from the FVL variant. The SNP in RGS7 (rs670659) is 71.48 megabases from FVL. Each was in weak linkage-disequilibrium with FVL (r2<0.01). Restricting analyses to non-carriers of FVL did not appreciably change the risk estimate of either SNP.


SNPs in CYP4V2 Region and DVT Risk


The SNP with the strongest association with DVT was rs13146272, located in the gene encoding a member of the cytochrome P450 family 4 (CYP4V2). 48 SNPs in this region were genotyped in the LETS population and the OR for DVT per copy of the risk-increasing allele was estimated. For many of the 48 SNPs, including rs13146272, the common allele was the risk allele. In LETS, rs13146272 had an OR for DVT of 1.22 (95% CI, 1.00-1.49). Higher ORs were observed for 9 of the other SNPs tested in this region. These SNPs were located in the CYP4V2, KLKB1 (coding for prekallikrein) and F11 (coding for coagulation factor XI) genes.


9 of the 48 SNPs that had an OR>1.22 (the OR of rs13146272) were then selected and investigated in MEGA-1. It was found that 5 of these SNPs were associated with DVT in both LETS and MEGA-1: rs13146272, rs3087505, rs3756008, rs2036914 and rs4253418 (Table 8). The rs3087505 SNP in KLKB1 had the highest risk estimate: OR 3.61 (95% CI, 1.48-8.82) for the major allele homozygotes versus minor allele homozygotes. Mutual adjustment among these 5 SNPs did not indicate that any of these 5 associations were explained by the other 4 SNPs.


SNPs in CYP4V2 Region and Factor XI Levels


Because the F11 gene is located close to rs13146272 and because factor XI levels have been previously reported to be associated with DVT in the LETS population, it was investigated whether an association between SNPs and factor XI levels explained the association between the SNPs and DVT (Meijers et al., N Engl J Med 2000; 342(10):696-701). In LETS, factor XI levels above the 90th percentile had been shown to be associated with a 2-fold increased risk of DVT (Meijers et al., N Engl J Med 2000; 342(10):696-701). It was found that high factor XI levels (>90th percentile) were also associated with DVT in MEGA (OR1.9, 95% CI, 1.6-2.3).


Only 9 of the 18 stage 3 SNPs were indeed tested in MEGA-2 DNA in stage 4. The reason for this was that in order to save MEGA-2 DNA, stage 4 SNPs were genotyped using multiplexed oligo ligation assays, and assays for only 9 stage 3 SNPs were available at the time of this study.


The 7 SNPs from the CYP4V2 region that were associated with DVT were all associated with factor XI levels in LETS and MEGA-1, with higher factor XI levels for those who carried the risk-increasing alleles (Table 8). It was investigated whether factor XI levels mediate the association between these 5 SNPs and DVT by adjusting for factor XI levels in the combined LETS and MEGA-1 studies. For all 5 SNPs, adjustment for factor XI levels weakened the association with DVT but none of the associations disappeared. Interestingly, the 5 SNPs that were not associated with DVT in the combined analysis of LETS and MEGA-1 (rs3736456, rs4253259, rs4253408, rs4253325 and rs3775302) were also not associated with factor XI levels in LETS.


All analyses were performed with and without adjustment for age and sex, and analyses in MEGA-1 and MEGA-2 were performed with and without restriction to the group with both parents born in North-West Europe. As neither influenced the results, the unadjusted OR is presented.


Discussion


7 SNPs were identified that were associated with DVT in 3 large, well characterized populations including 3155 cases and 5087 controls. The evidence was strongest for the 3 SNPs in CYP4V2, SERPINC1 and GP6. It is interesting to note that these SNPs are in or near genes that have a clear role in blood coagulation.


Testing 19,682 SNPs will result in false positive associations. Therefore, the SNPs were investigated in 3 large studies and the false discovery rate for the SNPs tested was estimated in the third study. The three SNPs in CYP4V2, SERPINC1 and GP6, were associated with DVT with a false discovery rate <10%, which means that <10% of these 3 SNPs would be expected to be false positive. Relaxing the false discovery rate to <20% would add 4 SNPs, in RGS7, NR1I2, NAT8B, and F9 as associated with DVT.


The 3 SNPs with the strongest evidence for association with DVT were in CYP4V2, SERPINC1, and GP6. CYP4V2 encodes a member of the CYP450 family 4 that is not known to be related to thrombosis (Lee et al., Invest Ophthalmol Vis Sci 2001; 42(8):1707-1714 and Li et al., Am J Hum Genet 2004; 74(5):817-826). CYP4V2 is located on chromosome 4 in a region containing genes encoding coagulation proteins prekallikrein (KLKB1) and factor XI (F11). 4 other SNPs in the CYPV42/KLKB1/F11 locus were also identified as being associated with DVT. No previous reports exist for an association of genetic variants in CYP4V2 and KLKB1 with DVT. There exists no evidence for an association between prekallikrein levels and DVT, while there is for elevated factor XI levels (Souto et al., Am J Hum Genet 2000; 67(6):1452-1459; Meijers et al., N Engl J Med 2000; 342(10):696-701; and Gallimore et al., Thromb Res 2004; 114(2):91-96).


SERPINC1 encodes antithrombin, a serine protease inhibitor located on chromosome 1 that plays a central role in natural anticoagulation. Deficiencies of antithrombin are rare but result in a strong thrombotic tendency (Gallimore et al., Thromb Res 2004; 114(2):91-96). The SNP in SERPINC1 (rs2227589) had a minor allele frequency of 10% in the controls and was associated with a modest thrombotic tendency. GP6 encodes glycoprotein VI, a 58-kD platelet membrane glycoprotein that plays a crucial role in the collagen-induced activation and aggregation of platelets and may play a role in DVT (Massberg et al., J Exp Med 2003; 197(1):41-49 and Chung et al., J Thromb Haemost 2007; 5(5):918-924).


The SNPs in the genes F9, NR1I2, RGS7 and NAT8B are of interest. F9 encodes factor IX, a vitamin K-dependent clotting factor, of which high levels have been shown to increase the risk of DVT (van Hylckama Vlieg et al., Blood 2000; 95(12):3678-3682). The SNP rs6048, also known as F9 Malmö, is a common polymorphism at the third amino acid residue of the activation peptide of factor IX (McGraw et al., Proc Natl Acad Sci USA 1985; 82(9):2847-2851).


The SNP in CYP4V2 (rs13146272) is located close to the gene encoding coagulation factor XI. Factor XI levels have been reported to be associated with DVT in LETS and in a large analysis of pedigrees (Souto et al., Am J Hum Genet 2000; 67(6):1452-1459 and Meijers et al., N Engl J Med 2000; 342(10):696-701). The association between DVT and factor XI levels was confirmed in MEGA. Interestingly, the 5 SNPs in the CYP4V2 region that were associated with DVT in both LETS and MEGA-1 were also associated with factor XI levels. However, the association between these 5 SNPs and DVT does not seem to be completely explained by variation in factor XI levels because adjusting for factor XI level did not remove the excess DVT risk of these 5 SNPs. Thus, if only part of the risk associated with these genetic variants is mediated through levels of factor XI, some of the risk might also be due to effects on protein function.


Several variants in the F11 gene (rs5974, rs5970, rs5971, rs5966, rs5976, and rs5973) were previously tested for association with factor XI levels in patients with DVT and atherosclerosis, but no relationship was observed (Gerdes et al., J Thromb Haemost 2004; 2(6):1015-1017). In the present study, rs5974 (r2=1.0 with 5970) and rs5971 (r2=1.0 with 5966 and rs5976) were not associated with DVT in LETS. rs5973 was not genotyped because its minor allele frequency was lower than 2% (HapMap CEPH population). In a study of West African volunteers, rs3822056 and rs3733403 were associated with transcription factor binding affinity and slightly increased factor XI levels, but neither SNP was associated with DVT in LETS. In a study among white postmenopausal women, rs3822057 and rs2289252 were associated with DVT (Tarumi et al., J Thromb Haemost 2003; 1(8):1854-1856 and Smith et al., JAMA 2007; 297(5):489-498). Both of these associations were indirectly confirmed in the present study because 2 of the 5 SNPs in the CYPV42 region that were consistently associated with DVT and factor XI levels are in linkage disequilibrium with rs3822057 (r2=0.9 with rs2036914) and rs2289252 (r2=0.8 with rs3756008).


Since the variants described herein are common, they may be particularly useful markers for determining DVT risk, especially when combined with other risk factors.


This analysis was limited to a North-West European population. In LETS, no information on ethnicity was collected. However, it is thought that population stratification did not bias the results because MEGA participants were recruited from the same population as LETS but 10 years later and 90% of MEGA had both parents born in North-West Europe. Furthermore, restricting the analyses to this 90% of MEGA did not modify the results.


Conclusions


Thousands of SNPs were tested for association with DVT in unrelated individuals, and 7 of these SNPs were found to be consistently associated with DVT risk. In the CYP4V2 region, several SNPs were identified that were associated with both DVT and factor XI levels.









TABLE 5







Characteristics of Cases and Controls in LETS, MEGA-1, and MEGA-2











LETS
MEGA-1
MEGA-2














Cases
Controls
Cases
Controls
Cases
Controls



(n = 443)
(n = 453)
(n = 1398)
(n = 1757)
(n = 1314)
(n = 2877)

















Men, No. (%)
190 (43)
192 (42)
 652 (47)
 843 (48)
 633 (48)
1348 (47)


Age, Mean (SD)
 45 (14)
 45 (14)
 47 (13)
 48 (12)
 48 (13)
 47 (12)


Both parents born


1247 (91)
1609 (92)
1149 (90)
2527 (89)


in North-West


Europe, N (%)a






aNo information on birth country was collected in LETS.














TABLE 6







Association of 18 SNPs from the SNP association study and factor V


Leiden and prothrombin G20210A with DVT in LETS and MEGA-1.










Risk allele

















Chr
Gene
SNP ID
SNP Typea
Study

Case (%)
Control (%)
ORb (95% CI)
P-Value



















3
NR1I2
rs1523127
5′UTR
LETS
C
 373 (42)
 300 (33)
1.44 (1.19-1.73)
<.001






MEGA-1

1185 (42)
1373 (39)
1.15 (1.04-1.27)
.008


19 
GP6
rs1613662
Ser219Pro
LETS
A
 749 (85)
 725 (80)
1.36 (1.07-1.74)
.01






MEGA-1

2318 (84)
2823 (81)
1.21 (1.06-1.38)
.004


17 
APOH
rs1801690
Ser335Trp
LETS
C
 850 (97)
 852 (95)
1.65 (1.02-2.68)
.04






MEGA-1

2676 (96)
3312 (94)
1.42 (1.12-1.79)
.004


2
NAT8B
rs2001490
Ala112Gly
LETS
C
 382 (43)
 348 (38)
1.23 (1.01-1.49)
.04






MEGA-1

1118 (40)
1301 (37)
1.14 (1.03-1.26)
.01


1
SERPINC1
rs2227589
Intronic
LETS
T
 105 (12)
 78 (9)
1.42 (1.04-1.94)
.03






MEGA-1

 303 (11)
313 (9)
1.24 (1.05-1.47)
.01


7
MET
rs2237712
Intronic
LETS
G
 45 (5)
 27 (3)
1.68 (1.05-2.70)
.03






MEGA-1

119 (4)
110 (3)
1.38 (1.06-1.80)
.02


11 
EPS8L2
rs3087546
Leu101Leu
LETS
T
 522 (60)
 487 (54)
1.26 (1.04-1.52)
.02






MEGA-1

1637 (59)
1964 (56)
1.12 (1.01-1.24)
.03


6
CASP8AP2
rs369328
Lys93Lys
LETS
A
 461 (52)
 406 (45)
1.35 (1.11-1.63)
.002






MEGA-1

1420 (51)
1680 (48)
1.13 (1.02-1.24)
.02


1
SELP
rs6131
Asn331Ser
LETS
T
 196 (22)
 161 (18)
1.29 (1.03-1.62)
.03






MEGA-1

 589 (21)
 636 (18)
1.21 (1.06-1.36)
.003


19 
ZNF544
rs6510130
Asp203His
LETS
G
 33 (4)
 13 (1)
2.54 (1.34-4.83)
.004






MEGA-1

 78 (3)
 64 (2)
1.56 (1.11-2.18)
.01


1
RGS7
rs670659
Intronic
LETS
C
 617 (70)
 584 (64)
1.27 (1.04-1.54)
.02






MEGA-1

1864 (67)
2249 (64)
1.13 (1.01-1.25)
.03


2
TACR1
rs881
3′UTR
LETS
C
 745 (85)
 713 (80)
1.38 (1.07-1.77)
.01






MEGA-1

2356 (85)
2894 (83)
1.15 (1.01-1.32)
.04


4
CYP4V2
rs13146272
Lys259Gln
LETS
A
 611 (69)
 588 (65)
1.22 (1.00-1.49)
.05






MEGA-1

1896 (68)
2245 (64)
1.19 (1.07-1.32)
.001


1
F5
rs4524
Arg858Lys
LETS
T
 708 (80)
 671 (74)
1.36 (1.09-1.69)
.006






MEGA-1

2184 (79)
2608 (74)
1.26 (1.12-1.42)
<.001


1
SMOYKEEBO/F5
rs6016
Ile736Ile
LETS
G
 704 (80)
 668 (74)
1.35 (1.09-1.69)
.006






MEGA-1

2188 (79)
2615 (75)
1.27 (1.13-1.43)
<.001


1
C1orf114
rs3820059
Ser172Phe
LETS
A
 320 (36)
 269 (30)
1.34 (1.10-1.64)
.004






MEGA-1

1065 (38)
1169 (33)
1.22 (1.10-1.35)
<.001


X
F9
rs6048
Ala194Thr
LETS Men
A
 146 (77)
 128 (67)
1.74 (1.10-2.74)
.02






LETS Women

 225 (70)
 238 (68)
1.09 (0.84-1.42)
.50






MEGA-1 Men

 464 (73)
 566 (68)
1.26 (1.00-1.58)
.05






MEGA-1

 674 (72)
 818 (71)
1.04 (0.90-1.21)
.61






Women


X
ODZ1
rs2266911
Intronic
LETS Men
C
 161 (85)
 147 (77)
1.66 (0.99-2.79)
.06






LETS Women

 422 (83)
 418 (80)
1.26 (0.91-1.73)
.17






MEGA-1 Men

 556 (85)
 671 (80)
1.47 (1.12-1.94)
.006






MEGA-1

1234 (82)
1430 (78)
1.25 (1.05-1.48)
.01






Women


1
F5 (Leiden)
rs6025
Arg534Gln
LETS
A
 95 (11)
 14 (2)
7.19 (4.05-(12.77)
<.001






MEGA-1

 291 (10)
 96 (3)
4.10 (3.23-5.21)
<.001


11 
F2 (G20210A)
rs1799963
3′UTR
LETS
A
 28 (3)
 10 (1)
2.98 (1.43-6.20)
<.001






MEGA-1

 81 (3)
 37 (1)
2.89 (1.94-4.29)
<.001





Chr denotes chromosome number.


All gene symbols, rs numbers, SNP types and chromosome numbers are from NCBI build 36.



aThe first amino acid corresponds to the non risk allele.




bOR were estimated by logistic regression using an additive model. Sex was included as a covariate in logistic regression models containing markers residing on the X chromosome and the number of risk alleles for these SNPs were coded as 0 or 1 for males and 0, 1 or 2 for females.














TABLE 7







Associations of SNPs from the SNP Association Study With Deep Vein Thrombosis in MEGA-2
















Chr
Gene
SNP
Risk allelea
Genotypeb
Case, N (%)c
Control, N (%)c
OR (95% CI)
P value
FDRd






















4
CYP4V2
rs13146272
A
CC
121
(10)
352
(13)
1
(ref)








CA
478
(41)
1178
(45)
1.18
(0.94-1.49)






AA
561
(48)
1094
(42)
1.49
(1.19-1.88)






Additive

(69)

(64)
1.24
(1.11-1.37)
<.001
<.001


1
SERPINC1
rs2227589
T
CC
1001
(77)
2325
(82)
1
(ref)






CT
278
(21)
483
(17)
1.34
(1.13-1.58)






TT
15
(1)
28
(1)
1.24
(0.66-2.34)






Additive

(12)

(11)
1.29
(1.10-1.49)
<.001
0.004


19 
GP6
rs1613662
A
GG
29
(2)
89
(3)
1
(ref)






GA
355
(27)
835
(29)
1.31
(0.84-2.02)






AA
915
(70)
1924
(68)
1.46
(0.95-2.24)






Additive

(84)

(82)
1.15
(1.01-1.30)
0.03
0.10


1
RGS7
rs670659
C
TT
129
(10)
355
(13)
1
(ref)






TC
615
(48)
1326
(47)
1.28
(1.02-1.60)






CC
548
(42)
1153
(41)
1.31
(1.04-1.64)






Additive

(66)

(64)
1.10
(1.00-1.22)
0.06
0.13


3
NR1I2
rs1523127
C
AA
480
(37)
1097
(39)
1
(ref)






AC
598
(46)
1340
(47)
1.02
(0.88-1.18)






CC
220
(17)
409
(14)
1.23
(1.01-1.50)






Additive

(40)

(38)
1.09
(0.99-1.20)
0.07
0.13


2
NAT8B
rs2001490
C
GG
490
(38)
1122
(39)
1
(ref)






GC
603
(46)
1334
(47)
1.04
(0.90-1.19)






CC
205
(16)
394
(14)
1.19
(0.98-1.45)






Additive

(39)

(37)
1.08
(0.98-1.19)
0.12
0.18


X
F9 (men)
rs6048
A
Additive

(73)

(70)
1.17
(0.94-1.445)
0.15
0.20


X
F9 (women)
rs6048
A
GG
56
(8)
148
(10)
1
(ref)






GA
275
(41)
615
(41)
1.18
(0.84-1.66)






AA
343
(51)
752
(50)
1.21
(0.86-1.68)






Additive

(71)

(70)
1.07
(0.93-1.23)
0.37
NA


19 
ZNF544
rs6510130
G
CC
1192
(95)
2626
(95)
1
(ref)






CG
60
(5)
137
(5)
0.97
(0.71-1.32)






GG
0
(0)
4
(0)








Additive

(2)

(3)
0.91
(0.67-1.24)
0.56
0.63


7
MET
rs2237712
G
AA
1183
(93)
2528
(93)
1
(ref)






AG
86
(7)
184
(7)
1.00
(0.77-1.30)






GG
3
(0)
3
(0)
2.14
(0.43-10.6)






Additive

(4)

(4)
1.03
(0.80-1.33)
0.79
0.79


11 
F2
rs1799963
A
GG
1219
(94)
2794
(98)
1
(ref)






GA
76
(6)
55
(2)
3.17
(2.22-4.51)






AA
0
(0)
0
(0)








Additive

(3)

(1)
3.17
(2.22-4.51)
<.001
NAf


1
F5
rs6025
A
GG
1029
(81)
2646
(95)
1
(ref)






GA
235
(18)
140
(5)
4.32
(3.46-5.39)






AA
8
(0)
2
(0)
10.30
(2.18-48.52)






Additive

(10)

(3)
4.24
(3.42-5.26)
<.001
NAf





Abbreviations:


OR, odds ratio;


CI, confidence interval;


FDR, false discovery rate;


NA, not applicable, not in FDR analysis.



aRisk increasing allele identified in LETS and MEGA-1.




bIn the additive model, the increase in risk per copy of the risk allele is calculated




cFor the additive model, only the allele frequency is presented, not the count.




dP value from the additive model was used for FDR estimation.




eAll gene symbols and rs numbers are from NCBI build 36.




fFactor V Leiden and the prothrombin G20210A mutation are presented for reference. Since these variants were not included in the SNP association study, their false discovery rate was not calculated.














TABLE 8







Association of SNPs in CYP4V2 region with DVT and Factor XI levels in the combined LETS and MEGA-1 studies.














FXIa




Risk
Control,
% difference
Deep Vein Thrombosis















SNP
Gene
allele
Genotype
Case, N (%)
N (%)
(95% CI)
OR (95% CI)
ORb (95% CI)




















rs13146272
CYP4V2
A
CC
181
(10)
293
(13)
reference
  1 (reference)
  1 (reference)





CA
808
(44)
995
(45)
 3 (1-6)
1.32 (1.07-1.62)
1.26 (1.03-1.56)





AA
850
(46)
919
(42)
 7 (4-9)
1.50 (1.22-1.84)
1.36 (1.10-1.68)





Additive

(68)

(64)
 3 (2-4)
1.20 (1.09-1.31)
1.14 (1.04-1.25)


rs3736456c
CYP4V2
T
CC
7
(0)
0
(0)





CT
162
(9)
222
(10)
reference
  1 (reference)
  1 (reference)





TT
1663
(91)
1973
(90)
 1 (−1-4)
1.16 (0.93-1.43)
1.15 (0.93-1.42)





Additive

(95)

(95)
 1 (−2-4)
1.06 (0.86-1.30)
1.05 (0.85-1.28)


rs3087505
KLKB1
C
TT
6
(0)
25
(1)
reference
  1 (reference)
  1 (reference)





TC
317
(17)
438
(20)
 11 (6-16)
3.02 (1.22-7.44)
2.59 (1.05-6.40)





CC
1509
(82)
1743
(79)
 19 (14-24)
3.61 (1.48-8.82)
2.81 (1.15-6.89)





Additive

(91)

(89)
 8 (6-10)
1.27 (1.09-1.47)
1.15 (0.99-1.34)


rs4253259
KLKB1
C
AA
5
(0)
6
(0)
reference
  1 (reference)
  1 (reference)





AC
168
(9)
219
(10)
 0 (−18-18)
0.92 (0.28-3.07)
0.95 (0.28-3.20)





CC
1652
(91)
1978
(90)
 0 (−19-18)
1.00 (0.31-3.29)
1.03 (0.31-3.43)





Additive

(95)

(95)
 0 (−3-2)
1.08 (0.88-1.32)
1.08 (0.88-1.32)


rs4253408
F11
A
GG
1526
(83)
1869
(85)
reference
  1 (reference)
  1 (reference)





GA
293
(16)
317
(14)
 4 (2-6)
1.13 (0.95-1.35)
1.06 (0.89-1.27)





AA
15
(1)
17
(1)
 13 (−1-27)
1.08 (0.54-2.17)
0.97 (0.48-1.98)





Additive

(9)

(8)
 5 (3-7)
1.11 (0.95-1.30)
1.05 (0.89-1.23)


rs4253325
F11
G
AA
21
(1)
23
(1)
reference
  1 (reference)
  1 (reference)





AG
308
(17)
392
(18)
 5 (0-16)
0.86 (0.47-1.58)
0.86 (0.46-1.59)





GG
1507
(82)
1785
(81)
 8 (−3-13)
0.93 (0.51-1.68)
0.88 (0.48-1.62)





Additive

(90)

(90)
  3 (1-5)
1.05 (0.91-1.21)
1.01 (0.87-1.17)


rs3775302
KLKB1
A
GG
1418
(77)
1686
(77)
reference
  1 (reference)
  1 (reference)





GA
380
(21)
481
(22)
 −1 (−3-1)
0.94 (0.81-1.09)
0.97 (0.83-1.13)





AA
38
(2)
34
(2)
 −4 (−11-3)
1.33 (0.83-2.12)
1.34 (0.83-2.14)





Additive

(12)

(12)
 −1 (−3-0)
1.00 (0.87-1.14)
1.02 (0.89-1.16)


rs3756008
F11
T
AA
526
(29)
788
(36)
reference
  1 (reference)
  1 (reference)





AT
903
(49)
1032
(47)
 7 (6-9)
1.31 (1.14-1.51)
1.21 (1.04-1.39)





TT
408
(22)
384
(17)
 15 (12-17)
1.59 (1.33-1.90)
1.32 (1.09-1.59)





Additive

(47)

(41)
 7 (6-8)
1.27 (1.16-1.38)
1.16 (1.05-1.27)


rs2036914
F11
C
TT
302
(17)
505
(23)
reference
  1 (reference)
  1 (reference)





TC
895
(49)
1081
(49)
 7 (5-9)
1.38 (1.17-1.64)
1.27 (1.07-1.51)





CC
633
(35)
620
(28)
 14 (12-16)
1.71 (1.43-2.05)
1.43 (1.19-1.73)





Additive

(59)

(53)
 7 (6-8)
1.30 (1.19-1.42)
1.19 (1.08-1.30)


rs4253418
F11
G
AA
3
(0)
4
(0)
reference
  1 (reference)
  1 (reference)





AG
120
(7)
199
(9)
 14 (10-19)
0.80 (0.18-3.65)
0.69 (0.15-3.14)





GG
1710
(93)
2000
(91)
 22 (18-26)
1.14 (0.26-5.10)
0.88 (0.20-3.94)





Additive

(97)

(95)
 8 (5-11)
1.39 (1.11-1.74)
1.24 (0.99-1.56)


rs3756011
F11
A
CC
361
(26)
598
(34)
reference
  1 (reference)
  1 (reference)





CA
697
(50)
839
(48)
 8 (7-10)
1.38 (1.17-1.62)
1.26 (1.07-1.49)





AA
326
(24)
313
(18)
 17 (15-20)
1.73 (1.41-2.11)
1.44 (0.16-1.78)





Additive

(49)

(42)
 9 (7-10)
1.32 (1.19-1.46)
1.21 (1.09-1.34)


rs3822057
F11
C
CC
406
(30)
422
(24)
reference
  1 (reference)
  1 (reference)





CA
690
(51)
876
(50)
 −8 (−10-−5)
0.82 (0.69-0.97)
0.89 (0.75-1.06)





AA
269
(20)
457
(26)
−14 (−16-−11)
0.61 (0.50-0.75)
0.72 (0.58-0.88)





Additive

(45)

(51)
 −7 (−8-−6)
0.78 (0.71-0.87)
0.85 (0.76-0.94)





Abbreviations:


CI, confidence 1 interval;


LETS, Leiden Thrombophilia Study;


MEGA, Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis;


NA, not applicable, not in false discovery rate analysis;


OR, odds ratio;


SNP, single nucleotide polymorphism.



aFactor XI level per genotype was calculated in controls. A Factor XI analysis with 95% CI not crossing zero is considered significant.




bOR for DVT, adjusted for factor XI level.




cAs there were no homozygous controls for the C allele of rs3736456, the CT genotype was taken as reference group for the factor XI difference and genotype OR.



For OR results, an analysis with 95% CI not crossing 1 is considered significant.


For rs4253529 (KLKB1), an exemplary genomic context sequence is provided in the Sequence Listing as SEQ ID NO: 2557. Note that the alleles presented in Table 8 for rs4253529 are based on a different orientation (i.e., the reverse complement) relative to SEQ ID NO: 2557.


For rs3775302 (KLKB1), an exemplary genomic context sequence is provided in the Sequence Listing as SEQ ID NO: 2558.


For the rest of the SNPs in Table 8, SEQ ID NOs of exemplary sequences are indicated in Tables 1-2.






Example Two
Association Between F9 Malmö and Deep Vein Thrombosis

Introduction


In LETS, elevated levels of factor IX above the 90th percentile (129 U/dL) have been associated with a 2-3 fold increased risk of DVT (van Hylckama Vlieg et al., Blood. 2000; 95:3678-3682). A genome-wide scan was recently performed for novel genetic polymorphisms associated with risk of DVT, as described above in Example One. One of the SNPs identified was an A-G polymorphism (rs6048, F9 “Malmö”) in the gene encoding Factor IX and was associated with an 18% decrease in DVT risk in 3 case-control studies of DVT. This common variant (minor allele frequency=0.32) causes a substitution of Ala for Thr at position 148 of the factor IX zymogen and is located within the region that is cleaved from the zymogen to activate the factor 1× protease and has not been previously associated with risk for DVT or hemophilia B (Graham et al., Am J Hum Genet. 1988; 42:573-580). Thus, the mechanism by which the F9 Malmö SNP leads to reduced risk of DVT is unclear.


In the study described here in Example Two, it was determined whether the association between the F9 Malmö SNP and DVT could be explained by the Malmö SNP affecting thrombin generation, Factor IX plasma levels, or activation of Factor IX. It was also determined whether the association between the F9 Malmö SNP and DVT could be explained by linkage disequilibrium between the Malmö SNP and other factor IX variants.


Methods


Study Populations and Data Collection


The case-control populations (LETS, MEGA-1 and MEGA-2) used to analyze the association of genotypes with DVT are derived from two large population-based case-control studies; the Leiden Thrombophilia Study (LETS) and the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study (van der Meer et al., Thromb Haemost. 1997; 78:631-635; Blom et al., JAMA. 2005; 293:715-722). The LETS and MEGA studies were approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, The Netherlands. All participants gave informed consent to participate in the studies, completed a questionnaire on risk factors for venous thrombosis and provided a blood or buccal swab sample. Diagnoses were objectively confirmed using hospital discharge records and information from general practitioners. LETS included only those patients with an confirmed DVT. In MEGA, 90% of patients gave permission to view their medical records and within this group 97% of diagnoses were confirmed. Patients for whom DVT was excluded according to the medical record were excluded from the MEGA study. Samples from the Northwick Park Heart Study-II (NPHS-II), were used to evaluate the association of F9 cleavage peptide and with the Malmö genotypes (Miller et al., Thromb Haemost. 1996; 75:767-771).


Collection and ascertainment of events in LETS has been described previously (van der Meer et al., Thromb Haemost. 1997; 78:631-635). Briefly, cases were recruited between Jan. 1, 1988 and Dec. 30, 1992 from three anticoagulation clinics in the western part of the Netherlands:


Leiden, Amsterdam, and Rotterdam. A total of 474 consecutive cases, 70 years or younger, with a diagnosis of a first DVT and without a known malignancy were included. For each case, an age- (±5 years) and sex-matched control participant who had no history of DVT was enrolled. In this study of LETS, 52 participants were excluded due to inadequate quantity or quality of DNA. After these exclusions, 443 cases and 453 controls remained.


Collection and ascertainment of events in MEGA has been described previously (Blom et al., JAMA. 2005; 293:715-722). Briefly, MEGA-1 enrolled consecutive patients aged 18 to 70 years who presented with their first diagnosis of DVT or pulmonary embolism (PE) at any of 6 anticoagulation clinics in the Netherlands (Amsterdam, Amersfoort, The Hague, Leiden, Rotterdam, and Utrecht) between Mar. 1, 1999 and May 31, 2004. Control subjects in MEGA included partners of patients and random population control subjects and were selected so that the distribution of age and sex matched that of the patient group. The first 4,500 MEGA participants who donated a blood sample were included in the MEGA-1 study. MEGA-1 participants with inadequate quantity or quality of DNA (n=370), malignancy (n=272), or a diagnosis of isolated PE (n=711) were excluded. After these exclusions, 1,398 cases and 1,785 controls remained in the MEGA-1 population. An additional 5,673 MEGA participants that donated either a blood sample or a buccal swab sample were included in the MEGA-2 study. MEGA-2 participants were excluded from the analysis if they had inadequate quantity or quality of DNA (n=467), malignancy (n=433), or a diagnosis of isolated PE (n=639). After these exclusions, 1,314 cases and 2,877 controls remained in the MEGA-2 study.


The Northwick Park Heart Study-II (NPHS-II) has been described previously (Miller et al., Thromb Haemost. 1996; 75:767-771). Briefly, 4600 men aged 50-63 years registered with 9 general medical practices in England and Scotland were screened for eligibility in the NPHS-II. Exclusion criteria for the original study included: a history of unstable angina or acute myocardial infarction (AMI); a major Q wave on the electrocardiogram (ECG); regular anti-platelet or anticoagulant therapy; cerebrovascular disease; life-threatening malignancy; conditions exposing staff to risk or precluding informed consent. Of these, 796 men gave written informed consent, were approved by the institutional ethics committee and had measurements of F9 cleavage peptide at baseline.


Allele Frequency and Genotype Determination


DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes, Invitrogen Corp, Carlsbad, Calif.) fluorescent dye. Genotyping of individual DNA samples was performed as previously described in Example One using 0.3 ng of DNA in kPCR assays or using multiplexed oligo ligation assays (OLA) (Iannone et al., Cytometry. 2000; 39:131-140). Genotyping accuracy of the multiplex methodology and kPCR has been assessed in three previous studies by comparing genotype calls from multiplex OLA assays with those from real time kPCR assays for the same SNPs, and the overall concordance of the genotype calls from these two methods was >99% in each of these studies (Iakoubova et al., Arterioscler Thromb Vasc Biol. 2006; 26:2763-2768; Shiffman et al., Arterioscler Thromb Vasc Biol. 2006; 26:1613-1618; and Shiffman et al., Am J Hum Genet. 2005; 77:596-605).


Statistical Analysis


Deviations from Hardy-Weinberg expectations were assessed using an exact test in controls (Weir, Genetic Data Analysis II. Sunderland: Sinauer Associates Inc.; 1996). Adjustments for covariates (age in years and sex) were performed using logistic regression analysis with the genotypes coded as 0, 1 and 2 for the non-risk homozygote, heterozygote, and risk homozygote, respectively. Logistic regression models were performed to assess the association of each genotype (heterozygote and risk homozygote coded as 2 indicator variables) with the outcome. All P values of statistical tests in LETS and MEGA-1 were two-sided. Analyses of SNPs were conducted separately in males and females since the SNP were on the X chromosome. SAS version 9 was used for all regression models.


Odds ratios (OR) and 95% confidence intervals (95% CI) were computed as an estimate of risk of DVT associated with each tag SNP in males using logistic regression with adjustments for age as previously described. For the allelic OR the major allele homozygote was used as reference group. Differences in the factor IX level between genotype categories were assessed in control subjects of LETS, MEGA-1 and MEGA-2 using a T-test. Subjects with oral anticoagulant were excluded. Factor IX level were available for 191 male and 261 female subjects in LETS, 829 male and 916 female subjects in MEGA1, 484 male and 2534 female subjects in MEGA2. Among 796 men that had measurements of F9 cleavage peptide at baseline in NPHS-II, the differences in factor IX cleavage peptide between genotype categories were assessed in NPHS-II using a T-test. Regression analyses and T-tests were performed with SAS. Regression in the NPHS-II was adjusted for age, levels of fibrinogen and creatinine.


Power to detect a difference in mean F9 cleavage peptide between groups defined by F9 genotype was calculated using nQuery Advisor version 4.0 (ref) for a two sample t-test at a 0.05 two-sided significance level and assuming equal variance among the groups (Elashoff, nQuery Advisor Version 4.0 User's Guide. Los Angeles, Calif. (2000)).


Meta analysis was performed using the meta package version 0.8-2 available in R software language version 2.4.1 (R: A Language and Environment for Statistical Computing, R Development Core Team, R Foundation for Statistical Computing, Vienna Australia, 2007, ISBN 3-900051-07-0) by treating the individual studies as fixed effects and using the inverse variance method to estimate the pooled effect of the SNP (Cooper et al., The Handbook of Research Synthesis. Newbury Park, Calif.: Russell Sage Foundation (1994)).


Gene Variants and DVT Risk in the F9 Region


To investigate whether other SNPs in this region might be associated with DVT, results from the HapMap Project were used to identify a region surrounding the Malmö SNP, rs6048 (chr X: 138,404,951 to 138,494,063). This region contained 48 SNPs with allele frequencies >2% (HapMap data release #221, phase II April 7, on NCBI B36 assembly, dbSNP 126 (Bertina et al., Pathophysiol Haemost Thromb. 2003; 33:395-400). Allele frequencies and LD were calculated from the SNP genotypes in the HapMap CEPH population, which includes Utah residents with ancestry from northern and western Europe. Eighteen SNPs were chosen using pairwise tagging in Tagger (implemented in Haploview (Schaid et al., Am J Hum Genet. 2002; 70:425-434)). 15 of these 18 SNPs were selected for genotyping. These 15 SNPs are reasonable surrogates for 45 of the 48 SNPs in this region because the 45 SNPs are either directly genotyped or in strong linkage disequilibrium (r2>0.8) with at least one of the 48 genotyped SNPs. Assays for 3 of the 18 SNPs could not be constructed (rs4149754, rs438601, and rs17340148); these 3 SNPs are unlikely to be responsible for the observed association between rs6048 and DVT since they were not in strong LD (r2<0.2) with rs6048. The remaining 14 of the 48 SNPs were candidates SNPs (Khachidze, Seattle SNPs db, Psaty JAMA). In total 29 SNPs were initially investigated in the males of LETS, and SNPs that were associated with DVT were investigated in the males of MEGA-1. The association between each genotype and DVT was assessed using the Fisher Exact method.


The association between haplotype and DVT was assessed using the R language package of haplo.stats (Schaid et al., Am J Hum Genet. 2002; 70:425-434), which uses the expectation maximization algorithm to estimate haplotype frequencies followed by testing for association between haplotype and disease using a score test. A sliding window was used to select and test haplotypes consisting of 3, 5, and 7 adjacent SNPs from the set of SNPs including the Malmö SNP and the 28 other tagging SNPs in male subjects.


Factor IX Assays


The levels of factor IX were determined by enzyme-linked immunosorbent assay (ELISA) as previously described (van Hylckama Vlieg et al., Blood. 2000; 95:3678-3682). This ELISA is highly specific for Factor 1× and results are not affected by the levels of the other vitamin K-dependent proteins. Under these conditions, the intra-assay and interassay CV was 7% (n 5 9) and 7.2% (n 5 41), respectively, at a factor IX antigen level of about 100 U/dL. Results are expressed in units per deciliter, where 1 U is the amount of factor IX present in 1 mL pooled normal plasma.


F9 Cleavage Peptide in NPHS-II


F9 cleavage peptide was determined by double antibody radioimmunoassay as markers of turnover of Factor IX in the NPHS-II samples (Bauer et al., Blood. 1990; 76:731-736). The coefficient of variation (CV) for measurements made during repeat measurements on split samples were 14.7% for Factor IX cleavage peptide. The level of cleavage peptide in plasma is dependent on Factor IX levels, which are affected by age and inflammation, and on kidney function. The effects of inflammation and kidney function were assessed by adjusting the analysis for the levels of fibrinogen and creatinine, respectively.


Endogenous Thrombin Potential (ETP)-Based Apc Sensitivity Test


Endogenous thrombin potential (ETP) is an activate protein C (APC) sensitivity test that quantifies the time integral of thrombin generated in plasma in which coagulation is initiated via the extrinsic pathway (Hemker et al., Thromb Haemost. 1995; 74:134-138 and Nicolaes et al., Blood Coagul Fibrinolysis. 1997; 8:28-38). The sensitivity of the plasma ETP to APC was measured under conditions where the test is insensitive for small amounts of phospholipid present in plasma as previously described (Rosing et al., Br J Haematol. 1997; 97:233-238; Tans et al., Br J Haematol. 2003; 122:465-470; and Curvers et al., Thromb Haemost. 2002; 87:483-492).


Results


The Malmö SNP was previously found to be associated with DVT in men and not in women. In the previous analysis, women that were heterozygotic for the Malmö SNP were excluded from the analysis because lyonization, the process in which all X chromosomes of the cells in excess of one are inactivated on a random basis, causes the expressed genotypes to be different from the determined genotypes. Removing the heterozygote in the analysis in women reduces the power to detect associations between genotypes and DVT in women, which could explain why the association of Malmö with DVT in women had an OR for DVT that was similar to that found in men, but was not significant. It was found that the Malmö SNP, rs6048, was associated with DVT in men: the pooled odds ratio was 0.80 (95% CI, 0.71-0.92) for the A genotype (n=2688) compared with G (n=1108), but the Malmö SNP was not associated with DVT in women: the pooled odds ratio was 0.86 (95% CI, 0.70-0.1.05) for the AA (n=2190) compared with GG genotypes (n=405) (FIG. 2). Thus, analyses for this study were done in men.


It was determined whether the association between the F9 Malmö SNP and DVT could be explained by an association between the Malmö SNP and endogenous thrombin potential (ETP). Among the 161 male subjects of LETS for whom ETP measurements were available, it was found that Malmö genotype was not associated with ETP (median ETP=1657±341 for the A genotype and 1583±361 for the G genotype).


It was determined whether the association between the F9 Malmö SNP and DVT could be explained by an association between the Malmö SNP and Factor IX plasma levels. Among the male subjects for whom Factor IX plasma levels were available (161 in LETS, 829 in MEGA1 and 484 in MEGA2), there was not a significant difference in Factor IX level between the A and the G genotype. For the LETS subjects the mean FIX levels were 104±17% for the A genotype and 109±24% for the G genotype, P=0.0965. For the MEGA-1 subjects the mean Factor IX levels were 104±17% for patients with genotype A and 102±18% for the G genotype, P=0.119. For the MEGA-2 subjects the mean Factor IX levels were 104±15% for the genotype A and 104±18% for the G genotype, P=1.0).


It was determined whether the association between the F9 Malmö SNP and DVT could be explained by an association between the Malmö SNP and activation of Factor IX. Among the 796 male subjects of NPHS-II for whom plasma F9 cleavage peptide levels were available, there was not a significant difference in Factor IX level between the A and G genotypes; the mean plasma concentration of F9 cleavage peptide was 210.9+−75.04 (95% Cl: 204.6 to 217.2) for A genotype and 214.1+−73.82 (95% Cl: 204.7 to 223.4) for the G genotype. Adjustments for age, fibrinogen and creatinine levels did not appreciably change this result. The study had 80% power to detect a difference in means of 0.22 standard deviations or greater, or 90% power to detect a difference in means of 0.25 standard deviations or greater.


It was then determined whether the Malmö SNP was in linkage disequilibrium (LD) with other F9 variants that were associated with DVT. In the LETS population, 29 SNPs were investigated that represented groups of SNPs with LD greater than 0.8 in an 89 kb region surrounding the Malmö SNP on the X chromosome. It was found that six of the 29 SNPs, including the Malmö SNP, were associated (P≦0.05) with DVT (Table 9). The association between these six SNPs and DVT were then investigated in the MEGA-1 study, and two of these SNPs were found to be significantly associated with DVT in MEGA-1: the Malmö SNP and rs422187, an intronic SNP 300 bp from the Malmö SNP (Table 9). The risk estimate for the association between rs422187 and DVT was similar to that of the Malmö SNP, and LD between rs422187 and the Malmö SNP was high (r2=0.94). Additionally, no SNPs or haplotypes were found to have a stronger association with DVT in the LETS or MEGA studies than the F9 Malmö SNP.


Discussion


It was investigated whether the previously reported association between DVT and the F9 Malmö SNP could be explained by changes in plasma levels of Factor IX, extrinsic coagulation, Factor IX activation, or LD with SNPs with stronger association with DVT than the Malmö SNP. However, analyses to directly or indirectly test these hypotheses did not provide support for any of them. Although the Malmö SNP did not affect ETP, an assay that measures extrinsic pathway coagulation initiated by TF:FVIIa, the Malmö SNP could have an affect on coagulation initiated by intrinsic pathway coagulation initiated by FXIa. The lack of an association of the Malmö SNP with Factor IX levels is consistent with the results of Khadhidze et al, which reported that 27 SNPs including F9 Malmö were not associated with FIX:C in the GAIT study (Khachidze et al., J Thromb Haemost. 2006; 4:1537-1545). The analysis of activation described here in Example Two used an indirect assay to estimate activation of Factor IX. The plasma level of the F9 cleavage peptide is dependent on the release of cleavage peptide that occurs when FIX is activated to FIXa and the steady clearance rate of the cleavage peptide in the kidneys (Lowe, Br J Haematol. 2001; 115:507-513). Direct measurements of Factor IX activation by TF:FVIIA or FXIa may reveal affects on the activation of Factor IX caused by F9 Malmö SNP.


The association of the Malmö SNP with DVT was previously reported in men as described in Example One. The result was not significant in women although the odds ratio in women was similar to that found in men. The LETS, MEGA-1 and MEGA-2 samples were pooled because these samples were collected in the Netherlands in the same health care system using similar inclusion criteria. The LETS inclusion and exclusion criteria were applied to the MEGA samples and they were pooled for meta-analysis. In the meta-analysis, the Malmö SNP was associated with DVT in men but was not with women although the odds ratio for men and women were similar. In the analysis of women, the AA genotype was compared with the GG genotype. However, the heterozygotes were excluded from the analysis because evaluation of female heterozygotes is confounded by lyonization. Therefore, the lack of association in female could be due to differences in penetrance between men and women or lack of power to detect the association in female homozygotes. The lack of an association between the Malmö SNP and DVT in women is consistent with recent results observed in postmenopausal women (Smith et al., JAMA. 2007; 297:489-498).


Fine mapping did not identify any SNPs that were more strongly associated with DVT than the Malmö SNP in the LETS and MEGA-1 samples. A recent study found that rs4149755 in the F9 gene was associated with DVT in postmenopausal women (Smith et al., JAMA. 2007; 297:489-498). rs4149755 was included in the fine mapping analysis in LETS, but rs4149755 was not associated with DVT in men (Table 9) or in women. No haplotypes were found using the evaluated fine mapping SNPs that were more strongly associated with DVT in both LETS and MEGA-1.


In conclusion, the Malmö SNP in F9 was significantly associated with an 18% reduction in risk of DVT in a pooled analysis of men from LETS, MEGA-1 and MEGA-2. Fine mapping of the F9 region surrounding the Malmö SNP did not reveal any additional SNPs associated with DVT in LETS and MEGA-1 or SNPs with greater significance than the Malmö SNP.









TABLE 9







The F9 Malmö SNP fine mapping results in LETS and MEGA-1
















Minor

P-

r2 with

X Chromosome



Study
Allele
MAF
Value
OR
Malmö
rs#
Position
SNP Type





LETS
A
0.32
0.088
0.67
0.40
rs4829996
138418800
Intergenic


LETS
G
0.08
0.849
0.92
0.02
rs7055668 (T)
138427049
Intergenic


LETS
A
0.39
0.067
0.66
0.26
rs411017
138439768
Intergenic


LETS
T
0.39
0.068
0.67
0.26
rs378815 (T)
138439863
TFBS synonymous


LETS
G
0.02
1.000
0.67
0.01
rs3817939 (T)
138440752
TFBS synonymous


LETS
C
0.44
0.538
1.14
0.06
rs371000 (T)
138443187
TFBS synonymous


LETS
T
0.38
0.190
0.74
0.65
rs4149674 (T)
138444467
Intron


LETS
T
0.08
1.000
1.07
0.03
rs392959 (T)
138449920
Intron


LETS
G
0.34
0.032
0.61
0.85
rs398101
138451623
Intron


LETS
A
0.06
0.423
1.42
0.03
rs4149755
138451778
Intron


LETS
A
0.08
0.543
0.73
0.18
rs4149758
138455143
Intron


LETS
G
0.07
1.000
1.00
0.02
rs374988 (T)
138458881
Intron


LETS
C
0.33
0.039
0.61
0.94
rs422187
138460525
Intron


MEGA-1
C
0.32
0.016
0.88
0.93


LETS
G
0.33
0.022
0.58
NA
rs6048 (T)
138460946
Missense Mutation


MEGA-1
G
0.30
0.021
0.88
NA


LETS
C
0.09
0.454
0.74
0.08
rs4149759 (T)
138462720
Intron


LETS
G
0.24
0.041
0.58
0.44
rs413957
138465182
Intron


LETS
T
0.01
0.248
N/A
0.01
rs4149761 (T)
138467129
Intron


LETS
T
0.03
1.000
0.99
0.02
rs4149730 (T)
138467398
Intron


LETS
C
0.24
0.029
0.56
0.45
rs421766
138468258
Intron/TFBS


LETS
A
0.05
0.230
1.76
0.00
rs4149762 (T)
138469863
Intron


LETS
C
0.25
0.041
0.57
0.45
rs370713
138470059
Intron


LETS
T
0.00
1.000
N/A
0.00
rs4149749
138470891
Intron/TFBS


LETS
A
0.00
1.000
N/A
0.00
rs4149763
138472372
UTR3


LETS
A
0.24
0.057
0.61
0.43
rs440051 (T)
138472583
TFBS/UTR3


LETS
G
0.26
0.008
0.50
0.42
rs434144
138474091
Intergenic


LETS
A
0.01
0.247
N/A
0.00
rs17342358 (T)
138482244
TFBS synonymous


LETS
T
0.45
0.411
1.21
0.00
rs5907573 (T)
138489652
TFBS


LETS
C
0.44
0.305
1.26
0.00
rs3128282
138490821
Intergenic


LETS
A
0.01
0.499
N/A
0.00
rs2235708
138506410
ESE





(T) = tagging SNP;


MAF = minor allele frequency


TFBS = Transcription Factor Binding Site;


ESE = exon splicing enhancer


N/A = Not applicable or the calculation contained a group with zero counts.


Unadjusted allelic odds ratios and P-values were calculated by the Fisher Exact method in men.


15/18 tag SNPs were run in LETS, 3 single SNP tags were not run in LETS






Example Three
Gene Variants of CYP4V2, SERPINC1 and GP6 are Associated with Pulmonary Embolism

Overview


Pulmonary embolism (PE) is a manifestation of venous thrombosis (VT) that may share genetic risk factors in common with deep vein thrombosis (DVT). To identify SNPs associated with isolated PE, 11 SNPs previously found to be associated with DVT were analyzed for their association with isolated PE in a case-control study of 1206 cases and 4634 controls from the Multiple Environmental and Genetic Assessment (MEGA) study. Odds ratios (OR) for isolated PE were estimated in logistic regression models that adjusted for age and sex.


SNPs determined to be associated with isolated PE included SNPs in genes for CYP4V2 (rs13146272: OR, 1.15; 95% CI, 1.04-1.27), GP6 (rs1613662: OR, 1.18; 95% CI, 1.04-1.33) and SERPINC1 (rs2227589: OR, 1.28; 95% CI, 1.11-1.48) and F9 in females (rs6048: OR, 1.20; 95% CI, 1.06-1.38). Many of these SNPs were found in genes not previously reported to be involved in VT. Factor V Leiden and prothrombin G20210A variants were associated with isolated DVT (rs6025: OR, 4.43; 95% CI, 3.76-5.22; rs1799963: OR, 3.01; 95% CI, 2.29-3.95) and with isolated PE (rs6025: OR, 1.82; 95% CI, 1.45-2.28; rs1799963: OR, 1.82; 95% CI, 1.27-2.62); however, the case frequencies were significantly lower in the isolated PE study compared to the isolated DVT study (P<0.01).


Introduction


Pulmonary embolism (PE) is a common and potentially fatal manifestation of VT, which occurs as a consequence of a DVT that embolizes to the lung. VT affects about 750,000 patients annually in the EU and about 600,000 patients annually in the US. It is the 3rd most common cardiovascular disease worldwide, behind CHD and stroke (Zidane et. al., Throm Haemost 2003 90:439-445 and Perrier, Chest 200 118:1234-6)


In the United States, the total incidence of symptomatic PE is approximately 630,000 cases per year. Approximately a third of these patients die, and in nearly half of these patients who die, PE is the sole cause of death (Diseases of the Veins. Pathology, diagnosis and treatment. In: Browse et al., editors. Pulmonary embolism. London:Edwards Arnolds; 1989. p 557-80). Estimates of the total number of non-fatal PE event across Europe exceed 400,000 per year and the total number of PE-related deaths is about 514,000 (Cohen, Thromb Haemost (2007) 98, 756-764 and Lindblad, BMJ 1991; 302; 709-711). PE is the major cause of VT deaths.


The genetic risk factors for PE may be different for DVT. It has been assumed that PE and DVT share the same genetic risk factors. However, studies that evaluated the factor V Leiden (FVL) variant (which is known to be associated with DVT) in patients with PE but without DVT found that it was weakly associated with PE. In addition, genetic variants may predispose the thrombus to particular vascular beds. For example, patients with PT G20210A mutations are predisposed to portal vein thrombosis whereas individuals with FVL variants are not, and it has been suggested that patient with FVL are predisposed to DVTs of the calf. Thus, although DVT and PE may be different manifestations of the same disease, they may not share all the same risk factors.


A functional genome-wide scan of DVT was recently performed and seven SNPs were identified that were associated with DVT in three case-controls studies, as described in Example One above. Here in Example Three, it was determined whether any of these seven SNPs, plus four other SNPs (in F2, F5, and F11), were also associated with isolated PE.


Methods


Study Populations and Data Collection


This genetic study of PE investigated patients with PE selected from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study (Blom et al., JAMA. Feb. 9, 2005; 293(6):715-722). The MEGA study was approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, The Netherlands. All participants gave informed consent to participate in the studies and completed an institutional review board-approved questionnaire. Diagnoses of PE and DVT in the studies were objectively confirmed using hospital discharge records and information from general practitioners. Patients with isolated PE had a confirmed PE and no record of a DVT, and patients with isolated DVT had a confirmed DVT and no record of a PE.


The Multiple Environmental and Genetic Assessment Study (MEGA)


Collection and ascertainment of events in MEGA has been described previously (Blom et al., JAMA. Feb. 9, 2005; 293(6):715-722). MEGA enrolled consecutive patients aged 18 to 70 years who presented with their first diagnosis of DVT or PE at any of 6 anticoagulation clinics in the Netherlands (Amsterdam, Amersfoort, The Hague, Leiden, Rotterdam, and Utrecht) between Mar. 1, 1999 and May 31, 2004. The anticoagulation clinics monitor the anticoagulant therapy of all patients in defined regions of the Netherlands, which allowed them to identify consecutive and unselected cases with DVT. Partners of cases were invited to take part as controls. Additional control participants were recruited by random digit dialing from the same region that the cases were collected (Chinthammitr et al., J Thromb Haemost. December 2006; 4(12):2587-2592). The age and sex of the controls were matched to cases. MEGA DNA was collected and extracted from blood or buccal swabs as previously described (Blom et al., JAMA. Feb. 9, 2005; 293(6):715-722). MEGA included ˜10,000 participants. Subjects were excluded due to inadequate quantity or quality of DNA (n=370+467), for malignancy (n=272+433).


Allele Frequency and Genotype Determination


Genotypes were determined by kPCR or multiplex oligo-ligation assay. DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes) fluorescent dye. Each allele was amplified separately by PCR using genotyping of individual DNA samples was similarly performed using 0.3 ng of DNA in kinetic polymerase chain reaction (kPCR) assays (Germer et al., Genome Res. February 2000; 10(2):258-266) or using multiplex PCR assays capable of genotyping up to 50 SNPs in a single reaction (Iannone et al., Cytometry. Feb. 1, 2000; 39(2):131-140). Genotyping accuracy of the multiplex methodology has been assessed in three previous studies by comparing genotype calls from the multiplex OLA assays to those from real time kinetic PCR assays for the same SNPs, and the overall concordance of the genotype calls from these two methods was >99% in each of these studies (Iakoubova et al., Arterioscler Thromb Vasc Biol. Sep. 28, 2006; 26(26):2763-2768; Shiffman et al., Arterioscler Thromb Vasc Biol. July 2006; 26(7):1613-1618; and Shiffman et al., Am J Hum Genet. October 2005; 77(4):596-605). The 7 assays associated with DVT in MEGA were successfully genotyped in >95% of the subjects in MEGA.


Study Design


To identify genetic risk variants that were associated with isolated PE, the risk allele of 11 SNPs previously associated with DVT were evaluated for their association with isolated PE in MEGA. The case-control studies of DVT that were used to identify 7 of these SNPs (out of the 11 SNPs) excluded patient with isolated PE. This study evaluates these patients with isolated PE who were excluded from the studies used to identify these SNPs. The same controls used in the DVT discovery studies were used for this study. The controls were subjects with no history of VT.


Study Populations


The baseline characteristics of the cases and controls in the isolated PE and isolated DVT studies of MEGA are presented in Table 10.


Statistical Analysis


Deviations from Hardy-Weinberg expectations were assessed using an exact test in controls (Weir, Genetic Data Analysis 2: Methods for Discrete Population Genetic Data 2nd edition (April 1996) ed. Sunderland: Sinauer Associates; 1996). Adjustments for covariates (age in years, and sex) were performed using logistic regression analysis with the genotypes coded as 0, 1 and 2 for the non-risk homozygote, heterozygote, and risk homozygote, respectively. For the SNPs presented in Table 11, logistic regression models were performed to assess the association of each genotype (heterozygote and risk homozygote coded as 2 indicator variables) with the outcome. All statistical tests in MEGA were two-sided.


Results


SNPs Associated with PE in MEGA


In MEGA, the association with isolated PE of 7 SNPs previously found to be associated with DVT was analyzed. In the controls of MEGA, the genotypes of the 11 SNPs did not deviate from the distributions expected under Hardy-Weinberg equilibrium (P≦0.01) (Weir, Genetic Data Analysis 2: Methods for Discrete Population Genetic Data 2nd edition (April 1996) ed. Sunderland: Sinauer Associates; 1996). The method of Bonferoni was used to correct for multiple comparisons. Both the isolated DVT and isolated PE studies of MEGA had greater than 80% to detect association of the 7 SNP (power=0.5 for 0.1 allele frequency)


Eight of the 11 SNPs evaluated were associated (P≦0.05) with isolated PE. These were in the genes for CYP4V2, GP6, SERPINC1, F2, F5, and F11. The risk allele and OR of these SNPs can be found in Table 11. The associations between isolated PE and each genotype of these eight associated SNPs are shown in Table 12.


Six of the 11 SNPs evaluated were associated (P≦0.05) with isolated DVT. These were in the genes for CYP4V2, GP6, SERPINC1, RGS7, NR1I2, and NAT8. The associations between isolated DVT and each genotype of these SNPs are shown in Table 13.


The case allele frequencies for FVL and PT are substantially lower (P<0.05) in the case frequencies of the isolated DVT study than in the isolated PE study, which is reflected as a lower risk estimates for FVL and PT in the isolated PE study than in the isolated DVT study. The three SNPs in genes for NR1I2, NAT8 and RGS7 that were associated with isolated DVT but not with isolated PE, also have slightly lower case frequencies in the isolated DVT study compared to the isolated PE study, although the frequency differences were not statistically significant.


Discussion


Eight SNPs in genes for CYP4V2, SERPINC1, GP6, F2, F5, and F11 (Table 12) were identified that were associated with isolated PE in a large, well characterized case-control population (MEGA) (1206 PE cases and 4634 controls). The associations were corrected for multiple testing using the Bonferroni method. The risk alleles associated with isolated PE for each of the SNPs are the same risk alleles previously reported to be associated with DVT, as described in Example One.


This study also confirmed that established genetic risk factors for venous thrombosis, notably FVL (Chinthammitr et al., J Thromb Haemost. December 2006; 4(12):2587-2592 and Bertina et al., Nature. May 5, 1994; 369(6475):64-67) and prothrombin G20210A (Chinthammitr et al., J Thromb Haemost. December 2006; 4(12):2587-2592 and Poort et al., Blood. Nov. 15, 1996; 88(10):3698-3703), are associated with isolated PE in MEGA. However, the risk estimates for FVL and prothrombin G20210A with isolated PE are about half of the risk estimated found for isolated DVT (FVL, OR=4.43 and OR=1.82, respectively; PT, OR=3.01 and OR=1.82) (Chinthammitr et al., J Thromb Haemost. December 2006; 4(12):2587-2592 and Poort et al., Blood. Nov. 15, 1996; 88(10):3698-3703).


These results are consistent with the previous associations of FVL and PT with isolated DVT and isolated PE. The most notable of the genetic risk factors for DVT is Factor V Leiden, which has an OR for DVT of 6. Intriguingly, studies of consecutive suspected PE patients found that there was no difference in the prevalence of FVL in patients with or with out confirmed PE. This was been replicated in many other studies (Perrier, Chest 200 118:1234-6). This weak association of FVL with PE is in sharp contrast to its association with DVT and has been called the Factor V Leiden paradox. It has been suggested that the reason for this paradox is that DVT patients with FVL are more likely to have a distal DVT which is less likely to embolize (i.e., lower tendency to develop iliofemoral DVT that carriers). However, this was not substantiated by Martinelli (JTH 5: 98-101). The paradox suggests that although FVL is an important risk factor for DVT, it may not increase the risk of PE. Since PE cause most VT deaths and is therefore more clinically important than DVT (Martinelli, JTH 5:98-101), it has been suggested that patient with FVL should be treated less aggressively rather than more aggressively (Bounameaux, Lancet (2000)356:182-183).


PT G20210A is another genetic risk factor associated with different manifestations of VT. PT G20210A is associated with increased portal vein VT, whereas FVL is not (Primignami et al., Heptology 2005 41:603-8). In addition, some studies suggest that carriers of PT G20210A have an increased risk of developing PE, which is similar to that seen for DVT. PT G20210 has an OR of 3.0 for DVT. However, other studies suggest that PT G20210A is not associated with risk in PE, which (like FVL) is not explained by a difference in the rate of distal versus proximal DVT. Unfortunately, these studies are complicated by the low allele frequency of the PT G20210A variant. One of the advantages of the MEGA study is it large size, which provides greater power for detecting associations. In the current study, FVL and PT were both found to be associated with isolated PE and isolated DVT. However, the risk estimates were lower in the isolated PE study than in the isolated DVT, which is consistent with literature reports of FVL and PT not being associated with isolated PE in smaller studies having less power.


Although SERPINC1 is located in the same region of chromosome 1 as the Factor V gene, its association with isolated DVT or isolated PE is not due to linkage-disequilibrium with the FVL variant (see Example One).


Conclusions


Eight SNPs were identified that were associated with isolated PE in the MEGA study. These variants are useful for assessing genetic risk of PE, and the genes containing these variants and the products encoded by these genes (e.g., protein and mRNA) are useful as therapeutic targets for treating PE.


Additional SNPs associated with PE are provided in Table 25 (Example Seven below).









TABLE 10







Characteristics of Cases and Controls in MEGA











Charac-
PE Cases
DVT Cases
Controls
P value












teristic
n = 1206
n = 2229
n = 4634
DVT*
PE





Male, %
498 (41.2)
(1032) 46.3
(2191) 47.3
0.45
1.7E−0.4


Age, years


Mean ±
47 (13)
47 (13)
47 (13)
0.46
0.64


SD


Range
18.1-70.0
18.2-70.0
18.0-70.0





Differences between characteristics were assessed by the Wilcoxon rank sum test (continuous variables) or by Fisher's exact test (discrete variables).


*Comparison between DVT cases and controls.



Comparison between PE cases and controls.














TABLE 11







Association of Nine SNPs with Isolated DVT or PE

















Frequency




Gene


Risk
(%)
Unadjusted
Adjusted
















Symbol
SNP
Endpoint
Allele*
Cases
Control
OR (95% CI)
P Value
OR (95% CI)
P Value



















CYP4V2
rs13146272
PE
A
67
64
1.15 (1.05-1.27)
0.004
1.15 (1.04-1.27)
0.005




DVT

68
64
1.19 (1.10-1.29)
<0.0001
1.19 (1.10-1.29)
<0.0001


SERPINC1
rs2227589
PE
T
12
9
1.28 (1.11-1.48)
0.0003
1.28 (1.11-1.48)
0.001




DVT

11
9
1.24 (1.10-1.39)
0.0004
1.24 (1.10-1.39)
0.0003


GP6
rs1613662
PE
A
84
82
1.18 (1.04-1.33)
0.009
1.18 (1.04-1.33)
0.008




DVT

84
82
1.15 (1.04-1.26)
0.005
1.15 (1.04-1.33)
0.005


RGS7
rs670659
PE
C
65
64
1.03 (0.93-1.13)
0.58
1.02 (0.93-1.13)
0.62




DVT

67
64
1.12 (1.04-1.21)
0.003
1.13 (1.04-1.21)
0.002


NR1I2
rs1523127
PE
C
40
38
1.05 (0.96-1.15)
0.30
1.05 (0.96-1.15)
0.30




DVT

41
38
1.12 (1.04-1.21)
0.002
1.12 (1.04-1.21)
0.002


NAT8B
rs2001490
PE
C
37
37
0.99 (0.91-1.09)
0.59
0.99 (0.91-1.09)
0.91




DVT

40
37
1.11 (1.03-1.20)
0.005
1.11 (0.91-1.09)
0.005


F9
rs6048
PE




Male
A
72
69
1.24 (0.99-1.55)
0.06
1.24 (1.00-1.55)
0.06




Female

90
88
1.21 (1.06-1.38)
0.005
1.20 (1.06-1.38)
0.006




DVT




Male
A
74
69
1.16 (0.99-1.37)
0.07
1.16 (0.98-1.37)
0.08




Female

90
88
1.07 (0.96-1.19)
0.20
1.06 (0.95-1.18)
0.29


F2
rs1799963
PE
A
2
1
1.85 (1.29-2.66)
0.0009
1.82 (1.27-2.62)
0.001




DVT

3
1
3.01 (2.30-3.96)
<0.0001
3.01 (2.29-3.95)
<0.0001


F5
rs6025
PE
A
5
3
1.81 (1.45-2.27)
<0.0001
1.82 (1.45-2.28)
<0.0001




DVT

11
3
4.42 (3.75-5.21)
<0.0001
4.43 (3.76-5.22)
<0.0001





SNP annotation based on build 126, (human genome map 36) of the NCBI SNP database.


The risk estimate was calculated based on the risk allele analyzed using the general DVT endpoint.


*Allele frequency for the risk allele.



OR denotes odds ratio, which were estimated and adjusted for age and sex by logistic regression using an additive model. Sex was included as a covariate in logistic regression models containing markers residing on the X chromosome and the number of risk alleles for these SNPs were coded as 0 or 1 for males and 0, 1 or 2 for females.














TABLE 12







Association of Eight SNPs with PE











Count (Frequency %)
Unadjusted
Adjusted
















Gene
SNP
Risk allele
Genotype
Case
Control
OR (95% CI)
P Value
OR (95% CI)
P Value



















SERPINC1
rs2227589
T
TT
20 (2)
 43 (1)
1.87 (1.09-3.20)
0.02
1.85 (1.08-3.16)
0.02





TC
239 (20)
 766 (17)
1.26 (1.07-1.48)
0.006
1.23 (1.08-1.41)
0.002





CC
940 (78)
3782 (82)
Ref

Ref


CYP4V2
rs13146272
A
AA
513 (45)
1814 (41)
1.35 (1.08-1.68)
0.008
1.35 (1.08-1.67)
0.008





AC
494 (44)
1983 (45)
1.19 (0.95-1.48)
0.13
1.18 (0.95-1.47)
0.14





CC
122 (11)
 581 (13)
Ref

Ref


GP6
rs1613662
A
AA
842 (71)
3059 (67)
1.29 (0.87-1.90)
0.20
1.30 (0.88-1.92)
0.19





GA
319 (27)
1388 (30)
1.08 (0.72-1.61)
0.72
1.08 (0.72-1.62)
0.70





GG
32 (3)
150 (3)
Ref

Ref


F2
rs1799963
A
AA
 1 (0)
 0 (0)









AG
42 (4)
 92 (2)
1.78 (1.23-2.58)
0.002
1.75 (1.21-2.54)
0.003





GG
1157 (96) 
4514 (98)
Ref

Ref


F5
rs6025
A
AA
 4 (0)
 7 (0)
2.29 (0.67-7.84)
0.19
2.29 (0.67-7.86)
0.19





AG
105 (9) 
226 (5)
1.86 (1.46-2.37)
<0.0001
1.87 (1.47-2.38)
<0.0001





GG
1076 (91) 
4312 (95)
Ref

Ref


F5
rs4524
T
TT
702 (60)
2466 (55)
Ref

Ref





CT
410 (35)
1713 (38)
0.84 (0.73-0.96)
0.013
0.84 (0.74-0.97)
0.015





CC
58 (5)
325 (7)
0.63 (0.47-0.84)
0.002
0.62 (0.46-0.83)
0.001


F11
rs4253418
G
GG
1095 (93) 
4120 (91)
Ref

Ref





AG
76 (6)
381 (8)
0.75 (0.58-0.97)
0.03
0.75 (0.58-0.97)
0.029





AA
 5 (0)
 11 (0)
1.71 (0.59-1.93)
0.32
1.68 (0.58-4.85)
0.338


F11
rs3756008
T
AA
368 (31)
1672 (37)
Ref

Ref





TA
573 (49)
2115 (47)
1.23 (1.06-1.42)
0.005
1.23 (1.07-1.43)
0.005





TT
234 (20)
 730 (16)
1.46 (1.21-1.75)
<0.001
1.46 (1.22-1.76)
<0.001





*Genotypic allele frequency.


†The risk estimate (odds ratio) was calculated based on the risk allele analyzed with the general DVT endpoint.



Adjusted for age and sex.














TABLE 13







Association of Five SNPs with Isolated DVT











Count





(Frequency %)
Unadjusted
Adjusted















Gene
SNP
Genotype
Case
Control
OR (95% CI)
P Value
OR (95% CI)
P Value


















SERPINC1
rs2227589
TT
 31 (1)
 43 (1)
1.57 (0.98-2.50)
0.06
1.57 (0.98-2.49)
0.06




TC
 434 (20)
 766 (17)
1.23 (1.08-1.40)
0.002
1.23 (1.08-1.41)
0.002




CC
1740 (79)
3782 (82)
Ref

Ref


CYP4V2
rs13146272
AA
 991 (47)
1814 (41)
1.37 (1.15-1.62)
0.0003
1.37 (1.15-1.62)
0.0003




AC
 879 (42)
1983 (45)
1.11 (0.94-1.32)
0.23
1.11 (0.93-1.32)
0.24




CC
 232 (11)
 581 (13)
Ref

Ref


GP6
rs1613662
AA
1546 (70)
3059 (67)
1.26 (0.93-1.72)
0.13
1.26 (0.93-1.71)
0.13




GA
 604 (27)
1388 (30)
1.09 (0.80-1.49)
0.60
1.09 (0.79-1.49)
0.60




GG
 60 (3)
 150 (3)
Ref

Ref


F2
rs1799963
AA
 0 (0)
 0 (0)








AG
128 (6)
 92 (2)
3.01 (2.29-3.96)
<0.0001
1.75 (1.21-2.54)
0.003




GG
2085 (94)
4514 (98)
Ref

Ref


F5
rs6025
AA
 16 (1)
 7 (0)
5.64 (2.32-13.74)
0.0001
2.29 (0.67-7.86)
0.19




AG
 431 (20)
226 (5)
4.71 (3.97-5.58)
<0.0001
1.87 (1.47-2.38)
<0.0001




GG
1746 (80)
4312 (95)
Ref

Ref





*Genotypic allele frequency.



The odds ratio was calculated based on the risk allele analyzed using the general DVT endpoint.




Adjusted for age and sex.







Example Four
Multiple SNPs Independently Associated with Expression of Factor XI and Risk of Deep Vein Thrombosis

Overview


Two recent studies have detected association of DVT risk with SNPs in the 4q35 locus that contains genes encoding cytochrome P450, family 4, subfamily V, polypeptide 2 (CYP4V2), factor XI (F11) and prekallikrein (KLKB1) (Smith et al., JAMA 297, 489-98 (2007) and Bezemer et al., JAMA 299, 1306-14 (2008)). To determine the risk gene(s) among these candidates and identify the variants most likely to have a functional role in altering the risk for DVT, an analysis involving dense genotyping and association testing of 103 SNPs over 200 kbp in the CYP4V2/KLKB1/F11 locus in large case control sample sets (up to 3,155 cases and 5,087 controls) was carried out. Disease-SNP modeling identified three independently risk-related SNPs: rs2289252 (in F11, ORhomozygote [95% CI]=1.84 [1.62-2.10], Pgenotypic=1.7×10−20), rs2036914 (in F11: ORhomozygote [95% CI]=1.84 [1.61-2.10], Pgenotypic=6.5×10−19), and rs13146272 (in CYP4V2, ORhomozygote [95% CI]=1.58 [1.29-1.76], Pgenotypic=2.1×10−7). Genotypes of these markers are associated with the level of factor XI (FXI) which is known to associate with DVT (e.g., P=2.1×10−20 for rs2289252) (Meijers et al., N Engl J Med 342, 696-701 (2000)), and carriers of risk genotypes have higher levels of FXI than non-carriers. These data indicate that SNPs in CYP4V2 and F11 confer risk of DVT that is at least partly explained by FXI levels.


Introduction


In a large scale, gene-centric SNP-based association study, statistically significant associations were found between DVT and SNPs in the CYP4V2 region on chromosome 4, SERPINC1 on chromosome 1, and GP6 on chromosome 19 (Bezemer et al., JAMA 299, 1306-14 (2008)), as described above in Example One. Additional genotyping in the CYP4V2 region identified several associated markers in the neighboring genes, encoding factor XI (F11) and prekallikrein (KLKB1). In a candidate gene-based association study, Smith et al. reported that two SNPs in F11 were associated with risk of DVT in postmenopausal women with DVT (Smith et al., JAMA 297, 489-98 (2007)).


However, because of LD and the limited coverage of the genome by the initial characterizations, it remained undetermined whether the observed markers are “causal” or serve as proxies to untested causal variants and whether other variants at this locus add to DVT risk. Identification of the causal variants enables a better assessment of proper effect size and further understanding of pertinent biological mechanisms. This is of particular interest for the 4q35 region, since F11 and its homologue KLKB1 are both known to be involved in the intrinsic blood coagulation cascade: in the initial contact phase, activation of Factor XII is triggered in the presence of prekallikrein, a serine protease, resulting in subsequent activation of factor XI (FXI) that further leads to the middle phase of the intrinsic pathway of blood coagulation (Gailani et al., J Thromb Haemost 5, 1106-12 (2007)). Therefore, functional genetic variants in either F11 or KLKB1 may modulate DVT risk. For example, it is known that high levels of FXI are associated with increased risk of DVT (Meijers et al., N Engl J Med 342, 696-701 (2000)). To identify causal markers, an analysis involving comprehensive genotyping and association with DVT testing in the CYP4V2/KLKB1/F11 locus was carried out, which is described here in Example Four.


Results and Discussion


According to the HapMap CEPH dataset, the entire locus containing CYP4V2, KLKB1 and F11 resides in a region of high LD that is distinct from adjacent LD regions. To identify the causal marker(s), the region containing these genes was interrogated with 103 SNPs. The majority of these markers (90.3%) were selected to cover SNP diversity in the region. These 103 SNPs were first evaluated in two sample sets that contained 2,210 controls and 1,841 DVT cases: The Leiden Thrombophilia Study (LETS) and a subset of The Multiple Environmental and Genetic Assessment (MEGA) study, MEGA-1. The allelic association between 54 SNPs and DVT reached a significance level of 0.05; the 7 most significant markers were clustered in the F11 gene (Table 17). Two highly correlated F11 SNPs, rs3756011 and rs2289252 (r2=0.98), showed the strongest association with DVT (P=5.2×10−9 and 3.2×10−9, and OR=1.30 [1.19-1.42] and 1.31 [1.20-1.43], respectively).


To examine whether significant associations of these 54 SNPs were independent of each other, logistic regression models were evaluated for each possible pair of SNPs. Attempting to identify the most parsimonious set of SNPs that showed independent association with DVT risk, it was observed that the two strongest markers in F11, rs3756011 and rs2289252, remained significant after adjustment for any other markers except each other. Furthermore, they were the only markers whose significance was not appreciably attenuated after adjustment by other markers. Because LD between rs3756011 and rs2289252 was very high (r2=0.98), further analysis only included rs2289252.


To determine if any of the other markers made contributions to DVT risk, a search was carried out for those markers that were significantly associated with DVT after adjustment for rs2289252, which lead to the identification of 17 markers. Significance of these 17 markers was modest after the adjustment (P ranged from 0.0043 to 0.046). Within these markers, six were identified that were in high LD with one of the other significant markers (r2>0.95); the marker with the weaker association was removed from the list of 17 markers, leaving 11 markers.


To further examine the relationship between the above 11 markers and rs2289252, the markers were then tested in another large DVT case-control study (MEGA-2: 1,314 cases and 2,877 controls). Further statistical analyses was performed in the three sample sets combined instead of using a discovery-replication approach, as the former provides greater power (Skol et al., Nat Genet. 38, 209-3 (2006)). All eleven SNPs remained significant in a combined analysis of all samples (Mantel-Haenszel P<0.05, Table 18).


To identify a subset of the 11 SNPs that independently contributed to the association signals, two different analyses were performed: forward stepwise logistic regression and multiple logistic regressions. For forward stepwise logistic regression analysis, the selection procedure required a P-value<0.05 as a criterion for entry into the model where sample set, sex and age were covariates. A final model was derived that contained 3 markers, rs2289252, rs2036914 and rs13146272 (Table 14). No other SNPs were able to enter the model at a significance threshold of 0.05. The multiple logistic regression analysis identified rs2289252 as the most significant association after adjustment for age, sex and study (OR [95% CI]=1.21 [1.11-1.32]). The next strongest associations were rs2036914 (OR [95% CI]=1.13 [0.98-1.32) and rs13146272 (OR [95% CI]=1.09 [0.98 to 1.21]). Thus these three markers were the most informative ones among those interrogated in this study.


Two of the independent markers, rs2289252 (the same marker as reported in Smith et al., JAMA 297, 489-98 (2007)) and rs2036914, are in F11, and the third one, rs13146272, is in CYP4V2. All three markers appeared to operate in an additive model, with odds ratios up to 1.84 for the risk homozygote (Table 15). LD was modest between the two F11 markers (r2=0.38) and low between either of the F11 markers and the CYP4V2 marker (r2=0.12 and 0.04, respectively) (Table 19). These markers are common (for example, ˜27% of the population tested in these sample sets are risk homozygote carriers of rs2036914), indicating high DVT risk among a sizable fraction of the population. Furthermore, in contrast to the infrequent Factor V Leiden variant and prothrombin G20210A polymorphism that are mostly present in Caucasians, all three independent SNPs noted here are of similarly high frequencies in Asians and Africans, indicating that they also make a substantial contribution to DVT risk in these populations.


Both the F11 SNPs, rs2036914 and rs2289252, are intronic, thus these markers (or variants in high LD) may alter transcriptional regulatory elements such as an enhancer and these variants may modulate expression of F11. Therefore, association of the individual genotype and the level of FXI was tested in the LETS sample set. The genotype of rs2289252 was significantly associated with FXI levels (Ptrend=2.1×10−20, N=895). The genotype of rs2036914 has been shown to be associated with the level of FXI (Bezemer et al., JAMA 299, 1306-14 (2008)). The third SNP, rs13146272, is a missense variant (K259Q) of CYP4V2. CYP4V2 may play a role in fatty acid and steroid metabolism, and mutations in the gene cause autosomal recessive retinal dystrophy (Li et al., Am J Hum Genet 74, 817-26 (2004)). However, given the correlation of the CYP4V2 marker with the level of FXI (Bezemer et al., JAMA 299, 1306-14 (2008)), its genetic effect on DVT susceptibility may be indirectly mediated through FXI protein. This indirect effect may arise from a long-range transcriptional regulatory element of F11 encompassing the CYP4V2 SNP or its proxies (for example, rs2292425, an intronic SNP also in CYP4V2, which is in perfect LD [r2=1]); rs13146272 lies 67 kb upstream of the F11 gene, and long range regulatory elements have been observed across multiple genes (Kapranov et al., Nat Rev Genet. 8, 413-23 (2007)). Alternatively, the CYP4V2 SNP may be in high LD with another variant in or more proximal to the F11 gene that is capable of directly regulating F11 expression.


For all three markers, risk allele carriers had higher levels of FXI than those without the risk allele, and risk homozygote carriers had higher levels of FXI than the heterozygote carriers. In addition, the relative difference of the average FXI levels among individuals of different genotypes was greater for the F11 markers than for the CYP4V2 marker. For example, the average level of FXI in risk homozygote carriers was 119% for rs2289252, 119% for rs2036914, and 108% for rs13146272 relative to the non-carriers. Furthermore, in the model with all three SNPs, each risk allele of rs2289252 resulted in an increase of 7.6 units of FXI levels on average (P=3.7×10−10; it had an effect of 8.8 units and P=2.1×10−20 prior to adjustment by the other two SNPs), while the effect of rs2036914 alleles was only 1.9 units of FXI level (P=0.15; compared to an effect of 7.2 and p=5.6×10−13 prior to adjustment), and the effect of rs13146272 was 0.6 units per allele after adjustment (P=0.60; compared to an effect of 3.4 and P=0.002 prior to adjustment). The direction of the effect was consistent with the expected increase of DVT risk with high levels of FXI (Meijers et al., N Engl J Med 342, 696-701 (2000)).


To determine whether FXI levels contributed to the observed SNP-disease association, association of the three independent markers with DVT was re-tested following adjustment by Factor XI levels. For each of the three SNPs in the combined LETS and MEGA-1 sample sets, the adjustment for FXI levels lowered the risk estimates and increased the P values, but the association with DVT remained significant (Table 16).


In summary, the majority of the common genetic variants in the CYP4V2/KLKB1/F11 locus were analyzed. In addition, the large case control collections, with a total of >8,000 individuals, offered high power to not only convincingly implicate common SNPs of even modest effect in disease susceptibility but also reasonably distinguish their relationship (dependence) among various markers. Three independent SNPs, in particular, in the CYP4V2/KLKB1/F11 locus were identified that are associated with DVT. In addition, there was a strong correlation between genotype of each of these three independent markers and FXI levels. Directionality of the genotypic effect on DVT risk and that on FXI levels were congruent with earlier evidence that individuals with high levels of FXI are at elevated risk of DVT (Bezemer et al., JAMA 299, 1306-14 (2008) and Meijers et al., N Engl J Med 342, 696-701 (2000)), and SNPs associated with higher increase in FXI show stronger association with disease risk. Furthermore, adjustment of SNP-disease association by FXI protein did not abate the observed association. These genetic variants may directly or indirectly modulate F11 expression, thereby contributing to the differential risk of DVT, although prekallikrein and FXI expression may be co-regulated.


These markers may also be associated with other conditions such as myocardial infarction (Doggen et al., Blood 108, 4045-51 (2006) and Merlo et al., Atherosclerosis 161, 261-7 (2002)) and ischemic stroke (Yang et al., Am J Clin Pathol 126, 411-5 (2006)), where high levels of FXI may be a risk factor as well. Thus, in addition to their utility in predicting DVT risk, these markers may also be useful for predicting an individual's risk for myocardial infarction, ischemic stroke, and other diseases in which high levels of FXI are a risk factor for the disease.


Methods


LETS and MEGA Samples


The three case control sample sets used in this study included Caucasian individuals, primarily Northwestern Europeans; all provided informed consent. The Leiden Thrombophilia Study (LETS) sample set consisted of 443 cases (43% male) with a first confirmed DVT and 453 controls (42% male) with no history of DVT or PE. The participants were 18 to 70 years old without cancer when enrolled in the study, with a mean age (±SD) of 45 (±14) years for cases and 45 (±15) years for controls. The Multiple Environmental and Genetic Assessment (MEGA) study comprised participants aged 18 to 80 years, cases with first DVT and controls without history of DVT or PE. Two sample sets were derived from this study, MEGA-1 with 1,398 cases (47% male) and 1,757 controls (48% male) and MEGA-2 with 1,314 cases (48% male) and 2,877 controls (47% male). The mean ages of the cases and controls are 47±13 and 48±12 years in MEGA-1 and 48±13 and 47±12 years in MEGA-2, respectively. The total sample size is 3,155 cases and 5,087 controls. Additional information can be found in Bezemer et al., JAMA 299, 1306-14 (2008).


SNP Selection


Upon initial discovery of the association of CYP4V2 with DVT, additional genotyping and statistical analysis was carried out in a limited scope (Bezemer et al., JAMA 299, 1306-14 (2008)). In the study described here in Example Four, a comprehensive analysis of SNPs in the 4q35 locus and those of putative functional significance was carried out. The fine-mapping region was determined by examination of the LD structure at the CYP4V2/KLKB1/F11 locus in the HapMap CEPH dataset and was defined by two SNP landmarks, rs4862644 at 187,294,806 bp and rs13150040 at 187,494,774 bp on chromosome 4 (NCBI Build 36), encompassing 200 kbp. The targeted region covers the LD block containing the initial significant marker and a portion of the neighboring blocks and contains 320 known SNPS (187 of these with allele frequency than 2%) in the HapMap dataset. Selected markers included those that capture the SNP diversity in the defined region; they were identified by the tagger program, using the HapMap CEPH dataset and the following criteria: minimum allele frequency of 0.02 and pair wise r2 threshold of 0.8. Additional markers included missense/nonsense SNPs and those that are in high LD with any of the three significant SNPs previously reported, rs13146272 in CYP4V2, rs2036914 and rs3756008, both in F11 (r2>0.2).


Genotyping


Genotyping of individual samples was determined by allele-specific real-time PCR using primers designed and validated in Celera's high-throughput genotyping laboratory (Germer et al., Genome Res 10, 258-66 (2000)). Case and control samples were randomly arrayed in 384-well plates for the PCR reaction, and genotypes were assigned by an automated algorithm and subjected to manual inspection of assay qualities by a technician without the knowledge of case and control status. Genotyping accuracy in this laboratory has been consistently higher than 99% (Li et al., Proc Natl Acad Sci USA 101, 15688-93 (2004)).


Statistical Analyses


Hardy-Weinberg equilibrium for each genotyped SNP was examined in cases and controls separately by an exact test. Linkage disequilibrium measurements, D′ and r2 were calculated from the unphased genotype data using LDMax in the GOLD package (Abecasis et al., Bioinformatics 16, 182-3 (2000)). Odds ratios in individual sample sets were calculated using the observed allele counts. Allelic association of the SNPs with disease was determined by the x2 test in individual sample sets and by Mantel-Haenszel methods to combine odds ratios (OR) across the sample sets. P-values were 2 sided. Evidence for heterogeneity of effects across sample sets was examined by the Breslow-Day test (Breslow et al., IARC Sci Publ, 5-338 (1980)). Logistic regression was used to estimate odds ratios while adjusting for covariates such as age, sex, sample set, and Factor XI levels. To assess the relative importance among the significant markers (reference Cordell and Clayton here), logistic regression models were performed for each possible pair of SNPs as well as stepwise logistic regression models. These models assumed an additive effect of each additional risk allele on the log odds of DVT. Linear regression models were performed to estimate the effect of SNPs on Factor XI levels and to test for an increasing trend of mean Factor XI levels assuming an additive effect of each additional risk allele for a given SNP.









TABLE 14







SNPs in the final model by forward selection procedures in LETS,


MEGA-1 and MEGA-2 samples combined












SNP
Model*
OR (95% CI)**
P***







rs2289252
TT vs CC
1.49 (1.25-1.76)
3.8 × 10−6




CT vs CC
1.28 (1.13-1.45)
1.0 × 10−4



rs2036914
CC vs TT
1.33 (1.11-1.59)
1.8 × 10−3




CT vs TT
1.19 (1.03-1.38)
1.9 × 10−2



rs13146272
AA vs CC
1.24 (1.05-1.46)
1.1 × 10−2




AC vs CC
1.14 (0.97-1.34)
9.5 × 10−2







*risk genotype vs reference genotype



**adjusted by age, sex, sample set, and other SNPs in the model



***chi-square test













TABLE 15







Association of the three independently significant SNPs with DVT in LETS, MEGA-1 and


MEGA-2 samples combined














SNP/

Case
Case
Control
Control




Gene
Genotype
(N)
(%)
(N)
(%)
OR (95% CI)
P*

















rs2289252
TT
716
23.5
849
17.1
1.84 (1.62-2.10)
1.7 × 10−20


F11
TC
1511
49.6
2341
47.1
1.41 (1.27-1.57)



CC
817
26.8
1785
35.9
1.00 (reference)


rs2036914
CC
1080
35.1
1364
27.4
1.84 (1.61-2.10)
6.5 × 10−19


F11
CT
1499
48.7
2450
49.3
1.42 (1.26-1.61)



TT
499
16.2
1159
23.3
1.00 (reference)


rs13146272
AA
1391
47.2
1986
41.8
1.58 (1.29-1.76)
2.1 × 10−7


CYP4V2
AC
1263
42.8
2132
44.9
1.28 (1.09-1.49)



CC
295
10.0
635
13.4
1.00 (reference)





*logistic regression analysis adjusted by sample sets













TABLE 16







Association of rs2289252, rs13146272 and rs2036914 with DVT in the


LETS and MEGA-1 sample sets after adjustment by Factor XI












SNP
Model*
OR (95% CI)
P
















rs2289252
CT vs CC
1.27 (1.09-1.47)
0.002




TT vs CC
1.39 (1.15-1.69)
0.001



rs2036914
CT vs TT
1.26 (1.07-1.48)
0.006




CC vs TT
1.42 (1.19-1.70)
<0.001



rs13146272
CA vs CC
1.27 (1.04-1.56)
0.018




AA vs CC
1.40 (1.14-1.71)
0.001







*adjusted for FXI and study













TABLE 17







Significant markers (P < 0.05) in the LETS and MEGA-1 sample sets combined












Risk Allele




Allele
Frequency
















SNP
Location (bp)*
SNP Type
Gene Symbol
Risk
Reference
Case
Control
OR (95% CI)
P





rs1877321
187,316,011
intron
FAM149A
G
A
0.784
0.763
1.13 (1.02-1.26)
2.24E−02


rs10017419
187,345,132
intergenic

T
G
0.442
0.415
1.12 (1.02-1.22)
1.62E−02


rs10866290
187,351,473
intron
CYP4V2
C
T
0.357
0.335
 1.1 (1-1.21)
4.62E−02


rs10013653
187,352,626
intron
CYP4V2
A
C
0.473
0.433
1.18 (1.08-1.28)
3.47E−04


rs7682918
187,352,835
intron
CYP4V2
T
C
0.436
0.401
1.15 (1.05-1.26)
1.82E−03


rs7684025
187,353,221
intron
CYP4V2
A
G
0.508
0.464
1.19 (1.09-1.3)
9.32E−05


rs4862662
187,355,656
intron
CYP4V2
T
G
0.458
0.416
1.19 (1.09-1.3)
1.67E−04


rs13146272
187,357,205
missense
CYP4V2
A
C
0.682
0.642
 1.2 (1.09-1.31)
1.51E−04


rs3817184
187,359,298
intron
CYP4V2
T
C
0.464
0.421
1.19 (1.09-1.3)
1.06E−04


rs2276917
187,366,989
intron
CYP4V2
A
G
0.639
0.615
1.11 (1.01-1.21)
2.75E−02


rs1877320
187,368,273
intron
CYP4V2
A
G
0.905
0.885
1.24 (1.08-1.44)
3.12E−03


rs9995366
187,368,378
intron
CYP4V2
C
T
0.902
0.882
1.22 (1.06-1.41)
5.98E−03


rs2102575
187,368,498
intron
CYP4V2
A
G
0.910
0.889
1.26 (1.09-1.46)
2.25E−03


rs1053094
187,370,025
3UTR
CYP4V2
T
A
0.545
0.497
1.21 (1.11-1.32)
2.36E−05


rs6842047
187,370,570
3UTR
CYP4V2
C
A
0.910
0.891
1.23 (1.06-1.43)
6.50E−03


rs4253236
187,385,065
5′ near gene
KLKB1
C
T
0.677
0.637
1.19 (1.09-1.31)
1.93E−04


rs2048
187,385,127
5′ near gene
KLKB1
T
G
0.565
0.515
1.23 (1.12-1.34)
7.13E−06


rs4253238
187,385,381
5′ near gene
KLKB1
T
C
0.564
0.515
1.22 (1.1-1.34)
8.52E−05


rs1912826
187,386,534
intron
KLKB1
A
G
0.565
0.515
1.22 (1.12-1.34)
9.43E−06


rs4253252
187,394,452
intron
KLKB1
G
T
0.566
0.516
1.22 (1.12-1.33)
1.04E−05


rs3733402
187,395,028
missense
KLKB1
A
G
0.566
0.518
1.22 (1.11-1.33)
1.30E−05


rs4253260
187,399,071
intron
KLKB1
G
C
0.859
0.835
 1.2 (1.07-1.36)
2.86E−03


rs4253302
187,410,482
intron
KLKB1
A
G
0.859
0.836
1.19 (1.06-1.35)
4.57E−03


rs4253303
187,410,540
intron
KLKB1
A
G
0.442
0.398
 1.2 (1.1-1.31)
6.06E−05


rs4253311
187,411,677
intron
KLKB1
G
A
0.565
0.519
1.21 (1.1-1.32)
3.37E−05


rs2292423
187,412,716
intron
KLKB1
A
T
0.465
0.417
1.22 (1.11-1.33)
1.38E−05


rs925453
187,416,204
synonymous
KLKB1
C
T
0.708
0.687
1.11 (1.01-1.22)
3.52E−02


rs3087505
187,416,480
3UTR
KLKB1
G
A
0.910
0.889
1.26 (1.09-1.46)
2.01E−03


rs4253332
187,416,797
3′ near gene

C
T
0.701
0.679
1.11 (1-1.22)
3.93E−02


rs6844764
187,418,527
intergenic

G
C
0.587
0.561
1.11 (1.02-1.22)
1.90E−02


rs3756008
187,422,379
5′ near gene

T
A
0.468
0.408
1.27 (1.17-1.39)
7.66E−08


rs925451
187,424,563
intron
F11
A
G
0.458
0.392
1.31 (1.19-1.43)
4.44E−09


rs4253399
187,425,088
intron
F11
G
T
0.450
0.388
1.29 (1.18-1.41)
2.18E−08


rs3822057
187,425,146
intron
F11
C
A
0.551
0.494
1.26 (1.15-1.37)
3.64E−07


rs4253405
187,427,804
intron
F11
A
G
0.664
0.628
1.17 (1.07-1.28)
7.14E−04


rs2036914
187,429,475
intron
F11
C
T
0.591
0.526
 1.3 (1.19-1.42)
4.89E−09


rs1593
187,432,545
intron
F11
A
T
0.896
0.873
1.26 (1.1-1.45)
1.09E−03


rs4253418
187,436,491
intron
F11
G
A
0.966
0.953
1.39 (1.1-1.74)
4.56E−03


rs2241817
187,437,995
intron
F11
A
G
0.674
0.645
1.14 (1.04-1.25)
5.03E−03


rs4253422
187,441,996
intron
F11
C
G
0.850
0.834
1.13 (1-1.28)
4.31E−02


rs3822058
187,443,174
intron
F11
G
A
0.675
0.644
1.15 (1.05-1.26)
3.15E−03


rs3756011
187,443,243
intron
F11
A
C
0.485
0.420
 1.3 (1.19-1.42)
5.15E−09


rs2289252
187,444,375
intron
F11
T
C
0.485
0.419
1.31 (1.2-1.43)
3.23E−09


rs4253430
187,447,058
3UTR
F11
G
C
0.676
0.645
1.15 (1.05-1.26)
3.61E−03


rs11938564
187,449,128
intergenic

T
G
0.807
0.786
1.14 (1.02-1.27)
1.85E−02


rs13136269
187,454,002
intergenic

T
C
0.758
0.721
1.21 (1.1-1.34)
1.49E−04


rs13116273
187,454,880
intergenic

G
A
0.758
0.723
 1.2 (1.08-1.32)
4.05E−04


rs10025152
187,462,298
intergenic

G
A
0.857
0.829
1.23 (1.09-1.39)
8.43E−04


rs1008728
187,463,667
intergenic

T
C
0.656
0.622
1.16 (1.06-1.27)
1.91E−03


rs12500826
187,464,445
intergenic

C
T
0.658
0.624
1.16 (1.06-1.27)
1.91E−03


rs13133050
187,467,731
intergenic

C
A
0.696
0.672
1.11 (1.01-1.23)
2.58E−02


rs6552971
187,475,382
intergenic

A
G
0.529
0.505
 1.1 (1.01-1.2)
3.44E−02


rs6552972
187,475,398
intergenic

C
T
0.224
0.197
1.17 (1.05-1.31)
3.72E−03


rs9993749
187,476,843
intergenic

T
G
0.275
0.254
1.11 (1.01-1.23)
3.79E−02





*on chromsome 4, based on NCBI Build 36






For the SNPs provided in Table 17, SEQ ID NOs of exemplary sequences are indicated in Tables 1-2, with the exception of the following SNPs for which SEQ ID NOs of exemplary genomic context sequences provided in the Sequence Listing are as follows:


rs10017419=SEQ ID NO:2559


rs10866290=SEQ ID NO:2560


rs2276917=SEQ ID NO:2561


rs1877320=SEQ ID NO:2562


rs9995366=SEQ ID NO:2563


rs2102575=SEQ ID NO:2564


rs6842047=SEQ ID NO:2565


rs2048=SEQ ID NO:2566


rs4253238=SEQ ID NO:2567


rs1912826=SEQ ID NO:2568


rs4253252=SEQ ID NO:2569


rs4253260=SEQ ID NO:2570


rs4253311=SEQ ID NO:2571


rs925453=SEQ ID NO:2572


rs4253332=SEQ ID NO:2573


rs1593=SEQ ID NO:2574


rs4253422=SEQ ID NO:2575


rs11938564=SEQ ID NO:2576


rs10025152=SEQ ID NO:2577


rs1008728=SEQ ID NO:2578


rs13133050=SEQ ID NO:2579


rs9993749=SEQ ID NO:2580









TABLE 18







Significant markers (P < 0.05) in the LETS, MEGA-1 and MEGA-2 sample sets combined












Risk Allele




Allele
Frequency














SNP
Gene Symbol
Risk
Reference
Case
Control
OR
P





rs13146272
CYP4V2
C
A
0.686
0.642
1.21 (1.13-1.30)
2.88E−08


rs3817184
CYP4V2
C
T
0.469
0.417
1.23 (1.16-1.32)
1.63E−10


rs1053094
CYP4V2
A
T
0.550
0.493
1.25 (1.17-1.33)
5.47E−12


rs4253236
CYP4V2
T
C
0.676
0.639
1.17 (1.09-1.25)
3.02E−06


rs3733402
KLKB1
G
A
0.568
0.517
1.23 (1.15-1.31)
3.35E−10


rs4253302
KLKB1
G
A
0.859
0.837
1.18 (1.08-1.30)
1.92E−04


rs4253303
KLKB1
G
A
0.448
0.395
1.24 (1.17-1.33)
4.44E−11


rs2292423
KLKB1
T
A
0.468
0.411
1.25 (1.18-1.34)
5.59E−12


rs2036914
F11
T
C
0.594
0.521
1.34 (1.26-1.43)
3.58E−19


rs4253418
F11
A
G
0.966
0.956
1.31 (1.10-1.55)
1.43E−03


rs2289252
F11
C
T
0.483
0.406
1.35 (1.27-1.45)
2.96E−20
















TABLE 19







Marker LD in the LETS, MEGA-1 and MEGA-2 sample sets combined (controls): D′ shown in the upper right triangle,


r2 shown in the lower left triangle



















rs13146272
rs3817184
rs1053094
rs4253236
rs3733402
rs4253302
rs4253303
rs2292423
rs2036914
rs4253418
rs2289252





















rs13146272

0.993
0.58
0.618
0.546
0.955
0.912
0.781
0.443
0.812
0.338


rs3817184
0.392

0.986
0.812
0.772
0.931
0.889
0.82
0.587
0.717
0.351


rs1053094
0.182
0.716

0.843
0.804
0.954
0.901
0.918
0.585
0.723
0.461


rs4253236
0.382
0.267
0.39

0.991
0.993
0.983
0.985
0.397
0.937
0.235


rs3733402
0.178
0.398
0.586
0.593

0.993
0.964
0.981
0.55
0.93
0.412


rs4253302
0.319
0.12
0.172
0.34
0.205

0.994
0.995
0.56
0.995
0.35


rs4253303
0.302
0.72
0.544
0.356
0.565
0.125

0.979
0.659
0.932
0.37


rs2292423
0.238
0.658
0.608
0.383
0.63
0.134
0.892

0.686
0.939
0.418


rs2036914
0.118
0.227
0.307
0.097
0.298
0.066
0.26
0.303

0.968
0.773


rs4253418
0.054
0.017
0.024
0.072
0.043
0.009
0.026
0.028
0.047

1


rs2289252
0.043
0.117
0.149
0.021
0.108
0.016
0.131
0.17
0.376
0.031









Example Five
SNPs Associated with Venous Thrombosis (Analysis in Lets, MEGA-1, and/or MEGA-2)

Tables 20-23 provide SNPs associated with VT, particularly DVT, in the LETS, MEGA-1, and/or MEGA-2 sample sets (these sample sets are described in Examples One through Four above). Specifically, Table 20 provides unadjusted additive and genotypic association with DVT for 149 SNPs that were tested in both MEGA-1 and LETS, and were associated with DVT in both of these sample sets (p-value cutoff <=0.05 in MEGA-1 and p-value cutoff <=0.1 in LETS, in at least one model). Table 21 provides unadjusted association of 92 SNPs with DVT in LETS (p<=0.05) that have not yet been tested in the MEGA-1 sample set, and Table 22 provides unadjusted association of 9 SNPs with DVT in MEGA-1 (p<=0.05) that have not yet been tested in the LETS sample set. Table 23 provides age- and sex-adjusted association with DVT for 41 SNPs that were tested in the three sample sets LETS, MEGA-1, and MEGA-2.


Example Six
SNPs Associated with Recurrent Venous Thrombosis

Table 24 provides three SNPs that are examples of SNPs associated with recurrence of VT (p-value cutoff <=0.05 in MEGA-1 and MEGA-2 combined).


The MEGA study has been described previously (Blom et al., JAMA 2005; 293(6):715-722). An analysis for association of SNPs specifically with recurrent VT in MEGA is ongoing. Briefly, approximately 4000 individuals (cases) who have had a first-time VT in MEGA are being followed-up for about 5 years, and time to the next event (if any) is being recorded. Currently, this recurrent VT analysis in MEGA is approximately at the halfway point, and approximately 600 recurrent cases have been recorded. Certain SNPs have been specifically identified as examples of SNPs that are associated with recurrent VT, and these SNPs are provided in Table 24 below. These SNPs are particularly useful for, for example, determining the risk for individual who has already had VT of having another occurrence of VT.









TABLE 24







Two examples of SNPs associated with VT recurrence in MEGA (combined) (p <= 0.05).



















VT
No VT


p-value




Risk

recurrence
recurrence


(Fisher


Gene
SNP
allele
Genotype
(counts)
(counts)
OR
95% CI
Exact)


















F5
rs6025
A
GG
406
2235
1







GA
101
387
1.44
1.13-1.83
0.004032





AA
5
16
1.72
0.63-1.72
0.355669


ABO
rs8176719

O
121
793
1





non-O
447
2245
1.31
1.05-1.62
0.015636









Example Seven
SNPs Associated with Pulmonary Embolism (PE)

Table 25 provides 52 SNPs that are examples of SNPs associated with pulmonary embolism (PE) (p-value cutoff <=0.05 in MEGA-1 and MEGA-2 combined). SNPs associated with PE are also described in Example Three above. Example Three also provides further information regarding PE as well as information pertaining to methods and study populations in MEGA for determining associations with PE. Cases were individuals with a confirmed PE and no history of VT, and controls were individuals with no history of either PE or VT. The SNPs provided in Table 25 had a p-value <=0.05 when comparing these cases and controls in the combined MEGA-1 and MEGA-2 studies. These SNPs are particularly useful for, for example, determining an individual's risk for PE.


Example Eight
SNPs Associated with Venous Thrombosis in Individuals Who have Cancer

Table 26 provides 31 SNPs that are examples of SNPs that are associated with VT, particularly DVT, in individuals who have cancer (p-value cutoff <=0.05 in MEGA-1 and MEGA-2 combined). The SNPs provided in Table 26 had a p-value <=0.05 when comparing individuals (cases) in the combined MEGA-1 and MEGA-2 studies who had both cancer (of any type) and DVT compared with individuals (controls) who had neither cancer nor DVT. These SNPs are particularly useful for, for example, determining risk for VT in individuals who have cancer.


Example Nine
Fine-Mapping/Linkage Disequilibrium SNPs Associated with Venous Thrombosis

Table 27 provides 123 SNPs associated with VT, particularly DVT, in LETS (p-value cutoff <=0.1 in LETS) based on fine-mapping/linkage disequilibrium analysis. Table 27 provides additive association with DVT for each SNP, as well as linkage disequilibrium data from Hapmap. Table 27 specifically provides SNPs based on fine-mapping/linkage disequilibrium analysis around the following target genes and SNPs (as indicated in Table 27): gene AKT3 (SNP hCV233148), gene SERPINC1 (SNP hCV16180170), gene RGS7 (SNP hCV916107), gene NR1I2 (SNP hCV263841), gene FGG (SNP hCV11503469), gene CYP4V2 (SNP hCV25990131), gene GP6 (SNP hCV8717873), and gene F9 (SNP hCV596331).


The AKT3 gene and SNP rs1417121/hCV233148 are an example of a target around which fine-mapping/linkage disequilibrium analysis was carried out. Results of the association of AKT3 SNPs with DVT are provided in Table 27 (in LETS), as well as in Tables 28-29 below (which provide results in MEGA-1 as well as in LETS (Table 29), and in MEGA-2 for rs1417121 (Table 28)).


SNP rs1417121/hCV233148 in the AKT3 gene was identified among 24,965 SNPs tested in a functional genome scan (scan WGS38-V0013; Bezemer et al., JAMA 299, 1306-14 (2008)) and found by genotyping to be associated with DVT and PE in LETS, MEGA-1, and MEGA-2 with a p-value <0.05 and a consistent risk allele in all three studies (Tables 28-29). The FDR for this SNP is 0.044 in MEGA-2. To determine whether other SNPs in this region are associated with DVT, results from the HapMap Project were used to identify a region surrounding SNP rs1417121/hCV233148 (chr1:241735973). This region contained 228 SNPs with allele frequencies >2% (HapMap NCBI build 36, 2005). Allele frequencies and linkage disequilibrium were calculated from the SNP genotypes in the HapMap CEPH population, which includes Utah residents with ancestry from northern and western Europe. 36 of these 228 SNPs were selected for genotyping in LETS as surrogates for 205 of these 228 SNPs. Thus, these 205 SNPs included the 36 SNPs that were directly genotyped plus 169 SNPs that were in strong linkage disequilibrium (r2>0.8) with at least one of the 36 genotyped SNPs (these 36 SNPs may be referred to as “tagging SNPs”). The 36 tagging SNPs were chosen using pairwise tagging in Tagger (de Bakker et al. 2005) (implemented in Haploview (Barrett et al. 2005)). 62 SNPs (including the 36 tagging SNPs) were initially investigated in LETS, and 29 SNPs that were equally or more strongly associated with DVT in LETS than SNP rs1417121/hCV233148 were investigated in MEGA-1. 20 SNPs were associated with DVT in both LETS and MEGA-1 with an additive p-value <0.05 and a consistent risk allele (these 20 SNPs are shown in Table 29 below).









TABLE 28







Age and sex-adjusted associations of an AKT3 SNP with DVT in MEGA-2














Gene Symbol


Case
Control





(RS Number)
Chr:B36 Region
parameter
(frequency)
(frequency)
P value
Odds ratio (95% CI)
FDR*





AKT3 (rs1417121)
1:241735973
CC_vs_GG
126 (0.1)
 214 (0.08)
0.009
1.38 (1.08-1.75)





CG_vs_GG
494 (0.4)
1074 (0.39)
0.333
1.07 (0.93-1.24)




G G
626 (0.5)
1458 (0.53)
ref
ref
0.044




C_vs_G

(0.27)
0.018
1.13 (1.02-1.26)
















TABLE 29







Additive associations of 20 replicated AKT3 fine-mapping SNPs in LETS and MEGA-1










LETS
MEGA-1













additive
p-

p-



annotation
comparison
value
OR (95% CI)
value
OR (95% CI)















AKT3 (rs10737888)
C_vs_A
4E−05
1.58 (1.27-1.96)
0.001
1.21 (1.08-1.36)


AKT3 (rs6656918)
G_vs_A
5E−05
1.56 (1.26-1.94)
0.003
1.19 (1.06-1.34)


AKT3 (rs1538773)
G_vs_T
1E−04
1.55 (1.24-1.92)
0.006
1.18 (1.05-1.32)


AKT3 (rs10927041)
C_vs_T
0.0001
1.59 (1.26-2)
0.007
1.18 (1.05-1.34)


AKT3 (rs2290754)
C_vs_A
0.0001
1.57 (1.24-1.97)
0.019
1.15 (1.02-1.3)


AKT3 (rs7517340)
T_vs_C
0.0002
1.58 (1.24-2)
0.003
 1.2 (1.07-1.36)


AKT3 (rs10754807)
A_vs_G
0.0002
1.57 (1.24-1.98)
0.002
1.21 (1.07-1.36)


AKT3 (rs320339)
T_vs_G
0.0003
1.51 (1.21-1.9)
0.002
1.21 (1.07-1.37)


AKT3 (rs1417121)
C_vs_G
0.0003
1.45 (1.18-1.78)
0.001
 1.2 (1.08-1.33)


AKT3 (rs6671475)
G_vs_A
0.0004
1.52 (1.21-1.91)
0.014
1.16 (1.03-1.31)


AKT3 (rs1058304)
T_vs_C
0.0004
1.45 (1.18-1.78)
0.008
1.16 (1.04-1.29)


AKT3 (rs1458023)
C_vs_T
0.0004
 1.5 (1.2-1.88)
0.006
1.18 (1.05-1.33)


AKT3 (rs12048930)
T_vs_C
0.001
1.47 (1.17-1.86)
0.026
1.15 (1.02-1.29)


AKT3 (rs1578275)
C_vs_G
0.0012
1.49 (1.17-1.89)
0.047
1.14 (1-1.29)


AKT3 (rs10927035)
C_vs_T
0.0019
1.36 (1.12-1.66)
0.002
1.18 (1.06-1.3)


AKT3 (rs12140414)
C_vs_T
0.0026
1.44 (1.14-1.82)
0.04
1.14 (1.01-1.3)


AKT3 (rs12037013)
A_vs_G
0.0029
1.49 (1.15-1.93)
0.021
1.18 (1.02-1.35)


AKT3 (rs12744297)
G_vs_A
0.0058
1.32 (1.08-1.61)
0.001
1.19 (1.07-1.32)


AKT3 (rs10927065)
A_vs_C
0.01
 1.4 (1.08-1.8)
0.013
1.18 (1.04-1.34)


AKT3 (rs12045585)
A_vs_G
0.0354
1.32 (1.02-1.72)
0.002
1.25 (1.08-1.43)









Example Ten
Additional SNPs in Linkage Disequilibrium with Venous Thrombosis-Associated Interrogated SNPs

An additional analysis was conducted to identify additional SNP markers in linkage disequilibrium (LD) with SNPs which have been found to be associated with VT, such as shown in the tables and described in the Examples. Briefly, the power threshold (T) was set at 51% for detecting disease association using LD markers. This power threshold is based on equation (31) above, which incorporates allele frequency data from previous disease association studies, the predicted error rate for not detecting truly disease-associated markers, and a significance level of 0.05. Using this power calculation and the sample size, a threshold level of LD, or r2 value, was derived for each interrogated SNP (rT2, equations (32) and (33)). The threshold value rT2 is the minimum value of linkage disequilibrium between the interrogated SNP and its LD SNPs possible such that the non-interrogated SNP still retains a power greater or equal to T for detecting disease-association.


Based on the above methodology, LD SNPs were found for the interrogated SNPs. LD SNPs are listed in Table 4, each associated with its respective interrogated SNP. Also shown are the public SNP IDs (rs numbers) for interrogated and LD SNPs, the threshold r2 value and the power used to determine this, and the r2 value of linkage disequilibrium between the interrogated SNP and its matching LD SNP. As an example, in Table 4, VT-associated interrogated SNP hCV11503414 (rs2066865) was calculated to be in LD with hCV11503416 (rs2066864) at an rT2 value of 1, using 51% power, thus establishing SNP hCV11503416 as a marker associated with VT as well.


In general, the threshold rT2 value can be set such that one of ordinary skill in the art would consider that any two SNPs having an r2 value greater than or equal to the threshold rT2 value would be in sufficient LD with each other such that either SNP is useful for the same utilities, such as determining an individual's risk for VT. For example, in various embodiments, the threshold rT2 value used to classify SNPs as being in sufficient LD with an interrogated SNP (such that these LD SNPs can be used for the same utilities as the interrogated SNP, for example, such as determining VT risk) can be set at, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99, 1, etc. (or any other r2 value in-between these values). Threshold rT2 values may be utilized with or without considering power or other calculations.


All publications and patents cited in this specification are herein incorporated by reference in their entirety. Modifications and variations of the described compositions, methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments and certain working examples, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention that are obvious to those skilled in the field of molecular biology, genetics and related fields are intended to be within the scope of the following claims.













TABLE 3






Al-





Marker
leles
Primer 1 (Allele-specific Primer)
Primer 2 (Allele-specific Primer)
Common Primer







hCV10008773
T/C
CACGTGTGCTCACTTACAGAT (SEQ ID NO: 1588)
CACGTGTGCTCACTTACAGAC (SEQ ID NO: 1589)
CGGCTCGATTGTCTCATAC (SEQ ID NO: 1590)





hCV11342584
A/T
GGCTGCTAGCCAAATACTATTA (SEQ ID NO: 1591)
GGCTGCTAGCCAAATACTATTT (SEQ ID NO: 1592)
AGACTGCAACCTGGGAAATCCTATAG (SEQ ID NO: 1593)





hCV11466393
C/G
GGATGGAATGTTTTCCCTAAC (SEQ ID NO: 1594)
GGATGGAATGTTTTCCCTAAG (SEQ ID NO: 1595)
CCTTCATGCATGGAAATTC (SEQ ID NO: 1596)





hCV11503414
A/G
TGTTTCCTAAGACTAGATACATGGTAT (SEQ ID
GTTTCCTAAGACTAGATACATGGTAC (SEQ ID NO: 1598)
CCCAAAGAGTTAGGCATAACATTTAGCAT (SEQ ID




NO: 1597)

NO: 1599)





hCV11503431
C/T
CCAGTGCTTGCCTTCTC (SEQ ID NO: 1600)
CCAGTGCTTGCCTTCTT (SEQ ID NO: 1601)
CATGGATGCTTGTTGACACATTAACCT (SEQ ID NO: 1602)





hCV11503469
A/T
AGTTTACAATCTAATGCAGTGGT (SEQ ID NO: 1603)
CAGTTTACAATCTAATGCAGTGGA (SEQ ID NO: 1604)
CTCAGCTAATCAGTTGTCAATCAAGTCA (SEQ ID NO: 1605)





hCV11503470
C/T
AAAATGATGGGAAGTTAGGG (SEQ ID NO: 1606)
CAAAATGATGGGAAGTTAGGA (SEQ ID NO: 1607)
AAGCTTAGATTTGTTTTCTCACATA (SEQ ID NO: 1608)





hCV11541681
C/G
CCACCTTCTCTTCAGATTCAC (SEQ ID NO: 1609)
CCACCTTCTCTTCAGATTCAG (SEQ ID NO: 1610)
CTGGACGCGGTATGTAGAC (SEQ ID NO: 1611)





hCV11559107
A/G
TGAGATTTTGAAGACATCTGGTA (SEQ ID NO: 1612)
GAGATTTTGAAGACATCTGGTG (SEQ ID NO: 1613)
CTGAATGCAAGCTGATGACT (SEQ ID NO: 1614)





hCV11629656
G/T
CCCCAATAAAAGGACACAGTTAG (SEQ ID NO: 1615)
GCCCCAATAAAAGGACACAGTTAT (SEQ ID NO: 1616)
TGAATTTGGGAGGCACTTAG (SEQ ID NO: 1617)





hCV11629657
A/G
TGTCCTAAGATTAGCTAATATTTAACAT (SEQ ID
TGTCCTAAGATTAGCTAATATTTAACAC (SEQ ID
AAGTGCCTCCCAAATTCAC (SEQ ID NO: 1620)




NO: 1618)
NO: 1619)






hCV11633415
C/T
CCCAGAGGTCTACTATCTGAC (SEQ ID NO: 1621)
CCCAGAGGTCTACTATCTGAT (SEQ ID NO: 1622)
CCCTCATTTTAGCATGTAGCAGTTCA (SEQ ID NO: 1623)





hCV11726971
A/G
GCAAGGTGTCTCCGAATTAT (SEQ ID NO: 1624)
GCAAGGTGTCTCCGAATTAC (SEQ ID NO: 1625)
TTTTGGGAGGTGATAGCCAGAATCA (SEQ ID NO: 1626)





hCV11786147
G/T
CGTGCGTGAATTGAATGG (SEQ ID NO: 1627)
ACGTGCGTGAATTGAATGT (SEQ ID NO: 1628)
GCACGGACATACTCGGAATCATC (SEQ ID NO: 1629)





hCV11786258
A/G
GTGGAGAATACCCACTCAGT (SEQ ID NO: 1630)
TGGAGAATACCCACTCAGC (SEQ ID NO: 1631)
GCGGGGATGGTATTCACAACATTTA (SEQ ID NO: 1632)





hCV11853483
A/G
CACACACATCTTTAAAATCCATTCTATT (SEQ ID
CACACACATCTTTAAAATCCATTCTATC (SEQ ID
CCCAATGCCTGTGCTCTTAAC (SEQ ID NO: 1635)




NO: 1633)
NO: 1634)






hCV11853496
A/T
CCTTTCTCACCTGATAGAATGAGT (SEQ ID NO: 1636)
CCTTTCTCACCTGATAGAATGAGA (SEQ ID NO: 1637)
TCATTGTGTGCTACTCCCACTTCA (SEQ ID NO: 1638)





hCV11922386
C/T
CCTGGCCCTTTCCTACG (SEQ ID NO: 1639)
CCTGGCCCTTTCCTACA (SEQ ID NO: 1640)
CACTGCTGGACAGCAATCTGT (SEQ ID NO: 1641)





hCV11942562
A/G
ACGAATGTGATGGCCACA (SEQ ID NO: 1642)
CGAATGTGATGGCCACG (SEQ ID NO: 1643)
GGCAGCCTGGTTGATGAGT (SEQ ID NO: 1644)





hCV11962159
C/T
ATTAAGCAACTGGTTTCCG (SEQ ID NO: 1645)
CATTAAGCAACTGGTTTCCA (SEQ ID NO: 1646)
TCAAGCAGTGGTGATCTCAG (SEQ ID NO: 1647)





hCV11975250
T/C
AGGACAAAATACCTGTATTCCTT (SEQ ID NO: 1648)
AGGACAAAATACCTGTATTCCTC (SEQ ID NO: 1649)
GATGAACCCACAGAAAATGAT (SEQ ID NO: 1650)





hCV11975296
T/C
CAGTCCATGGTTCCTTCAT (SEQ ID NO: 1651)
CAGTCCATGGTTCCTTCAC (SEQ ID NO: 1652)
CTCCACCTGCATTTCAGAG (SEQ ID NO: 1653)





hCV11975651
C/G
CACCTTCCCCACTCTCTTAG (SEQ ID NO: 1654)
ACCTTCCCCACTCTCTTAC (SEQ ID NO: 1655)
GCCTTTTGCATGCCTTAACACT (SEQ ID NO: 1656)





hCV11975658
A/G
GGTGACAGGGGAGAAAAGA (SEQ ID NO: 1657)
GGTGACAGGGGAGAAAAGG (SEQ ID NO: 1658)
GTCTGACCTAGGCTAATGTCTAACACT (SEQ ID NO: 1659)





hCV1198623
C/G
CCATGCCTGATACAGAAGAC (SEQ ID NO: 1660)
CCATGCCTGATACAGAAGAG (SEQ ID NO: 1661)
TGTGTCAGGTGGGATGAGA (SEQ ID NO: 1662)





hCV1202883
G/A
GCGTGATGATGAAATCGG (SEQ ID NO: 1663)
GCGTGATGATGAAATCGA (SEQ ID NO: 1664)
AGCCTCTCCTGACTGTCATC (SEQ ID NO: 1665)





hCV12066124
C/T
GCAGCTTTTGCCAGTAAAGAC (SEQ ID NO: 1666)
GCAGCTTTTGCCAGTAAAGAT (SEQ ID NO: 1667)
GGTACGTTGGCTTCAATGGAATTG (SEQ ID NO: 1668)





hCV12073840
C/T
ACGGACACTGGACATACC (SEQ ID NO: 1669)
AACGGACACTGGACATACT (SEQ ID NO: 1670)
GTGACATCAGCTCTGTGTTGAGAT (SEQ ID NO: 1671)





hCV12086148
A/G
GTGAAGGTTTCCCTTTAAGTTACT (SEQ ID NO: 1672)
TGAAGGTTTCCCTTTAAGTTACC (SEQ ID NO: 1673)
CCTTCTCCCTCTTGCCTTCACT (SEQ ID NO: 1674)





hCV12092542
T/C
GCCTTGTCTTCAATTTTGGT (SEQ ID NO: 1675)
CCTTGTCTTCAATTTTGGC (SEQ ID NO: 1676)
AACAGTTAAGATGTTGGAATACCT (SEQ ID NO: 1677)





hCV12098639
C/G
GGATGTGGCTTCCCC (SEQ ID NO: 1678)
GGATGTGGCTTCCCG (SEQ ID NO: 1679)
GACTCGGACCCTGACTGA (SEQ ID NO: 1680)





hCV134275
A/G
GGTGCTTAGAATACATCAACAAAAT (SEQ ID NO: 1681)
GGTGCTTAGAATACATCAACAAAAC (SEQ ID NO: 1682)
CCAATCTTCCTTACCCGATTTCTTCT (SEQ ID NO: 1683)





hCV134278
C/T
TAACCTGATCCATTATCCAAGATAC (SEQ ID NO: 1684)
GTAACCTGATCCATTATCCAAGATAT (SEQ ID NO: 1685)
GGAGCCACCCGACACTTAC (SEQ ID NO: 1686)





hCV1376206
C/T
AGCAGGCTACTACTCCTTC (SEQ ID NO: 1687)
AAGCAGGCTACTACTCCTTT (SEQ ID NO: 1688)
GCAGCAATTCCTGTTTGATGTC (SEQ ID NO: 1689)





hCV1376207
C/G
CGTACAGACAGCCGAGG (SEQ ID NO: 1690)
CGTACAGACAGCCGAGC (SEQ ID NO: 1691)
TCACCGGACATCAAACAGGAATTG (SEQ ID NO: 1692)





hCV1376227
A/C
TCTCAACTTGGCTATCTTACAAATA (SEQ ID NO: 1693)
TCTCAACTTGGCTATCTTACAAATC (SEQ ID NO: 1694)
GCCCATCCCGAGTCAAATTCT (SEQ ID NO: 1695)





hCV1376246
A/C
CTTATTGAGTTCATCATTAAAGTCATCT (SEQ ID
TTATTGAGTTCATCATTAAAGTCATCG (SEQ ID
CTGTGCCTCCTTAACAGACTTTCAG (SEQ ID NO: 1698)




NO: 1696)
NO: 1697)






hCV1376342
C/T
ACTCACCAGTTGTGAAGACTTC (SEQ ID NO: 1699)
TACTCACCAGTTGTGAAGACTTT (SEQ ID NO: 1700)
TCAGGGAGCCTAGATATCTCA (SEQ ID NO: 1701)





hCV1420741
C/G
CAGGCTTTAAGGACAGGC (SEQ ID NO: 1702)
CAGGCTTTAAGGACAGGG (SEQ ID NO: 1703)
CCAGCATTCGTGGACTCAA (SEQ ID NO: 1704)





hCV1455329
A/G
CATGTTTTGTGAACAAAGATTCCAT (SEQ ID NO: 1705)
TGTTTTGTGAACAAAGATTCCAC (SEQ ID NO: 1706)
GGGGCACTTACACAGCTATAGACA (SEQ ID NO: 1707)





hCV1547677
A/G
AGGTGACAGTCCCAACACT (SEQ ID NO: 1708)
GTGACAGTCCCAACACC (SEQ ID NO: 1709)
TGATTCTGGAATGATGGTAAGTC (SEQ ID NO: 1710)





hCV15755949
A/G
AATACTTAGTTCTCCCCTCCATAA (SEQ ID NO: 1711)
ATACTTAGTTCTCCCCTCCATAG (SEQ ID NO: 1712)
GGTGAAGAATGTTTGGCTCCTAGAAATA (SEQ ID NO: 1713)





hCV15793897
A/G
AGCTCTGAGTGCACTGTGTT (SEQ ID NO: 1714)
AGCTCTGAGTGCACTGTGTC (SEQ ID NO: 1715)
CAGAGTCTAGGCAATTTTTACAAC (SEQ ID NO: 1716)





hCV15860433
C/T
ACCCAAGACTTAGTAAACATTCAG (SEQ ID NO: 1717)
ACCCAAGACTTAGTAAACATTCAA (SEQ ID NO: 1718)
CCTGTACTTTATCTGGCAATCCTACCT (SEQ ID NO: 1719)





hCV15864094
A/G
GTGGATCAAGCTTCGTTGTTAT (SEQ ID NO: 1720)
TGGATCAAGCTTCGTTGTTAC (SEQ ID NO: 1721)
GACCCAAGTGTCATTCTCAGTAGACA (SEQ ID NO: 1722)





hCV15871021
G/A
AAATCTTGCTCTTTATGAGTATTTG (SEQ ID NO: 1723)
GAAATCTTGCTCTTTATGAGTATTTA (SEQ ID NO: 1724)
CATGTCTGAGGGTGATATTTATTC (SEQ ID NO: 1725)





hCV15885425
A/C
CATTTACAATGTAACAGCAAAACCA (SEQ ID NO: 1726)
TTTACAATGTAACAGCAAAACCC (SEQ ID NO: 1727)
TCCACCTCTTCCCGTGAGAAAG (SEQ ID NO: 1728)





hCV15947925
C/T
GCTCCAGGACAGAGAACG (SEQ ID NO: 1729)
GCTCCAGGACAGAGAACA (SEQ ID NO: 1730)
CACCGCTTACCTCCCTTCTG (SEQ ID NO: 1731)





hCV15949414
A/G
GGCTTTCATAATGCAAATGT (SEQ ID NO: 1732)
GCTTTCATAATGCAAATGC (SEQ ID NO: 1733)
TCTTGCAGGTGGAACAGAT (SEQ ID NO: 1734)





hCV15952952
A/G
AAAGTGGAGAAGGCTCTGAT (SEQ ID NO: 1735)
AAAGTGGAGAAGGCTCTGAC (SEQ ID NO: 1736)
CACACACACACGAAACAATACTAC (SEQ ID NO: 1737)





hCV15953063
A/G
GTTGGAAATAATGTAGGATGAAGACA (SEQ ID
TGGAAATAATGTAGGATGAAGACG (SEQ ID NO: 1739)
GGATCCCGGCAGTGACT (SEQ ID NO: 1740)




NO: 1738)







hCV15956034
A/C
CACTGAGCTGAAATGATCCATA (SEQ ID NO: 1741)
ACTGAGCTGAAATGATCCATC (SEQ ID NO: 1742)
CACGGGGCCTAGGATGGTATATT (SEQ ID NO: 1743)





hCV15956054
C/T
CACCCAGTGCAGATTCAC (SEQ ID NO: 1744)
CACCCAGTGCAGATTCAT (SEQ ID NO: 1745)
CGGCTTTGCACCTCTGTTCTT (SEQ ID NO: 1746)





hCV15956055
G/T
GCAAGAAGGCAAGTCCC (SEQ ID NO: 1747)
GCAAGAAGGCAAGTCCA (SEQ ID NO: 1748)
GGGTCTGTGTGTGGGTACTG (SEQ ID NO: 1749)





hCV15956059
C/T
TGTAGTTGAAGGACAGAGTGG (SEQ ID NO: 1750)
TGTAGTTGAAGGACAGAGTGA (SEQ ID NO: 1751)
GGTGCAAAGCCGGAGAGAA (SEQ ID NO: 1752)





hCV15956077
A/G
TTACTCTAACACAGGGTTCCA (SEQ ID NO: 1753)
ACTCTAACACAGGGTTCCG (SEQ ID NO: 1754)
CCTCTCATGGGAGATGAACAGTACA (SEQ ID NO: 1755)





hCV15968043
A/T
GCCCAGTTTCAAACAGGA (SEQ ID NO: 1756)
GCCCAGTTTCAAACAGGT (SEQ ID NO: 1757)
GAGAAAGGTGTATCTTTTGTAATGTCTGACAGAT (SEQ ID






NO: 1758)





hCV15977624
A/G
GTCCTCTTCACCAAGGAGT (SEQ ID NO: 1759)
TCCTCTTCACCAAGGAGC (SEQ ID NO: 1760)
CTCCCATCAGCCTAGGATCATG (SEQ ID NO: 1761)





hCV15990789
A/G
TGAACCTGAGCGTGTCAA (SEQ ID NO: 1762)
TGAACCTGAGCGTGTCAG (SEQ ID NO: 1763)
GCCAGTGCCTTCCTACAA (SEQ ID NO: 1764)





hCV16000557
C/T
ACAAAGTCACACCGAATCG (SEQ ID NO: 1765)
AACAAAGTCACACCGAATCA (SEQ ID NO: 1766)
CCCCTGCGTGATCATTAAAGTG (SEQ ID NO: 1767)





hCV1605386
A/G
AGTGGGAAACACACAGAAATTTA (SEQ ID NO: 1768)
GTGGGAAACACACAGAAATTTG (SEQ ID NO: 1769)
GCACCATTGCCCTCCAG (SEQ ID NO: 1770)





hCV16135173
C/G
GGCAACCTCAACACAGAC (SEQ ID NO: 1771)
GGCAACCTCAACACAGAG (SEQ ID NO: 1772)
GCCTGCTACATTTGAACTTGCTCTTA (SEQ ID NO: 1773)





hCV16170613
A/G
ACAGCAGGCATTGTTTTCT (SEQ ID NO: 1774)
AGCAGGCATTGTTTTCC (SEQ ID NO: 1775)
CCTATAAACAGCATGTGATCATATT (SEQ ID NO: 1776)





hCV16172935
A/G
GGAGTTACACCCATAAACCAT (SEQ ID NO: 1777)
GGAGTTACACCCATAAACCAC (SEQ ID NO: 1778)
GAGCAAGCTCAGAAAATTTTTAT (SEQ ID NO: 1779)





hCV16177220
C/T
ATCTGGTGGTCATTCAAATG (SEQ ID NO: 1780)
CATCTGGTGGTCATTCAAATA (SEQ ID NO: 1781)
TGATTGTGAGGTTCTAAAAGAGATA (SEQ ID NO: 1782)





hCV16180170
C/T
GGGAGAGCACTTGAAATGAC (SEQ ID NO: 1783)
GGGAGAGCACTTGAAATGAT (SEQ ID NO: 1784)
CAAAGGACTCACAGGAATGAC (SEQ ID NO: 1785)





hCV1650632
C/T
TCATCCAGCCACTCC (SEQ ID NO: 1786)
ATTCATCCAGCCACTCT (SEQ ID NO: 1787)
CTTCAAAGGTGATGACATC (SEQ ID NO: 1788)





hCV1678674
C/T
GGCTTCAAAGTGATAAATTCTATATTCG (SEQ ID
GGCTTCAAAGTGATAAATTCTATATTCA (SEQ ID
ACTATTCATAGATGCCTGTCACTATTCAGAA (SEQ ID




NO: 1789)
NO: 1790)
NO: 1791)





hCV1678682
G/T
GGACACAACTCATTATTCTGGG (SEQ ID NO: 1792)
GGACACAACTCATTATTCTGGT (SEQ ID NO: 1793)
TGGGGAAGGCCTGATGTCA (SEQ ID NO: 1794)





hCV1703855
C/T
AACGAATGGCATGTATTTTATGG (SEQ ID NO: 1795)
AAACGAATGGCATGTATTTTATGA (SEQ ID NO: 1796)
CAAGTGAAACATGGCGTCTTGT (SEQ ID NO: 1797)





hCV1703867
C/T
CGATGATTTTGTTCTCATGTTCG (SEQ ID NO: 1798)
CGATGATTTTGTTCTCATGTTCA (SEQ ID NO: 1799)
CCATCACCCAGGGATTTCAACTTAC (SEQ ID NO: 1800)





hCV1703892
A/T
CCTGTTGCATTCTGGATACT (SEQ ID NO: 1801)
CCTGTTGCATTCTGGATACA (SEQ ID NO: 1802)
GCTTCTACCGCTTCCCTCTACT (SEQ ID NO: 1803)





hCV1703910
A/G
ACCTATGTAACACACCCTTCTATT (SEQ ID NO: 1804)
ACCTATGTAACACACCCTTCTATC (SEQ ID NO: 1805)
CCTTGCATCTTCGTATACTGTTAATTCTAAACC (SEQ ID






NO: 1806)





hCV1723643
A/C
ACCCTCACAGCTCTGAAGA (SEQ ID NO: 1807)
CCCTCACAGCTCTGAAGC (SEQ ID NO: 1808)
TCCACACGCACAAGATGA (SEQ ID NO: 1809)





hCV1825046
C/T
TGCACAGTCCCCTGAC (SEQ ID NO: 1810)
CTGCACAGTCCCCTGAT (SEQ ID NO: 1811)
CTTCGAAGAAGACATGGGCTCTAGA (SEQ ID NO: 1812)





hCV1833991
C/T
GGGAGCCTTAATAAGATTAACAGC (SEQ ID NO: 1813)
GGGAGCCTTAATAAGATTAACAGT (SEQ ID NO: 1814)
CCTCTCCAACATCCTCTCCTTGTTAT (SEQ ID NO: 1815)





hCV1834242
A/G
CCTACTTTCACAAACATATCTTTGAA (SEQ ID
CCTACTTTCACAAACATATCTTTGAG (SEQ ID NO: 1817)
CTTACCATCTTTGGTTCTTGCCATCTT (SEQ ID NO: 1818)




NO: 1816)







hCV1841975
A/T
TCGTGGAGATACTGCAAGTT (SEQ ID NO: 1819)
GTCGTGGAGATACTGCAAGTA (SEQ ID NO: 1820)
GCTAGTGCCACTGTTTGTCTATG (SEQ ID NO: 1821)





hCV1842260
G/T
TCTCAGGCACCTGGATTAG (SEQ ID NO: 1822)
GTCTCAGGCACCTGGATTAT (SEQ ID NO: 1823)
TTATCCAAATTTCACCATCTCA (SEQ ID NO: 1824)





hCV1859855
C/T
GGCCTCACTAGAGAAGGAGAG (SEQ ID NO: 1825)
GGCCTCACTAGAGAAGGAGAA (SEQ ID NO: 1826)
GGAAGGAGGCTGGTGTGT (SEQ ID NO: 1827)





hCV1874482
A/G
AAAGGTTTCTTCTGATCACTGAT (SEQ ID NO: 1828)
AAAGGTTTCTTCTGATCACTGAC (SEQ ID NO: 1829)
CCCTTTTTGCAGCTGTATTC (SEQ ID NO: 1830)





hCV18996
C/T
TGAAGTAATACTGGAGATCAAATTAC (SEQ ID
TGAAGTAATACTGGAGATCAAATTAT (SEQ ID NO: 1832)
TGCTGCCCCATTTTCTAATA (SEQ ID NO: 1833)




NO: 1831)







hCV1900162
C/T
CAGTATACCTAGAGCATAGTGG (SEQ ID NO: 1834)
AACCAGTATACCTAGAGCATAGTGA (SEQ ID NO: 1835)
TGTTCTTTGGTGGGTAACTTTA (SEQ ID NO: 1836)





hCV1937195
A/G
CACAGGGCACAGATAACT (SEQ ID NO: 1837)
CAGGGCACAGATAACC (SEQ ID NO: 1838)
GGCCTCTTCCCTTTGATTA (SEQ ID NO: 1839)





hCV1974936
C/T
TGTGCACAAAGATAGGTCAC (SEQ ID NO: 1840)
GTGTGCACAAAGATAGGTCAT (SEQ ID NO: 1841)
AGGCTTAGACAAGGTGGTGACTTAC (SEQ ID NO: 1842)





hCV1974951
A/G
CGGGACACCATCCACA (SEQ ID NO: 1843)
CGGGACACCATCCACG (SEQ ID NO: 1844)
TCCTCCATGCTGGGTACCTC (SEQ ID NO: 1845)





hCV1974967
A/G
CACATCCAACGAGAAATTGCTA (SEQ ID NO: 1846)
ACATCCAACGAGAAATTGCTG (SEQ ID NO: 1847)
AGGGTCCACGTCTGACAAGT (SEQ ID NO: 1848)





hCV2017876
A/G
ACTGCTTCCAGAAGATCAAGT (SEQ ID NO: 1849)
CTGCTTCCAGAAGATCAAGC (SEQ ID NO: 1850)
TCCAGACAGCAGAGGATTACTGG (SEQ ID NO: 1851)





hCV2086329
A/G
CCCAGCCACACTGTTGA (SEQ ID NO: 1852)
CCAGCCACACTGTTGG (SEQ ID NO: 1853)
CTTGCCTGCATTTTTAACAC (SEQ ID NO: 1854)





hCV2103346
C/T
AGGAGCCATGATGCCC (SEQ ID NO: 1855)
GAGGAGCCATGATGCCT (SEQ ID NO: 1856)
ACTGGTGTGGTCAACGTGTATCA (SEQ ID NO: 1857)





hCV2103392
C/T
CCTCCTCCATGAAGCTGTC (SEQ ID NO: 1858)
CCTCCTCCATGAAGCTGTT (SEQ ID NO: 1859)
CCATAATGCAATGTGGCAAGTTCTAC (SEQ ID NO: 1860)





hCV2144411
A/G
AAGCTCCGGGGTTATTGT (SEQ ID NO: 1861)
GCTCCGGGGTTATTGC (SEQ ID NO: 1862)
CCCGTGTGCTTCTGTTTC (SEQ ID NO: 1863)





hCV2211618
C/G
GGCCATGTGCTGCCATC (SEQ ID NO: 1864)
GGCCATGTGCTGCCATG (SEQ ID NO: 1865)
AGTGTGGCTAGCTTGCTCTATAT (SEQ ID NO: 1866)





hCV22272267
A/G
CTGGCAGCGAATGTTAT (SEQ ID NO: 1867)
CTGGCAGCGAATGTTAC (SEQ ID NO: 1868)
CCTCTAGAAAGAAAATGGACTGTAT (SEQ ID NO: 1869)





hCV2288095
C/T
TGAGTTAATATTTGTGTAAAGTATGATGTTTAG (SEQ ID
TGAGTTAATATTTGTGTAAAGTATGATGTTTAA (SEQ ID
CGAGGAAGGATAGGGTGGTATTGT (SEQ ID NO: 1872)




NO: 1870)
NO: 1871)






hCV2303891
C/G
CACAGTTCTCTGGCTTTTTG (SEQ ID NO: 1873)
ACACAGTTCTCTGGCTTTTTC (SEQ ID NO: 1874)
TGGATGAACAAGAAACAAGTGT (SEQ ID NO: 1875)





hCV233148
C/G
TCATCACAGGACATTTATGAGAAG (SEQ ID NO: 1876)
TCATCACAGGACATTTATGAGAAC (SEQ ID NO: 1877)
CCGCTGACAATCACAGTGTT (SEQ ID NO: 1878)





hCV2403368
C/G
AAAGGTGAGCTCCACCATAC (SEQ ID NO: 1879)
AAAGGTGAGCTCCACCATAG (SEQ ID NO: 1880)
GGCATCGGCACATAGTAGA (SEQ ID NO: 1881)





hCV2456747
A/G
CCTCCACTAGAAGACACTACTACTTT (SEQ ID
CCTCCACTAGAAGACACTACTACTTC (SEQ ID NO: 1883)
TTCTTCACAGCTTCCATTAGTAAG (SEQ ID NO: 1884)




NO: 1882)







hCV2494846
G/T
CTTCTTCCCTTCGCTCTG (SEQ ID NO: 1885)
ACTTCTTCCCTTCGCTCTT (SEQ ID NO: 1886)
CAACAGGCAGGTTTCTTCTC (SEQ ID NO: 1887)





hCV2532034
C/T
CTGAAGCGCAACCATAAC (SEQ ID NO: 1888)
CTGAAGCGCAACCATAAT (SEQ ID NO: 1889)
TCCCATAGAAAAATGCACTAAG (SEQ ID NO: 1890)





hCV25473516
T/C
CCACCCAATGCCAAGT (SEQ ID NO: 1891)
CACCCAATGCCAAGC (SEQ ID NO: 1892)
GCACATGCGCAATAGC (SEQ ID NO: 1893)





hCV25474413
A/C
GCATTCACAGTGTTCTCATTATAAT (SEQ ID NO: 1894)
GCATTCACAGTGTTCTCATTATAAG (SEQ ID NO: 1895)
GGCTTCTGCAGAGCTGTAAGA (SEQ ID NO: 1896)





hCV25474414
G/T
CTGCAGAGCTGTAAGAGTG (SEQ ID NO: 1897)
TCTGCAGAGCTGTAAGAGTT (SEQ ID NO: 1898)
AAGAAATAGGGAGAGAGGGGAGTAGT (SEQ ID NO: 1899)





hCV25596789
C/G
TCTGCTCCATTTTTCTCATG (SEQ ID NO: 1900)
ATCTGCTCCATTTTTCTCATC (SEQ ID NO: 1901)
TTTAAGCCTTCTACCTACAACATTAC (SEQ ID NO: 1902)





hCV25602230
G/T
AGCTGAGGAGAGTCCG (SEQ ID NO: 1903)
GAAGCTGAGGAGAGTCCT (SEQ ID NO: 1904)
ACGTCCGAGACACAGTC (SEQ ID NO: 1905)





hCV25611352
C/T
AATAATTGTAACTCTAGAACAAAAGTATTC (SEQ ID
AATAATTGTAACTCTAGAACAAAAGTATTT (SEQ ID
AGAAACTTTTCTTTGCTGATGA (SEQ ID NO: 1908)




NO: 1906)
NO: 1907)






hCV25615302
C/T
GTTCCAGTTCCGATAGC (SEQ ID NO: 1909)
GGTTCCAGTTCCGATAGT (SEQ ID NO: 1910)
GGGTTGGGCTTAATGACTT (SEQ ID NO: 1911)





hCV25620145
A/G
CACACCAGCAATGATGAAACT (SEQ ID NO: 1912)
CACCAGCAATGATGAAACC (SEQ ID NO: 1913)
GGGCTAACTCTTTGCATGTTC (SEQ ID NO: 1914)





hCV25634754
C/T
GTCACTTATTTGAATCCCATTGC (SEQ ID NO: 1915)
AGTCACTTATTTGAATCCCATTGT (SEQ ID NO: 1916)
GCAAACTAAGGGACCACCTGAATC (SEQ ID NO: 1917)





hCV25649928
G/A
AAGACTTTTTCCAGGAATGC (SEQ ID NO: 1918)
GAAGACTTTTTCCAGGAATGT (SEQ ID NO: 1919)
TTCTTAAAGGGTCATGAAACTTAC (SEQ ID NO: 1920)





hCV25748719
T/C
CGGCAGCCAATGACAT (SEQ ID NO: 1921)
CGGCAGCCAATGACAC (SEQ ID NO: 1922)
AACCTCCAGCTTTCAGACAC (SEQ ID NO: 1923)





hCV2575036
A/G
CAGTTTATGCCTGCAACAAT (SEQ ID NO: 1924)
CAGTTTATGCCTGCAACAAC (SEQ ID NO: 1925)
TTGGCTCTGGAGAATGAGA (SEQ ID NO: 1926)





hCV25752810
C/A
GCCCATAAGGAGACAGAAAAG (SEQ ID NO: 1927)
GCCCATAAGGAGACAGAAAAT (SEQ ID NO: 1928)
AATGCAGTAATTTGTGAGTTTTACTAC (SEQ ID NO: 1929)





hCV25767872
A/G
CACCATGTGTGTGTTCCAT (SEQ ID NO: 1930)
CACCATGTGTGTGTTCCAC (SEQ ID NO: 1931)
AATCCAGAGCTTCAGATTCTG (SEQ ID NO: 1932)





hCV25768636
A/G
AGAATTTGGCCACAAAGAGT (SEQ ID NO: 1933)
AATTTGGCCACAAAGAGC (SEQ ID NO: 1934)
CCCCGCCAGACATCTT (SEQ ID NO: 1935)





hCV2590858
C/T
GAGTGAGAATTCTGTCAAGAGG (SEQ ID NO: 1936)
AGAGTGAGAATTCTGTCAAGAGA (SEQ ID NO: 1937)
GGTGAAGCCCACGATATCT (SEQ ID NO: 1938)





hCV25932979
A/G
AAAAGAGGGAGTAAACAACTGT (SEQ ID NO: 1939)
AAAGAGGGAGTAAACAACTGC (SEQ ID NO: 1940)
TCCCTTCTTGGACTTCACATTGATGA (SEQ ID NO: 1941)





hCV25951992
A/C
CTGGAAAGATGGAGGCAT (SEQ ID NO: 1942)
TGGAAAGATGGAGGCAG (SEQ ID NO: 1943)
GAGGGCACCAATCATTACA (SEQ ID NO: 1944)





hCV25959466
T/C
AAGCGATTCCTCAGCAGT (SEQ ID NO: 1945)
GCGATTCCTCAGCAGC (SEQ ID NO: 1946)
TGTGCTGATCAGCAAAGTGT (SEQ ID NO: 1947)





hCV25959498
G/A
ACAACATAAAACTGACTTGGAAG (SEQ ID NO: 1948)
ACAACATAAAACTGACTTGGAAA (SEQ ID NO: 1949)
AATGGGCTGGCTACCAT (SEQ ID NO: 1950)





hCV25990131
A/C
TGTTGGTAAAAGTATGTAGGATCTT (SEQ ID NO: 1951)
TGTTGGTAAAAGTATGTAGGATCTG (SEQ ID NO: 1952)
CCATTTATAGAATGAGTGAGATGATAT (SEQ ID NO: 1953)





hCV25991132
A/G
CCAGGAATGGAGACCATCT (SEQ ID NO: 1954)
CAGGAATGGAGACCATCC (SEQ ID NO: 1955)
AGTAAAGGGCAGGAACATAGAG (SEQ ID NO: 1956)





hCV25995678
C/T
TCTGTCTTCCACAACCAAAG (SEQ ID NO: 1957)
TCTGTCTTCCACAACCAAAA (SEQ ID NO: 1958)
TGTGGTTGTAAGAATCAATCCTAA (SEQ ID NO: 1959)





hCV25996277
A/T
TATCTCCTTCAAAGGATGCA (SEQ ID NO: 1960)
ACTATCTCCTTCAAAGGATGCT (SEQ ID NO: 1961)
GCACAGAGCTTAGGAGACATAG (SEQ ID NO: 1962)





hCV26034142
C/T
CAACCTAATTTAAGCCATCATTAACG (SEQ ID
CAACCTAATTTAAGCCATCATTAACA (SEQ ID NO: 1964)
GCAACAGGCTGATGTTCATATATTTCTCTT (SEQ ID




NO: 1963)

NO: 1965)





hCV26034157
C/T
CAACTCAAACAGGACACTGAG (SEQ ID NO: 1966)
CAACTCAAACAGGACACTGAA (SEQ ID NO: 1967)
ATACGACGATCATGAGCCATGTCTA (SEQ ID NO: 1968)





hCV26038139
A/G
TCAGCTGGCGAAGTTGA (SEQ ID NO: 1969)
CAGCTGGCGAAGTTGG (SEQ ID NO: 1970)
TGCCATGTAGCCATCTTGAGTGTA (SEQ ID NO: 1971)





hCV2605707
C/G
GCTGTTAATTCAGGAGGTAAAGC (SEQ ID NO: 1972)
GCTGTTAATTCAGGAGGTAAAGG (SEQ ID NO: 1973)
CTTGGAGGCCAGAACAATAGGTAGAA (SEQ ID NO: 1974)





hCV26175114
A/G
CCAGTCATCTCTGCAGAAAAA (SEQ ID NO: 1975)
CCAGTCATCTCTGCAGAAAAG (SEQ ID NO: 1976)
GGATCACACTTCACCATCTG (SEQ ID NO: 1977)





hCV26265231
A/G
GGGATAAATATTACAAACCCATGCTA (SEQ ID
GGATAAATATTACAAACCCATGCTG (SEQ ID NO: 1979)
TGACCCAAATCCTTTTCTCACCATACT (SEQ ID NO: 1980)




NO: 1978)







hCV26338456
A/G
CACAGAAGATACAGCAAATGGAA (SEQ ID NO: 1981)
ACAGAAGATACAGCAAATGGAG (SEQ ID NO: 1982)
AGGTGTTCCTGATGTCATTTCACAGTA (SEQ ID NO: 1983)





hCV26338482
C/T
AAACAGTAACAGGCTCAGC (SEQ ID NO: 1984)
CAAACAGTAACAGGCTCAGT (SEQ ID NO: 1985)
CATCTCAAGGGTAGGGAGAAGTCAA (SEQ ID NO: 1986)





hCV26338512
A/G
CAGGCCTCGGAAAATGAA (SEQ ID NO: 1987)
CAGGCCTCGGAAAATGAG (SEQ ID NO: 1988)
TTTGAAACGCCCGACATTCTTCTATTC (SEQ ID NO: 1989)





hCV26338513
C/T
CGCACTTTTAGTGGCTGG (SEQ ID NO: 1990)
CGCACTTTTAGTGGCTGA (SEQ ID NO: 1991)
GGGCAGTACAGGACATACATTCTC (SEQ ID NO: 1992)





hCV263841
A/C
AGCTAATACTCCTGTCCTGAAA (SEQ ID NO: 1993)
AAGCTAATACTCCTGTCCTGAAC (SEQ ID NO: 1994)
AAGTTCTTTGCTCCGACTTCT (SEQ ID NO: 1995)





hCV26719108
C/T
GCAGGGGCATTGGTG (SEQ ID NO: 1996)
GGCAGGGGCATTGGTA (SEQ ID NO: 1997)
CCTTTACCCACCTTCCTCTGTATCT (SEQ ID NO: 1998)





hCV26719113
C/T
CTTACGATTAGTTCCAACATGAATAC (SEQ ID
CTTACGATTAGTTCCAACATGAATAT (SEQ ID NO: 2000)
TCTTCCACCATCCCAAAGTTACTAAACA (SEQ ID NO: 2001)




NO: 1999)







hCV26719121
C/T
CCCACTAAGCACAGGAAAG (SEQ ID NO: 2002)
CCCACTAAGCACAGGAAAA (SEQ ID NO: 2003)
CAGTTGAAGTGGACAGGCATTACT (SEQ ID NO: 2004)





hCV26719154
C/T
TGGTCTGTGCCCTCAG (SEQ ID NO: 2005)
ATGGTCTGTGCCCTCAA (SEQ ID NO: 2006)
CCTATTGCTCCCACTCTTCCTACTAC (SEQ ID NO: 2007)





hCV26719227
A/C
TGCCTTGGATATGCTTTAAAGAT (SEQ ID NO: 2008)
TGCCTTGGATATGCTTTAAAGAG (SEQ ID NO: 2009)
AAACATTTGCCACAAGGCAAGTTTTG (SEQ ID NO: 2010)





hCV26887403
A/C
CTAGCACTGGAACGATAATAAAGA (SEQ ID NO: 2011)
AGCACTGGAACGATAATAAAGC (SEQ ID NO: 2012)
CCTTGCAAATAACCATTAAGACCCTTACA (SEQ ID






NO: 2013)





hCV26887434
A/C
GACTTTACGACTAATTAGGTATAAAGGTTA (SEQ ID
CTTTACGACTAATTAGGTATAAAGGTTC (SEQ ID
GTTGCTAAATCTCCCATTTCTGCTCTTAT (SEQ ID




NO: 2014)
NO: 2015)
NO: 2016)





hCV26887464
A/G
GCAGGTCAGATAACTTCTTTATGA (SEQ ID NO: 2017)
GCAGGTCAGATAACTTCTTTATGG (SEQ ID NO: 2018)
CTGTTCCATTCTCCCCAGAGACTA (SEQ ID NO: 2019)





hCV26895255
C/T
CACCGTATTCAGCTGAGAC (SEQ ID NO: 2020)
ACACCGTATTCAGCTGAGAT (SEQ ID NO: 2021)
GTCTGGGGTGAATCCAGTCAT (SEQ ID NO: 2022)





hCV2699725
C/G
GTACCTCTTGGTCTCTCTCC (SEQ ID NO: 2023)
GTACCTCTTGGTCTCTCTCG (SEQ ID NO: 2024)
GGAGCATGTTGTGTTTCTGATTGTA (SEQ ID NO: 2025)





hCV27020269
C/G
CCAGTTTTGCACATTTAAAGATACG (SEQ ID NO: 2026)
CCAGTTTTGCACATTTAAAGATACC (SEQ ID NO: 2027)
GGCTCTCTGCCCCATGAAC (SEQ ID NO: 2028)





hCV2706410
C/T
CCTCCATGTCATCCTACG (SEQ ID NO: 2029)
CCTCCATGTCATCCTACA (SEQ ID NO: 2030)
TGCCGAGTCTGAGAAGATTC (SEQ ID NO: 2031)





hCV27102953
C/T
TTAGTGTAATGGGCAAGACG (SEQ ID NO: 2032)
ATTTAGTGTAATGGGCAAGACA (SEQ ID NO: 2033)
CACAGCCTGTATCGGTTTGAACTAAC (SEQ ID NO: 2034)





hCV27102978
A/C
CTCCTCCTGTCTCCGTT (SEQ ID NO: 2035)
CTCCTCCTGTCTCCGTG (SEQ ID NO: 2036)
GATTTTGGAGCTGGGTCACTCAC (SEQ ID NO: 2037)





hCV27103080
G/T
GGGATGTGCAACCCG (SEQ ID NO: 2038)
TGGGATGTGCAACCCT (SEQ ID NO: 2039)
GTTCCAGGACAACCCTCAGATACT (SEQ ID NO: 2040)





hCV27103182
C/T
GGCATCTCTCAATCCCTACG (SEQ ID NO: 2041)
GGCATCTCTCAATCCCTACA (SEQ ID NO: 2042)
GCATCTGAGTTTGCCTGACACA (SEQ ID NO: 2043)





hCV27103188
A/G
TGTTTGGACAATGACTTGGAAAT (SEQ ID NO: 2044)
GTTTGGACAATGACTTGGAAAC (SEQ ID NO: 2045)
CCTGAACCCAGGAGGTCATCT (SEQ ID NO: 2046)





hCV27103189
A/G
AAGAGGTCAAGCCAATGAAAT (SEQ ID NO: 2047)
AGAGGTCAAGCCAATGAAAC (SEQ ID NO: 2048)
GGGGCAGATGTGAATTAGTGTCT (SEQ ID NO: 2049)





hCV27103207
A/G
GGCTGCCAGGGACAT (SEQ ID NO: 2050)
GGCTGCCAGGGACAC (SEQ ID NO: 2051)
CTGTGGTACCCCTTGGAGGAG (SEQ ID NO: 2052)





hCV2716314
A/C
GGCATACAAATTCAAAATACTGTATA (SEQ ID
GGCATACAAATTCAAAATACTGTATC (SEQ ID NO: 2054)
GGTGTCTTGGTGATCTCACATAA (SEQ ID NO: 2055)




NO: 2053)







hCV2734332
A/G
GCCATGTTGACTCGAGAAT (SEQ ID NO: 2056)
GCCATGTTGACTCGAGAAC (SEQ ID NO: 2057)
TGTGAGGGAGGCTGTCTACT (SEQ ID NO: 2058)





hCV2744023
A/G
CTACCTGTGTCTGTATTTCTTTAAAT (SEQ ID
CTACCTGTGTCTGTATTTCTTTAAAC (SEQ ID NO: 2060)
ATCTGCCTTCTTAGTGAATTGAT (SEQ ID NO: 2061)




NO: 2059)







hCV27474895
A/C
GGAGGATACTGAAGTAGCAAACT (SEQ ID NO: 2062)
GAGGATACTGAAGTAGCAAACG (SEQ ID NO: 2063)
GAGTTCGGTATGCATCCTCACAT (SEQ ID NO: 2064)





hCV27474984
A/G
ACTTGAGTTACACCAGACCTA (SEQ ID NO: 2065)
CTTGAGTTACACCAGACCTG (SEQ ID NO: 2066)
TCAGCCGTTCAGACAATATTGTTA (SEQ ID NO: 2067)





hCV27476043
A/G
CAGGCCAGGTCAACA (SEQ ID NO: 2068)
CAGGCCAGGTCAACG (SEQ ID NO: 2069)
CAGGACCCTCCCTCAGAGAC (SEQ ID NO: 2070)





hCV27477533
A/T
GAGGTTCCATGGAGTAAACAATA (SEQ ID NO: 2071)
GAGGTTCCATGGAGTAAACAATT (SEQ ID NO: 2072)
CATTGCCTTTTATGAGGCTCAAACATA (SEQ ID NO: 2073)





hCV27480803
C/T
GCACTAGAAACCTGCCG (SEQ ID NO: 2074)
TGCACTAGAAACCTGCCA (SEQ ID NO: 2075)
CATCCAAGGGTATACTGTGCCATTAT (SEQ ID NO: 2076)





hCV27490984
A/G
CTTACTTAGGTCACTTTCAGCA (SEQ ID NO: 2077)
CTTACTTAGGTCACTTTCAGCG (SEQ ID NO: 2078)
GTCTGGAAACAACTCGGAGGATACT (SEQ ID NO: 2079)





hCV27502514
A/G
ATATTGGCGAGTTATCTAATGTCTT (SEQ ID NO: 2080)
ATTGGCGAGTTATCTAATGTCTC (SEQ ID NO: 2081)
CTCACAATTGCATAGTGCCCTCTTA (SEQ ID NO: 2082)





hCV27833944
C/T
TGCTAGGGACTAACCTTGG (SEQ ID NO: 2083)
CTGCTAGGGACTAACCTTGA (SEQ ID NO: 2084)
CAACTTGTATTCCTCTGCAGGATTTACTG (SEQ ID






NO: 2085)





hCV27878067
A/G
CCCAACTGACCCAAAGGT (SEQ ID NO: 2086)
CCAACTGACCCAAAGGC (SEQ ID NO: 2087)
CCAGAATGCAACAGGTAAATATAACATCAAATCC (SEQ ID






NO: 2088)





hCV27902808
C/T
CAGGCCTGAAGTCTAGGTC (SEQ ID NO: 2089)
CAGGCCTGAAGTCTAGGTT (SEQ ID NO: 2090)
CCCCAGCACCAGGATTCAG (SEQ ID NO: 2091)





hCV27904396
A/G
GACTACACTACTATGCAATATATCTATGTA (SEQ ID
ACTACACTACTATGCAATATATCTATGTG (SEQ ID
ACCTTCCCCTGATTTCCTGACATAT (SEQ ID NO: 2094)




NO: 2092)
NO: 2093)






hCV27937396
C/T
GCCTGAATTCTGAGAAGACATAG (SEQ ID NO: 2095)
GCCTGAATTCTGAGAAGACATAA (SEQ ID NO: 2096)
AGGCCAATCTTAGGTTCTACAAACAGT (SEQ ID NO: 2097)





hCV27956129
A/C
CCATTTATGCAAAAGCAGAATCA (SEQ ID NO: 2098)
CCATTTATGCAAAAGCAGAATCC (SEQ ID NO: 2099)
GACATTTGGCTTGGTTCCAAGTCTT (SEQ ID NO: 2100)





hCV2811695
A/C
AGTGTTGTATTTGTATGTGTGTCT (SEQ ID NO: 2101)
GTGTTGTATTTGTATGTGTGTCG (SEQ ID NO: 2102)
GGTTTATGAGCAGCAGGCATACA (SEQ ID NO: 2103)





hCV2852784
G/A
CACAGCTCTTCTACTCCACC (SEQ ID NO: 2104)
CCACAGCTCTTCTACTCCACT (SEQ ID NO: 2105)
GAGGCTCTTGGGGTACTT (SEQ ID NO: 2106)





hCV2879752
A/G
GGCCTCCTGCTCCAA (SEQ ID NO: 2107)
GGCCTCCTGCTCCAG (SEQ ID NO: 2108)
TCCCAGCCCCACAAGAG (SEQ ID NO: 2109)





hCV2892855
C/T
GGTAATCATTTAACACATTTCATGTTCC (SEQ ID
GGTAATCATTTAACACATTTCATGTTCT (SEQ ID
GCATCTCAGGAAATTCAGCACAACT (SEQ ID NO: 2112)




NO: 2110)
NO: 2111)






hCV2892869
A/G
TGTGCCAGTCCTTGTGT (SEQ ID NO: 2113)
GTGCCAGTCCTTGTGC (SEQ ID NO: 2114)
CTGCCACTCTCGCATGTCATT (SEQ ID NO: 2115)





hCV2892877
C/T
GCTCTGGACCTGGAAGTG (SEQ ID NO: 2116)
GAGCTCTGGACCTGGAAGTA (SEQ ID NO: 2117)
CCAGAGCCTGGGCTATCT (SEQ ID NO: 2118)





hCV2892893
A/T
AGTGTGCTCATGATGAAAGAAAA (SEQ ID NO: 2119)
AGTGTGCTCATGATGAAAGAAAT (SEQ ID NO: 2120)
TTGTCCCTCATCCTTGTCATCACT (SEQ ID NO: 2121)





hCV2892905
C/T
GTGTGATATGACTTTCATTTAGAACG (SEQ ID
CGTGTGATATGACTTTCATTTAGAACA (SEQ ID
CATGGCTTCCTGTAATGGAAACACAT (SEQ ID NO: 2124)




NO: 2122)
NO: 2123)






hCV2892918
A/T
TGCATCCACATAAAATGCTACT (SEQ ID NO: 2125)
TGCATCCACATAAAATGCTACA (SEQ ID NO: 2126)
CATCTCCCAGCTGAGTCAACAAC (SEQ ID NO: 2127)





hCV2892926
C/T
GTTCAAGTTAAATGATAGGGTAATACC (SEQ ID
GTTCAAGTTAAATGATAGGGTAATACT (SEQ ID
GAACGATTAGAATGCTGAACTTTCACATTTAGAC (SEQ ID




NO: 2128)
NO: 2129)
NO: 2130)





hCV2892927
A/T
GTACTTTCTGTTCAACATCTTTTAAGT (SEQ ID
GTACTTTCTGTTCAACATCTTTTAAGA (SEQ ID
CAGTGTTAATGAGTGTAGACCTCAGAGAT (SEQ ID




NO: 2131)
NO: 2132)
NO: 2133)





hCV28960679
C/G
CCAGACCTCATATTTTCCTTCAG (SEQ ID NO: 2134)
CCAGACCTCATATTTTCCTTCAC (SEQ ID NO: 2135)
CGGCCTGGCTGCTAACA (SEQ ID NO: 2136)





hCV2915511
C/T
CTGGCTCCTTCTCCGTC (SEQ ID NO: 2137)
CTGGCTCCTTCTCCGTT (SEQ ID NO: 2138)
GGGACTGAGGCTCCAACTAC (SEQ ID NO: 2139)





hCV29210363
A/G
GCCATCTACAGGCTTACTCAT (SEQ ID NO: 2140)
GCCATCTACAGGCTTACTCAC (SEQ ID NO: 2141)
GCTGCTATAATAAAGTTGCTCCTTCAAGTA (SEQ ID






NO: 2142)





hCV29269378
A/G
CATAATTTGCTTTTGACCACAACA (SEQ ID NO: 2143)
ATTTGCTTTTGACCACAACG (SEQ ID NO: 2144)
CACTCAAGTACTCAAGCCTCTTTTATAAGC (SEQ ID






NO: 2145)





hCV29271569
C/T
CCAGCCTCAGGTTAAGGATC (SEQ ID NO: 2146)
CCAGCCTCAGGTTAAGGATT (SEQ ID NO: 2147)
AACTCCCGACCCCAGGTAATC (SEQ ID NO: 2148)





hCV29521317
A/G
TCCATTGATACTGCATTAAACCATA (SEQ ID NO: 2149)
CCATTGATACTGCATTAAACCATG (SEQ ID NO: 2150)
TCTTTGTGTTGCCTGCCTATG (SEQ ID NO: 2151)





hCV2969899
C/G
GCATCCTGTCAAATACTCTCATTATAG (SEQ ID
GCATCCTGTCAAATACTCTCATTATAC (SEQ ID
CACCTGAGACAGAATTGGGTCTAAC (SEQ ID NO: 2154)




NO: 2152)
NO: 2153)






hCV29821005
C/T
GCAAACTAAAGCAACAATAAGACAC (SEQ ID NO: 2155)
GCAAACTAAAGCAACAATAAGACAT (SEQ ID NO: 2156)
CTCCTGTTGCTTCACATCCTCTCTA (SEQ ID NO: 2157)





hCV2986575
A/T
CCTTTGTACTTTAAATCATCTCTAGGT (SEQ ID
CCTTTGTACTTTAAATCATCTCTAGGA (SEQ ID
ATGGTTGCATCTCTACTGAACATGTACA (SEQ ID NO: 2160)




NO: 2158)
NO: 2159)






hCV29983641
A/G
AGAAAATTAAGCCAGGAGAAGTTAA (SEQ ID NO: 2161)
AGAAAATTAAGCCAGGAGAAGTTAG (SEQ ID NO: 2162)
CCCTCCCCATTTGTTGTCATGA (SEQ ID NO: 2163)





hCV30002208
A/G
TGCTTTCAGGCAATTTTGAGA (SEQ ID NO: 2164)
GCTTTCAGGCAATTTTGAGG (SEQ ID NO: 2165)
GAGGCCTCTGTCTTTGGTTTTGTA (SEQ ID NO: 2166)





hCV30040828
C/T
GGGGTGAAGAAGAAACCTCC (SEQ ID NO: 2167)
GGGGTGAAGAAGAAACCTCT (SEQ ID NO: 2168)
GACAGTGAATGGGTCAGCACATAC (SEQ ID NO: 2169)





hCV30205817
C/T
GATGAAGTAGTTCATTTTGAATGGC (SEQ ID NO: 2170)
GATGAAGTAGTTCATTTTGAATGGT (SEQ ID NO: 2171)
CCCCAACTGCAGCTCCTAAATATTATAC (SEQ ID NO: 2172)





hCV30440155
C/G
CTTTGGAGTCTGCTTGTACC (SEQ ID NO: 2173)
CTTTGGAGTCTGCTTGTACG (SEQ ID NO: 2174)
GGAAGATGGTGCTTGCAAAGAAGAT (SEQ ID NO: 2175)





hCV30505633
C/T
CGCTTAACAAAGGTGTTAGAAC (SEQ ID NO: 2176)
ACGCTTAACAAAGGTGTTAGAAT (SEQ ID NO: 2177)
CAGGCAGAAGAATAAGGGTTGAA (SEQ ID NO: 2178)





hCV30548253
A/C
GAGAGATAGAGGCAAAGGAAAAT (SEQ ID NO: 2179)
GAGAGATAGAGGCAAAGGAAAAG (SEQ ID NO: 2180)
TTCATCTGGTTCTCCTCTGGATAGTCT (SEQ ID NO: 2181)





hCV30562347
A/G
GGCTGTCATTTCAGAAGCA (SEQ ID NO: 2182)
GGCTGTCATTTCAGAAGCG (SEQ ID NO: 2183)
GCCTTCAGAACAATGCCTGATACAT (SEQ ID NO: 2184)





hCV305844
C/G
CTGTGCCCTTCCTGG (SEQ ID NO: 2185)
CTGTGCCCTTCCTGC (SEQ ID NO: 2186)
GACCCTGAGCCCAAAGAAACT (SEQ ID NO: 2187)





hCV30626715
G/T
AGGATGTCTGCCATTATTTCC (SEQ ID NO: 2188)
CAGGATGTCTGCCATTATTTCA (SEQ ID NO: 2189)
GGAGACCCAATTGATTAATGCTCATGT (SEQ ID NO: 2190)





hCV30690777
A/G
CCGTGTGCCTGAGAAGT (SEQ ID NO: 2191)
CGTGTGCCTGAGAAGC (SEQ ID NO: 2192)
GCCCACAGCATACAGTAACACTA (SEQ ID NO: 2193)





hCV30690778
C/T
AGGCAGAGTTTCCACTCAG (SEQ ID NO: 2194)
AGGCAGAGTTTCCACTCAA (SEQ ID NO: 2195)
AAGGCCTATGCCCATGATTTCTACT (SEQ ID NO: 2196)





hCV30690780
A/C
GTGTTCATTGACAGATGAGTGT (SEQ ID NO: 2197)
TGTTCATTGACAGATGAGTGG (SEQ ID NO: 2198)
GTACTCTTTATCTGGCTTGTTCATTTAGCA (SEQ ID






NO: 2199)





hCV30690784
C/T
AGCGATGGCCTTAGGTATC (SEQ ID NO: 2200)
AGCGATGGCCTTAGGTATT (SEQ ID NO: 2201)
GTGTTTCCCTGTGTGTGTGATGTAT (SEQ ID NO: 2202)





hCV30699692
C/T
GGAAAGAACCACCTCGATATG (SEQ ID NO: 2203)
GGGAAAGAACCACCTCGATATA (SEQ ID NO: 2204)
CCTCGAGGCCCACTGTTTTATAATAC (SEQ ID NO: 2205)





hCV30711231
A/G
GTGTATGTGTGTGTGTGAGAA (SEQ ID NO: 2206)
GTGTATGTGTGTGTGTGAGAG (SEQ ID NO: 2207)
TCTAAGCCATCCAGTTTGTGGTACTT (SEQ ID NO: 2208)





hCV30922162
C/T
ACTGTTACTAGAGACAAGGGATAC (SEQ ID NO: 2209)
AACTGTTACTAGAGACAAGGGATAT (SEQ ID NO: 2210)
CTCTGAAATCTGTCAGTTTTGTTTCATG (SEQ ID






NO: 2211)





hCV31056155
C/G
GTTTTCTCTTTGTTACTAATATGTCACAC (SEQ ID
GTTTTCTCTTTGTTACTAATATGTCACAG (SEQ ID
CAAGAAATCTATCAACAGGAGCTTGGTTAT (SEQ ID




NO: 2212)
NO: 2213)
NO: 2214)





hCV31199195
A/C
GAGATATCAATTGAAAACGGACATT (SEQ ID NO: 2215)
GAGATATCAATTGAAAACGGACATG (SEQ ID NO: 2216)
CAAGGAATCCTACCTCACCTTCTCATA (SEQ ID NO: 2217)





hCV31475431
G/T
ATTGTGATTGGGGAACTTCC (SEQ ID NO: 2218)
GTATTGTGATTGGGGAACTTCA (SEQ ID NO: 2219)
GGAGTCCTGGAGAGCAGAGTC (SEQ ID NO: 2220)





hCV31523557
A/G
AGGTAGTTTGTTCCACAGCA (SEQ ID NO: 2221)
GGTAGTTTGTTCCACAGCG (SEQ ID NO: 2222)
GGCAACACCCTCACAGATACAC (SEQ ID NO: 2223)





hCV31523608
A/G
CATTAAATGAGTTCCACTGCCT (SEQ ID NO: 2224)
TTAAATGAGTTCCACTGCCC (SEQ ID NO: 2225)
CTGTGCACGTGGTAACTAATTGACT (SEQ ID NO: 2226)





hCV31523638
A/G
TTCTTCTGCCTCTCTCATACA (SEQ ID NO: 2227)
TCTTCTGCCTCTCTCATACG (SEQ ID NO: 2228)
GGAGATTCCAATGGTGTTAGTCAATATGT (SEQ ID






NO: 2229)





hCV31523643
A/G
TGCAAACCATGCTGGATTAA (SEQ ID NO: 2230)
TGCAAACCATGCTGGATTAG (SEQ ID NO: 2231)
GGGCCCCTTCAGTCACAGTA (SEQ ID NO: 2232)





hCV31523650
C/T
TCAACTTTTAACCAGTACTGTTCC (SEQ ID NO: 2233)
CTCAACTTTTAACCAGTACTGTTCT (SEQ ID NO: 2234)
CGAATTCCTTAAGGGCACCTTATCTT (SEQ ID NO: 2235)





hCV31523658
A/C
TTGCTAATACTGCATTTCTTACAAAT (SEQ ID
TGCTAATACTGCATTTCTTACAAAG (SEQ ID NO: 2237)
TGACACAGAGGCACAACATAAGC (SEQ ID NO: 2238)




NO: 2236)







hCV3164397
C/T
TGTGCCTTACAGAATCCG (SEQ ID NO: 2239)
CTTGTGCCTTACAGAATCCA (SEQ ID NO: 2240)
GAGCAGTTGCTCTTCATCATC (SEQ ID NO: 2241)





hCV3170967
C/G
GGAGGGTGAGGTCAAGC (SEQ ID NO: 2242)
GGAGGGTGAGGTCAAGG (SEQ ID NO: 2243)
TCATCTTCCTCTTCCTCTGTGT (SEQ ID NO: 2244)





hCV31714450
C/T
CACCTTGACCTTGGACTTC (SEQ ID NO: 2245)
CACCTTGACCTTGGACTTT (SEQ ID NO: 2246)
CAGGGTGCTATAACAGAATGCAATAGAC (SEQ ID NO: 2247)





hCV31749285
C/T
GTTGGAATTGAGGCTTATGC (SEQ ID NO: 2248)
GGTTGGAATTGAGGCTTATGT (SEQ ID NO: 2249)
GGAAGGAATGAAAGCTTTGGGTTTGA (SEQ ID NO: 2250)





hCV3180954
A/G
TCCTGGGAGCCTTTGA (SEQ ID NO: 2251)
CCTGGGAGCCTTTGG (SEQ ID NO: 2252)
CAACCATATCCTGGTGTGTG (SEQ ID NO: 2253)





hCV31863982
A/G
ACAAATCCTTTGACAATCACTGT (SEQ ID NO: 2254)
CAAATCCTTTGACAATCACTGC (SEQ ID NO: 2255)
CTGCTTTCAAACCACAAATTCATGTGT (SEQ ID NO: 2256)





hCV3187716
A/C
CCTTCAATTCTGAAAAGTAGCTAAT (SEQ ID NO: 2257)
CCTTCAATTCTGAAAAGTAGCTAAG (SEQ ID NO: 2258)
TTTGAGGTTGAGTGACATGTTC (SEQ ID NO: 2259)





hCV31965333
C/T
AGCCCTTCAGAAGAAAACAG (SEQ ID NO: 2260)
CAGCCCTTCAGAAGAAAACAA (SEQ ID NO: 2261)
GTGCTGGAGCAATTTGGTTCAGATA (SEQ ID NO: 2262)





hCV31997958
A/G
CCCTGCTGGAGAAAATCA (SEQ ID NO: 2263)
CCCTGCTGGAGAAAATCG (SEQ ID NO: 2264)
CGTGTGAGGGGACAGAGAGAA (SEQ ID NO: 2265)





hCV3205858
C/T
GTGCTCACTCAGAATAAAATGC (SEQ ID NO: 2266)
AGTGCTCACTCAGAATAAAATGT (SEQ ID NO: 2267)
TGTGAGAGCAACAGCTTGAAT (SEQ ID NO: 2268)





hCV3210786
C/T
CCCATGAATATTGTACTTAGGAAC (SEQ ID NO: 2269)
CCCATGAATATTGTACTTAGGAAT (SEQ ID NO: 2270)
CCTCCCTTGCTCAGTCACT (SEQ ID NO: 2271)





hCV3216426
A/T
TTATTTTCAGAGTCTTGAATATTATTGA (SEQ ID
GTTATTTTCAGAGTCTTGAATATTATTGT (SEQ ID





NO: 2272)
NO: 2273)
ACAGACAGTGGACAGACAATCT (SEQ ID NO: 2274)





hCV3216649
A/G
CAGCTTGTACATCGTACTTAACAGT (SEQ ID NO: 2275)
GCTTGTACATCGTACTTAACAGC (SEQ ID NO: 2276)
GCCACGTGGTAAAAATGACT (SEQ ID NO: 2277)





hCV32209605
C/T
GTGAAATTACTCCTTCATCAGGG (SEQ ID NO: 2278)
GTGAAATTACTCCTTCATCAGGA (SEQ ID NO: 2279)
CTCTTTGACAATGCAATGGTCACT (SEQ ID NO: 2280)





hCV32209620
C/T
CAGGCTTTTATGTGTGCATG (SEQ ID NO: 2281)
TTCAGGCTTTTATGTGTGCATA (SEQ ID NO: 2282)
GAAGCAACAGGAGCTCTCATTCAT (SEQ ID NO: 2283)





hCV32209621
A/G
ATGCATGTCTTGGTATTTATCCA (SEQ ID NO: 2284)
TGCATGTCTTGGTATTTATCCG (SEQ ID NO: 2285)
GGTGCTTTCTAGTTTTGGCAATTATGAGT (SEQ ID






NO: 2286)





hCV32212664
A/G
TGATTGGAAGCATTTCCCATAAT (SEQ ID NO: 2287)
GATTGGAAGCATTTCCCATAAC (SEQ ID NO: 2288)
CTAGGTTCCTGGAAGCAGCTCTTAT (SEQ ID NO: 2289)





hCV32291301
A/G
TCAGGTTGGTCAGTGCTT (SEQ ID NO: 2290)
TCAGGTTGGTCAGTGCTC (SEQ ID NO: 2291)
CTTCACCGCCATGTGACTTTATGAA (SEQ ID NO: 2292)





hCV3230016
A/G
AGCCAGCACAGACCATCT (SEQ ID NO: 2293)
GCCAGCACAGACCATCC (SEQ ID NO: 2294)
ATATTGGTTACTCACAGGTGAAAT (SEQ ID NO: 2295)





hCV3230030
A/G
GGGCAAAACCCACAGTAAAA (SEQ ID NO: 2296)
GGGCAAAACCCACAGTAAAG (SEQ ID NO: 2297)
GTGTTTCTGTTTAGCCTGTTAGCTATACAAA (SEQ ID






NO: 2298)





hCV3230038
C/T
CCAGGATGAGAGGGCG (SEQ ID NO: 2299)
CCAGGATGAGAGGGCA (SEQ ID NO: 2300)
GGGATGAAGGATTGAAGGTTAGAACAATT (SEQ ID






NO: 2301)





hCV3230083
A/C
CACAACTTTCTCATCTTGATTGAATTTA (SEQ ID
ACAACTTTCTCATCTTGATTGAATTTC (SEQ ID
CGGCATGTGGCGGTATTC (SEQ ID NO: 2304)




NO: 2302)
NO: 2303)






hCV3230084
C/T
GAGAATCTCACCAGAATCAATATAAC (SEQ ID
TGAGAATCTCACCAGAATCAATATAAT (SEQ ID
TCCCAGGATTCGGGCTATACC (SEQ ID NO: 2307)




NO: 2305)
NO: 2306)






hCV3230096
C/T
AGAAGCATGTGATTATCATTCAAATC (SEQ ID
CAGAAGCATGTGATTATCATTCAAATT (SEQ ID
GTCAAGAAAGGCCCTGCGTTTAT (SEQ ID NO: 2310)




NO: 2308)
NO: 2309)






hCV3230099
C/T
ACGCCAATGAAGACTGC (SEQ ID NO: 2311)
GAACGCCAATGAAGACTGT (SEQ ID NO: 2312)
TTCCCTTCGTCATCAGTCACACTTA (SEQ ID NO: 2313)





hCV3230113
A/T
AAATGAAGACTATAAGTGCACGAT (SEQ ID NO: 2314)
AAATGAAGACTATAAGTGCACGAA (SEQ ID NO: 2315)
GTGGGACCAGTTATGACAAGAATAATCATTATAGTAC (SEQ






ID NO: 2316)





hCV3230119
C/G
GCCACTACTTGGTTATTTTCTGG (SEQ ID NO: 2317)
GCCACTACTTGGTTATTTTCTGC (SEQ ID NO: 2318)
AAACTCCCGTTCTATGATCGTTGTAGTT (SEQ ID NO: 2319)





hCV3230131
C/T
CCGGTGTTGTTTCAGCATAC (SEQ ID NO: 2320)
CCGGTGTTGTTTCAGCATAT (SEQ ID NO: 2321)
GAGAGGCCTGGAACCTCAGATAC (SEQ ID NO: 2322)





hCV3230136
A/G
CTAATTATGTCCACAGCCACTAT (SEQ ID NO: 2323)
CTAATTATGTCCACAGCCACTAC (SEQ ID NO: 2324)
CATCCTTGGAGTGAGGACCTG (SEQ ID NO: 2325)





hCV3272537
A/T
AATTTGACACTAGTCATAGCCAT (SEQ ID NO: 2326)
AATTTGACACTAGTCATAGCCAA (SEQ ID NO: 2327)
TGGTGGCACACACCTATAGTC (SEQ ID NO: 2328)





hCV356522
C/T
ACCAAGCATGAACAGGATATATTAC (SEQ ID NO: 2329)
ACCAAGCATGAACAGGATATATTAT (SEQ ID NO: 2330)
AACCCAGACTGGTTTGATATAGTATCT (SEQ ID NO: 2331)





hCV4041
C/T
AAGTCCATCACATCTCCCC (SEQ ID NO: 2332)
GAAGTCCATCACATCTCCCT (SEQ ID NO: 2333)
CCGTTTTTGTTTTTTGTTTTGTA (SEQ ID NO: 2334)





hCV470708
G/T
CAACCCTCATTCCAGCTC (SEQ ID NO: 2335)
CAACCCTCATTCCAGCTA (SEQ ID NO: 2336)
AGTGCTGGAGCCAAGATAAC (SEQ ID NO: 2337)





hCV491830
C/T
TCCAGCAGCCGCAG (SEQ ID NO: 2338)
TCCAGCAGCCGCAA (SEQ ID NO: 2339)
CCTGGCCACATTCATCAT (SEQ ID NO: 2340)





hCV505733
A/G
ACACGGTGGCATAAGCA (SEQ ID NO: 2341)
CACGGTGGCATAAGCG (SEQ ID NO: 2342)
TGATCTGACTCCAAGCTGAGTTTAC (SEQ ID NO: 2343)





hCV540410
A/T
ACTCACTCTGACTTCAGTTTCTTAT (SEQ ID NO: 2344)
ACTCACTCTGACTTCAGTTTCTTAA (SEQ ID NO: 2345)
TGTACTGAATGGTGTCATTTACTC (SEQ ID NO: 2346)





hCV596326
A/G
CCCTGAATTTGACTATATTGATTACATCA (SEQ ID
CCTGAATTTGACTATATTGATTACATCG (SEQ ID
ACTGGGGTTTACTGCTCCAATTACT (SEQ ID NO: 2349)




NO: 2347)
NO: 2348)






hCV596330
A/C
CATCCCTGAATGGAAGTCTT (SEQ ID NO: 2350)
CATCCCTGAATGGAAGTCTG (SEQ ID NO: 2351)
CCTTGGAATCTAGAAGGCCTTTTAGTCT (SEQ ID NO: 2352)





hCV596331
A/G
AGTCCACATCAGGAAAATCAGT (SEQ ID NO: 2353)
GTCCACATCAGGAAAATCAGC (SEQ ID NO: 2354)
CCATTTGCCAATGAGAAATATCAGGTTACT (SEQ ID






NO: 2355)





hCV596335
C/G
CCCTGGAATAAGGTAAGAAATGAG (SEQ ID NO: 2356)
CCCTGGAATAAGGTAAGAAATGAC (SEQ ID NO: 2357)
GTTCACCTGGCCAGAGATCAGA (SEQ ID NO: 2358)





hCV596336
C/T
CCCAGTCTCCATCCACTTC (SEQ ID NO: 2359)
CCCAGTCTCCATCCACTTT (SEQ ID NO: 2360)
CTTTGCATGTTATCTGCCACTGAGAT (SEQ ID NO: 2361)





hCV596337
C/G
GGAAGTGCACCCTACAATTTAAG (SEQ ID NO: 2362)
GGAAGTGCACCCTACAATTTAAC (SEQ ID NO: 2363)
CAGTGACAAGGGAAGATTGACACAT (SEQ ID NO: 2364)





hCV596663
A/G
CACCCTATCCTTCCTCGAT (SEQ ID NO: 2365)
CACCCTATCCTTCCTCGAC (SEQ ID NO: 2366)
GAGGGATAAATACATCAATGGCACAAAGA (SEQ ID






NO: 2367)





hCV596669
A/G
GTATTTGGGACTACTTCCTGAT (SEQ ID NO: 2368)
GTATTTGGGACTACTTCCTGAC (SEQ ID NO: 2369)
GCAGGGATGTCAAGGGACTAGA (SEQ ID NO: 2370)





hCV7422466
A/C
TGCTACAATTATGGAAACCCTAAA (SEQ ID NO: 2371)
TGCTACAATTATGGAAACCCTAAC (SEQ ID NO: 2372)
GTTTGGGATGGCACAATGATTTATG (SEQ ID NO: 2373)





hCV7429782
A/T
GCAAGAGATGTATCTCAACTACAAA (SEQ ID NO: 2374)
GCAAGAGATGTATCTCAACTACAAT (SEQ ID NO: 2375)
ATCCTCCAATCTTCCTCCCCATATC (SEQ ID NO: 2376)





hCV7429793
C/T
GCCTTGTGCTATGGAGACC (SEQ ID NO: 2377)
GCCTTGTGCTATGGAGACT (SEQ ID NO: 2378)
CTCTGGCTTGAAGGGCAAAGAC (SEQ ID NO: 2379)





hCV7459627
A/G
CTGAGTTGGAGGTCCAT (SEQ ID NO: 2380)
CTGAGTTGGAGGTCCAC (SEQ ID NO: 2381)
TGCCACATGCTTCTTCTAAC (SEQ ID NO: 2382)





hCV7504118
A/G
CTCAACCAGCTTGACACT (SEQ ID NO: 2383)
CTCAACCAGCTTGACACC (SEQ ID NO: 2384)
AAACAGTTCGAGGATACACACAATCTCA (SEQ ID NO: 2385)





hCV7574127
A/G
GGTCTTCTGAGATGGATAAATATTCAA (SEQ ID
GGTCTTCTGAGATGGATAAATATTCAG (SEQ ID
GAAACAGTTGGTCAAACTGACAAGA (SEQ ID NO: 2388)




NO: 2386)
NO: 2387)






hCV7581501
C/G
AACCCTCACAACCACCTTAC (SEQ ID NO: 2389)
AACCCTCACAACCACCTTAG (SEQ ID NO: 2390)
TCCATCCACCGCTTACTG (SEQ ID NO: 2391)





hCV7584272
A/G
GACACCACCCAGCTCA (SEQ ID NO: 2392)
ACACCACCCAGCTCG (SEQ ID NO: 2393)
TGGCTCAGTTCTTTTTCTTCTAT (SEQ ID NO: 2394)





hCV7625318
A/G
ATCAGGGCATCGGAGT (SEQ ID NO: 2395)
CAGGGCATCGGAGC (SEQ ID NO: 2396)
TCAAGCTGAGGGTGGTCTAG (SEQ ID NO: 2397)





hCV788647
A/G
GCACATGGCATGATTCTATTTAT (SEQ ID NO: 2398)
GCACATGGCATGATTCTATTTAC (SEQ ID NO: 2399)
TGTCCACTCCTGGCACACTT (SEQ ID NO: 2400)





hCV813581
G/T
GCAGCAAAATAACAGTGTGC (SEQ ID NO: 2401)
TGCAGCAAAATAACAGTGTGA (SEQ ID NO: 2402)
GAGCATATTCCCCACCACAGTT (SEQ ID NO: 2403)





hCV815038
C/T
CCTGACTCAGCAATTAATAGTCG (SEQ ID NO: 2404)
CCTGACTCAGCAATTAATAGTCA (SEQ ID NO: 2405)
CATTTTGCACCCAACCACAACT (SEQ ID NO: 2406)





hCV8241630
A/G
CATCTCTACAAAGCTAAATCAGACAT (SEQ ID
TCTCTACAAAGCTAAATCAGACAC (SEQ ID NO: 2408)
CCTCTCAAGCAAATACGCCTTGAA (SEQ ID NO: 2409)




NO: 2407)







hCV8361354
A/C
CATGGCCATCGCTCAA (SEQ ID NO: 2410)
CATGGCCATCGCTCAC (SEQ ID NO: 2411)
GCAATGCACGTGACCATCTT (SEQ ID NO: 2412)





hCV837462
A/C
TGGCATACTTTCGATATACTCA (SEQ ID NO: 2413)
TGGCATACTTTCGATATACTCC (SEQ ID NO: 2414)
TGGACATATGCTATTGACTTTAAAA (SEQ ID NO: 2415)





hCV8598986
C/T
GACTGTGGTGTCTGAAACTC (SEQ ID NO: 2416)
GACTGTGGTGTCTGAAACTT (SEQ ID NO: 2417)
GGAGGCCCTGCCAGATG (SEQ ID NO: 2418)





hCV8688111
C/G
AGAACTTGGGGATTTTCCATAC (SEQ ID NO: 2419)
AAGAACTTGGGGATTTTCCATAG (SEQ ID NO: 2420)
GTCACAGATCATTTATCACAGTGTACCAT (SEQ ID






NO: 2421)





hCV8703249
G/T
CTTTTATGGATCTTTCTAGTCTTGTTTC (SEQ ID
CTTTTATGGATCTTTCTAGTCTTGTTTA (SEQ ID
AAGCTAGAGGATGGTCCCAGTTTTAC (SEQ ID NO: 2424)




NO: 2422)
NO: 2423)






hCV8717752
A/G
CCGGCTCCATCACCA (SEQ ID NO: 2425)
CCGGCTCCATCACCG (SEQ ID NO: 2426)
GGCAGAAGTGACAGTAGGTTAGTCT (SEQ ID NO: 2427)





hCV8717873
A/G
AACAGAACCACCTTCCT (SEQ ID NO: 2428)
ACAGAACCACCTTCCC (SEQ ID NO: 2429)
TGTGAAAGAACCAACTGAATTAAA (SEQ ID NO: 2430)





hCV8717893
A/G
GACAGTTCGGTGAAGTGA (SEQ ID NO: 2431)
GACAGTTCGGTGAAGTGG (SEQ ID NO: 2432)
CGCTGAACTGACCGTCTCATTC (SEQ ID NO: 2433)





hCV8717916
A/C
ATGAGAAGAAGGCCTTTCTT (SEQ ID NO: 2434)
TGAGAAGAAGGCCTTTCTG (SEQ ID NO: 2435)
TTGTACCCCAGGTTGAAAAT (SEQ ID NO: 2436)





hCV8717949
A/C
GTCGTAAGTCTCTCCTCTCTTA (SEQ ID NO: 2437)
TCGTAAGTCTCTCCTCTCTTC (SEQ ID NO: 2438)
GGGAACAGGTGTTCACATCA (SEQ ID NO: 2439)





hCV8726802
A/G
CCAATAAAAGTGACTCTCAGCA (SEQ ID NO: 2440)
CAATAAAAGTGACTCTCAGCG (SEQ ID NO: 2441)
CCAGGTGGTGGATTCTTAAGT (SEQ ID NO: 2442)





hCV8727391
G/A
GGAGCTTCTTCATTTACCTTC (SEQ ID NO: 2443)
GGAGCTTCTTCATTTACCTTT (SEQ ID NO: 2444)
TTCCTAGGCCCAAACAGA (SEQ ID NO: 2445)





hCV8827309
C/T
CTTTCTCAGCAAGAGCAC (SEQ ID NO: 2446)
CTTTCTCAGCAAGAGCAT (SEQ ID NO: 2447)
AAGTTGGATCGAGTTATAACAACTATA (SEQ ID NO: 2448)





hCV8856223
C/G
AGACATTTTCTCAAGATCATGGC (SEQ ID NO: 2449)
AGACATTTTCTCAAGATCATGGG (SEQ ID NO: 2450)
CCTGCTTTGCGTCTGAAGAGATAT (SEQ ID NO: 2451)





hCV8857351
C/T
GATAGATAGATAGATAGATAGAGATTTTGAGG (SEQ ID
GATAGATAGATAGATAGATAGAGATTTTGAGA (SEQ ID
AGCCTGCTGTCCTGCTCTAT (SEQ ID NO: 2454)




NO: 2452)
NO: 2453)






hCV8911768
C/T
GAAAGCAGGGTGAGACTG (SEQ ID NO: 2455)
GGAAAGCAGGGTGAGACTA (SEQ ID NO: 2456)
CTGATTTTGCTCCAATAGGCACTTTT (SEQ ID NO: 2457)





hCV8919442
T/C
AAGTCAAGAACATGCTAAGCA (SEQ ID NO: 2458)
AGTCAAGAACATGCTAAGCG (SEQ ID NO: 2459)
GGTGTCTCCCAACTTTATGTG (SEQ ID NO: 2460)





hCV8919444
C/T
TGGTGCTGGAGAATTCAG (SEQ ID NO: 2461)
TGGTGCTGGAGAATTCAA (SEQ ID NO: 2462)
GGTGTCTCCCAACTTTATGTG (SEQ ID NO: 2463)





hCV8919450
A/G
TCCGAAACTCATCATTGAAT (SEQ ID NO: 2464)
TCCGAAACTCATCATTGAAC (SEQ ID NO: 2465)
CAAGGTTATTGACAGTGAACTTACT (SEQ ID NO: 2466)





hCV8919451
A/G
GATGAGTTTCGGAATGACCTA (SEQ ID NO: 2467)
TGAGTTTCGGAATGACCTG (SEQ ID NO: 2468)
TTTGAACCTCCAGAATCTACAG (SEQ ID NO: 2469)





hCV8941510
A/C
TGGTAGGGTGAACCGGA (SEQ ID NO: 2470)
GGTAGGGTGAACCGGC (SEQ ID NO: 2471)
GGGCTACTTCACCAAAGAGAA (SEQ ID NO: 2472)





hCV8957432
C/G
CCATTTCTTAAGACTTTCTGCTG (SEQ ID NO: 2473)
CCATTTCTTAAGACTTTCTGCTC (SEQ ID NO: 2474)
CCTGACTGGCAAGGTTTAAA (SEQ ID NO: 2475)





hCV9102827
C/T
GTAAGGGATGAGAAGGATG (SEQ ID NO: 2476)
TGTAAGGGATGAGAAGGATA (SEQ ID NO: 2477)
TGCTGACTCCAGCTCTTTC (SEQ ID NO: 2478)





hCV9114656
C/T
CCATCACTGGAGTATTTTTAGTTATAC (SEQ ID
CCATCACTGGAGTATTTTTAGTTATAT (SEQ ID
ATATTCGGATCTGTTTTCAACTTA (SEQ ID NO: 2481)




NO: 2479)
NO: 2480)






hCV916106
A/G
ACATCACAAGCATAGCAAAGATAT (SEQ ID NO: 2482)
CATCACAAGCATAGCAAAGATAC (SEQ ID NO: 2483)
GTGGTTGTCTGCAGTTTTCAAATGTT (SEQ ID NO: 2484)





hCV916107
C/T
AGAATCCGAGAAGTCTGATG (SEQ ID NO: 2485)
GAAGAATCCGAGAAGTCTGATA (SEQ ID NO: 2486)
TTCAGCTTTTTATTGAACACATTATA (SEQ ID NO: 2487)





hCV926518
G/T
GAGTTAACGTGGACATGAAGTAG (SEQ ID NO: 2488)
GAGTTAACGTGGACATGAAGTAT (SEQ ID NO: 2489)
CCCAGCTGCCAAATTTC (SEQ ID NO: 2490)





hCV9327878
C/G
TCATGAATGTCCATTTCTGG (SEQ ID NO: 2491)
TCATGAATGTCCATTTCTGC (SEQ ID NO: 2492)
TGACCTGAACGACTTCACAG (SEQ ID NO: 2493)





hCV9493081
C/T
GGCAGTAGTGCGGTTG (SEQ ID NO: 2494)
TGGCAGTAGTGCGGTTA (SEQ ID NO: 2495)
TTCATCCCTGGCTTCACAGTACAT (SEQ ID NO: 2496)





hCV949676
C/T
CATTAGCCTGGGAAATAAATAAC (SEQ ID NO: 2497)
CATTAGCCTGGGAAATAAATAAT (SEQ ID NO: 2498)
CACCCCCACTTGTCAAAT (SEQ ID NO: 2499)





hCV9596963
A/G
TGCCCCCAGCCAGAA (SEQ ID NO: 2500)
TGCCCCCAGCCAGAG (SEQ ID NO: 2501)
GGCCCTCCAGGATCTG (SEQ ID NO: 2502)





hCV9680592
A/G
TTGTACATGAAAATACAGGATTACA (SEQ ID NO: 2503)
TGTACATGAAAATACAGGATTACG (SEQ ID NO: 2504)
TTTGAACAGGCACTCACTAATAG (SEQ ID NO: 2505)





hCV97631
G/T
CACAGGCAGCAGATTCTC (SEQ ID NO: 2506)
TCACAGGCAGCAGATTCTA (SEQ ID NO: 2507)
GCACACACACGTCATCATATCTTCA (SEQ ID NO: 2508)





hCV9860072
A/C
GCATAGACACCATGTTCCCT (SEQ ID NO: 2509)
CATAGACACCATGTTCCCG (SEQ ID NO: 2510)
GCTCTCCCTGTTTCAGACAT (SEQ ID NO: 2511)





hDV70662128
A/G
AAGAGACCATATCAGAGGCAA (SEQ ID NO: 2512)
AGAGACCATATCAGAGGCAG (SEQ ID NO: 2513)
GCGGACGGGAAGATGTTGAT (SEQ ID NO: 2514)





hDV70683187
C/G
AATTTTCAAAGTTCCTTCTCTAGAATC (SEQ ID
AATTTTCAAAGTTCCTTCTCTAGAATG (SEQ ID
CTGTAAGCAGTTTGGGCTCTTTTAAT (SEQ ID NO: 2517)




NO: 2515)
NO: 2516)






hDV70683212
C/G
CCCGCAATGAACTTTAATTCTG (SEQ ID NO: 2518)
CCCGCAATGAACTTTAATTCTC (SEQ ID NO: 2519)
CCAGCCAGGCAAGGTTAAGTC (SEQ ID NO: 2520)





hDV70683382
C/G
AGAATGTTTTCCTCCAGTTCAC (SEQ ID NO: 2521)
AGAATGTTTTCCTCCAGTTCAG (SEQ ID NO: 2522)
CAACTACTCTTAGAATTAAAGGCACAGCT (SEQ ID






NO: 2523)





hDV70941043
A/G
GAAGAAATACTTGACTTGAAGAGAAATT (SEQ ID
GAAGAAATACTTGACTTGAAGAGAAATC (SEQ ID
AGGAAGAAGGCTCCTGTGTTCTAAT (SEQ ID NO: 2526)




NO: 2524)
NO: 2525)






hDV70965621
A/G
GCTCCCGTTCCACTCT (SEQ ID NO: 2527)
GCTCCCGTTCCACTCC (SEQ ID NO: 2528)
GGGAGTGGAACACAGGTGAGA (SEQ ID NO: 2529)





hDV71075942
T/G
CAGCCAAGGGGTACCA (SEQ ID NO: 2530)
AGCCAAGGGGTCACC (SEQ ID NO: 2531)
TGCCAGAGGCGCATGTG (SEQ ID NO: 2532)





hDV76976792
C/T
CAATTTAAGCCAGAATCAGGTAAAC (SEQ ID NO: 2533)
CAATTTAAGCCAGAATCAGGTAAAT (SEQ ID NO: 2534)
GGCAGGCATTCTCAAGAATCCT (SEQ ID NO: 2535)





hDV76976795
A/G
AAAGTGGACAAAGCAGTGAT (SEQ ID NO: 2536)
AAGTGGACAAAGCAGTGAC (SEQ ID NO: 2537)
GAACTGAAATCCTCCAAGTCGATCTAG (SEQ ID NO: 2538)





hCV1841974
A/G
GAAGCCCACCTATGCCT (SEQ ID NO: 2539)
AGCCCACCTATGCCC (SEQ ID NO: 2540)
CCCTCAGCCAGCCACTATG (SEQ ID NO: 2541)





hCV1952126
A/C
TCGGTCTCCTTTCTGAGTTT (SEQ ID NO: 2542)
TCGGTCTCCTTTCTGAGTTG (SEQ ID NO: 2543)
GGTCACTTCTAGTCTGGTATCCATTATCAT (SEQ ID






NO: 2544)





hCV22272816
A/G
TCTGTTCCACCACCTCTT (SEQ ID NO: 2545)
TCTGTTCCACCACCTCTC (SEQ ID NO: 2546)
CGGCGCTGGTGAGAC (SEQ ID NO: 2547)





hCV25597241
A/G
GACAGAGGCAGAGAGAGAA (SEQ ID NO: 2548)
GACAGAGGCAGAGAGAGAG (SEQ ID NO: 2549)
TCCTGCTTTGCTCTGGTATCA (SEQ ID NO: 2550)





hCV30500334
A/G
ACGCATCTACTTTCTGTCTGTATA (SEQ ID NO: 2551)
CGCATCTACTTTCTGTCTGTATG (SEQ ID NO: 2552)
AGTGTGGAGGGACCCTGATAAC (SEQ ID NO: 2553)





hCV30747430
C/T
GGAAACTTCTCTTTGGGACTC (SEQ ID NO: 2554)
GGAAACTTCTCTTTGGGACTT (SEQ ID NO: 2555)
AAGCTTATGGTGGTCCCAGTTAGT (SEQ ID NO: 2556)






















TABLE 4





Interrogated SNP
Interrogated rs
LD SNP
LD SNP rs
Power
Threshold r2
r2





















hCV11503414
rs2066865
hCV11503416
rs2066864
0.51
0.528621503
1


hCV11503414
rs2066865
hCV11503431
rs2066861
0.51
0.528621503
1


hCV11503414
rs2066865
hCV11853483
rs12644950
0.51
0.528621503
1


hCV11503414
rs2066865
hCV11853489
rs7681423
0.51
0.528621503
1


hCV11503414
rs2066865
hCV11853496
rs7654093
0.51
0.528621503
1


hCV11503414
rs2066865
hCV27020277
rs6825454
0.51
0.528621503
0.9115


hCV11503414
rs2066865
hCV2892859
rs13130318
0.51
0.528621503
0.8654


hCV11503414
rs2066865
hCV2892869
rs13109457
0.51
0.528621503
0.9571


hCV11503414
rs2066865
hCV2892877
rs6050
0.51
0.528621503
0.9148


hCV11503414
rs2066865
hCV31863982
rs7659024
0.51
0.528621503
1


hCV11503431
rs2066861
hCV11503414
rs2066865
0.51
0.521395339
1


hCV11503431
rs2066861
hCV11503416
rs2066864
0.51
0.521395339
1


hCV11503431
rs2066861
hCV11853483
rs12644950
0.51
0.521395339
1


hCV11503431
rs2066861
hCV11853489
rs7681423
0.51
0.521395339
1


hCV11503431
rs2066861
hCV11853496
rs7654093
0.51
0.521395339
1


hCV11503431
rs2066861
hCV15860433
rs2070006
0.51
0.521395339
0.5225


hCV11503431
rs2066861
hCV27020269
rs7659613
0.51
0.521395339
0.5225


hCV11503431
rs2066861
hCV27020277
rs6825454
0.51
0.521395339
0.9115


hCV11503431
rs2066861
hCV2892859
rs13130318
0.51
0.521395339
0.8654


hCV11503431
rs2066861
hCV2892869
rs13109457
0.51
0.521395339
0.9571


hCV11503431
rs2066861
hCV2892877
rs6050
0.51
0.521395339
0.9148


hCV11503431
rs2066861
hCV31863982
rs7659024
0.51
0.521395339
1


hCV11853483
rs12644950
hCV11503414
rs2066865
0.51
0.506269027
1


hCV11853483
rs12644950
hCV11503416
rs2066864
0.51
0.506269027
1


hCV11853483
rs12644950
hCV11503431
rs2066861
0.51
0.506269027
1


hCV11853483
rs12644950
hCV11853489
rs7681423
0.51
0.506269027
1


hCV11853483
rs12644950
hCV11853496
rs7654093
0.51
0.506269027
1


hCV11853483
rs12644950
hCV27020277
rs6825454
0.51
0.506269027
0.9041


hCV11853483
rs12644950
hCV2892859
rs13130318
0.51
0.506269027
0.8547


hCV11853483
rs12644950
hCV2892869
rs13109457
0.51
0.506269027
0.9537


hCV11853483
rs12644950
hCV2892877
rs6050
0.51
0.506269027
0.9079


hCV11853483
rs12644950
hCV31863982
rs7659024
0.51
0.506269027
1


hCV11853496
rs7654093
hCV11503414
rs2066865
0.51
0.521395339
1


hCV11853496
rs7654093
hCV11503416
rs2066864
0.51
0.521395339
1


hCV11853496
rs7654093
hCV11503431
rs2066861
0.51
0.521395339
1


hCV11853496
rs7654093
hCV11853483
rs12644950
0.51
0.521395339
1


hCV11853496
rs7654093
hCV11853489
rs7681423
0.51
0.521395339
1


hCV11853496
rs7654093
hCV27020277
rs6825454
0.51
0.521395339
0.9109


hCV11853496
rs7654093
hCV2892859
rs13130318
0.51
0.521395339
0.8643


hCV11853496
rs7654093
hCV2892869
rs13109457
0.51
0.521395339
0.9568


hCV11853496
rs7654093
hCV2892877
rs6050
0.51
0.521395339
0.9143


hCV11853496
rs7654093
hCV31863982
rs7659024
0.51
0.521395339
1


hCV1198623
rs2638504
hCV16269565
rs2682338
0.51
0.946056388
0.9622


hCV1198623
rs2638504
hCV444705
rs6580917
0.51
0.946056388
0.9614


hCV12066124
rs2036914
hCV2103343
rs4241824
0.51
0.734459115
0.9351


hCV12066124
rs2036914
hCV25474413
rs3822057
0.51
0.734459115
0.9351


hCV15860433
rs2070006
hCV27020269
rs7659613
0.51
0.884364576
1


hCV15860433
rs2070006
hCV2892870
rs2070011
0.51
0.884364576
0.9647


hCV15885425
rs2290754
hCV15760229
rs3006939
0.51
0.641487193
0.6943


hCV15885425
rs2290754
hCV15760238
rs3006936
0.51
0.641487193
0.7059


hCV15885425
rs2290754
hCV15823024
rs2125230
0.51
0.641487193
1


hCV15885425
rs2290754
hCV15965338
rs2291410
0.51
0.641487193
1


hCV15885425
rs2290754
hCV16082410
rs2881275
0.51
0.641487193
1


hCV15885425
rs2290754
hCV1678656
rs1458024
0.51
0.641487193
1


hCV15885425
rs2290754
hCV1678674
rs1458023
0.51
0.641487193
0.8095


hCV15885425
rs2290754
hCV1678682
rs320339
0.51
0.641487193
0.8718


hCV15885425
rs2290754
hCV26034158
rs4515770
0.51
0.641487193
0.6976


hCV15885425
rs2290754
hCV26719082
rs10927046
0.51
0.641487193
0.8715


hCV15885425
rs2290754
hCV26719085
rs10927047
0.51
0.641487193
0.8649


hCV15885425
rs2290754
hCV26719107
rs7538011
0.51
0.641487193
0.81


hCV15885425
rs2290754
hCV26719113
rs7517340
0.51
0.641487193
0.9318


hCV15885425
rs2290754
hCV26719116
rs10927039
0.51
0.641487193
0.8711


hCV15885425
rs2290754
hCV26719120
rs10927040
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719121
rs10927041
0.51
0.641487193
0.8181


hCV15885425
rs2290754
hCV26719149
rs6675851
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719162
rs4132509
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719176
rs10927076
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719192
rs10803161
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719201
rs4478795
0.51
0.641487193
0.7462


hCV15885425
rs2290754
hCV26719219
rs9782958
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719222
rs4553169
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719227
rs10927065
0.51
0.641487193
0.8095


hCV15885425
rs2290754
hCV26719232
rs10803158
0.51
0.641487193
1


hCV15885425
rs2290754
hCV26719233
rs10927067
0.51
0.641487193
1


hCV15885425
rs2290754
hCV27498250
rs3766673
0.51
0.641487193
0.8792


hCV15885425
rs2290754
hCV29210363
rs6656918
0.51
0.641487193
0.6952


hCV15885425
rs2290754
hCV29542869
rs7534117
0.51
0.641487193
1


hCV15885425
rs2290754
hCV29560960
rs7519673
0.51
0.641487193
0.8095


hCV15885425
rs2290754
hCV29741723
rs7517921
0.51
0.641487193
0.7042


hCV15885425
rs2290754
hCV29994467
rs6694738
0.51
0.641487193
0.81


hCV15885425
rs2290754
hCV30084348
rs9287269
0.51
0.641487193
1


hCV15885425
rs2290754
hCV30372886
rs9782883
0.51
0.641487193
1


hCV15885425
rs2290754
hCV30690780
rs10737888
0.51
0.641487193
0.7059


hCV15885425
rs2290754
hCV31523557
rs10754807
0.51
0.641487193
1


hCV15885425
rs2290754
hCV31523563
rs10927051
0.51
0.641487193
0.923


hCV15885425
rs2290754
hCV31523638
rs12037013
0.51
0.641487193
0.8715


hCV15885425
rs2290754
hCV31523639
rs12034588
0.51
0.641487193
1


hCV15885425
rs2290754
hCV31523643
rs6671475
0.51
0.641487193
0.9347


hCV15885425
rs2290754
hCV31523650
rs12048930
0.51
0.641487193
0.8181


hCV15885425
rs2290754
hCV31523658
rs12047209
0.51
0.641487193
0.7481


hCV15885425
rs2290754
hCV31523688
rs12049228
0.51
0.641487193
1


hCV15885425
rs2290754
hCV31523691
rs12021907
0.51
0.641487193
0.8095


hCV15885425
rs2290754
hCV31523707
rs10803152
0.51
0.641487193
0.8652


hCV15885425
rs2290754
hCV31523710
rs10927059
0.51
0.641487193
1


hCV15885425
rs2290754
hCV31523723
rs12140040
0.51
0.641487193
0.7484


hCV15885425
rs2290754
hCV31523736
rs12124113
0.51
0.641487193
0.8091


hCV15885425
rs2290754
hCV31523740
rs12032342
0.51
0.641487193
1


hCV15885425
rs2290754
hCV31523744
rs12031994
0.51
0.641487193
0.8095


hCV15885425
rs2290754
hCV804126
rs320320
0.51
0.641487193
1


hCV15885425
rs2290754
hCV97631
rs1538773
0.51
0.641487193
0.7059


hCV15885425
rs2290754
hDV71836703
rs6429433
0.51
0.641487193
0.81


hCV16000557
rs2377041
hCV1642008
rs1563471
0.51
0.48606158
0.8362


hCV16000557
rs2377041
hCV1974943
rs6672381
0.51
0.48606158
0.4957


hCV16000557
rs2377041
hCV1974944
rs6667605
0.51
0.48606158
0.4885


hCV16000557
rs2377041
hCV27102953
rs4648360
0.51
0.48606158
0.8987


hCV16000557
rs2377041
hCV27102978
rs7537581
0.51
0.48606158
0.8288


hCV16000557
rs2377041
hCV27103080
rs4648459
0.51
0.48606158
1


hCV16000557
rs2377041
hCV27103144
rs11584658
0.51
0.48606158
0.8636


hCV16000557
rs2377041
hCV27103182
rs4609377
0.51
0.48606158
0.7742


hCV16000557
rs2377041
hCV27103185
rs10797389
0.51
0.48606158
0.8506


hCV16000557
rs2377041
hCV27103186
rs4648481
0.51
0.48606158
0.8659


hCV16000557
rs2377041
hCV27103188
rs7511879
0.51
0.48606158
0.7719


hCV16000557
rs2377041
hCV27103189
rs12031493
0.51
0.48606158
0.738


hCV16000557
rs2377041
hCV27103192
rs6680471
0.51
0.48606158
0.6533


hCV16000557
rs2377041
hCV27103207
rs6424062
0.51
0.48606158
1


hCV16000557
rs2377041
hCV31475436
rs4486391
0.51
0.48606158
0.503


hCV16000557
rs2377041
hCV31965210
rs10909880
0.51
0.48606158
0.8659


hCV16000557
rs2377041
hCV31965333
rs10797390
0.51
0.48606158
0.7352


hCV16000557
rs2377041
hCV788647
rs729045
0.51
0.48606158
0.5863


hCV16000557
rs2377041
hCV8725828
rs1456461
0.51
0.48606158
0.5812


hCV1678674
rs1458023
hCV15823024
rs2125230
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV15885425
rs2290754
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV15965338
rs2291410
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV16082410
rs2881275
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV1678656
rs1458024
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV1678682
rs320339
0.51
0.6955117
0.7908


hCV1678674
rs1458023
hCV26719082
rs10927046
0.51
0.6955117
0.9284


hCV1678674
rs1458023
hCV26719085
rs10927047
0.51
0.6955117
0.9242


hCV1678674
rs1458023
hCV26719107
rs7538011
0.51
0.6955117
0.8655


hCV1678674
rs1458023
hCV26719113
rs7517340
0.51
0.6955117
0.721


hCV1678674
rs1458023
hCV26719116
rs10927039
0.51
0.6955117
0.7473


hCV1678674
rs1458023
hCV26719120
rs10927040
0.51
0.6955117
0.7884


hCV1678674
rs1458023
hCV26719149
rs6675851
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV26719162
rs4132509
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV26719176
rs10927076
0.51
0.6955117
0.776


hCV1678674
rs1458023
hCV26719192
rs10803161
0.51
0.6955117
0.7993


hCV1678674
rs1458023
hCV26719201
rs4478795
0.51
0.6955117
0.9


hCV1678674
rs1458023
hCV26719219
rs9782958
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV26719222
rs4553169
0.51
0.6955117
0.8086


hCV1678674
rs1458023
hCV26719227
rs10927065
0.51
0.6955117
1


hCV1678674
rs1458023
hCV26719232
rs10803158
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV26719233
rs10927067
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV29542869
rs7534117
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV29560960
rs7519673
0.51
0.6955117
1


hCV1678674
rs1458023
hCV29994467
rs6694738
0.51
0.6955117
0.8655


hCV1678674
rs1458023
hCV30084348
rs9287269
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV30372886
rs9782883
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV31523557
rs10754807
0.51
0.6955117
0.8091


hCV1678674
rs1458023
hCV31523638
rs12037013
0.51
0.6955117
0.9284


hCV1678674
rs1458023
hCV31523639
rs12034588
0.51
0.6955117
0.7993


hCV1678674
rs1458023
hCV31523643
rs6671475
0.51
0.6955117
0.7467


hCV1678674
rs1458023
hCV31523658
rs12047209
0.51
0.6955117
0.9286


hCV1678674
rs1458023
hCV31523688
rs12049228
0.51
0.6955117
0.7998


hCV1678674
rs1458023
hCV31523691
rs12021907
0.51
0.6955117
1


hCV1678674
rs1458023
hCV31523707
rs10803152
0.51
0.6955117
0.9244


hCV1678674
rs1458023
hCV31523710
rs10927059
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV31523723
rs12140040
0.51
0.6955117
0.9245


hCV1678674
rs1458023
hCV31523736
rs12124113
0.51
0.6955117
1


hCV1678674
rs1458023
hCV31523740
rs12032342
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hCV31523744
rs12031994
0.51
0.6955117
1


hCV1678674
rs1458023
hCV804126
rs320320
0.51
0.6955117
0.8095


hCV1678674
rs1458023
hDV71836703
rs6429433
0.51
0.6955117
0.7358


hCV1678682
rs320339
hCV15823024
rs2125230
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV15885425
rs2290754
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV15965338
rs2291410
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV16082410
rs2881275
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV1678656
rs1458024
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV1678674
rs1458023
0.51
0.68963884
0.7908


hCV1678682
rs320339
hCV26719082
rs10927046
0.51
0.68963884
0.8604


hCV1678682
rs320339
hCV26719085
rs10927047
0.51
0.68963884
0.8524


hCV1678682
rs320339
hCV26719107
rs7538011
0.51
0.68963884
0.801


hCV1678682
rs320339
hCV26719113
rs7517340
0.51
0.68963884
0.7898


hCV1678682
rs320339
hCV26719116
rs10927039
0.51
0.68963884
0.8086


hCV1678682
rs320339
hCV26719120
rs10927040
0.51
0.68963884
0.8575


hCV1678682
rs320339
hCV26719121
rs10927041
0.51
0.68963884
0.7003


hCV1678682
rs320339
hCV26719149
rs6675851
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV26719162
rs4132509
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV26719176
rs10927076
0.51
0.68963884
0.8492


hCV1678682
rs320339
hCV26719192
rs10803161
0.51
0.68963884
0.8649


hCV1678682
rs320339
hCV26719201
rs4478795
0.51
0.68963884
0.7099


hCV1678682
rs320339
hCV26719219
rs9782958
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV26719222
rs4553169
0.51
0.68963884
0.8711


hCV1678682
rs320339
hCV26719227
rs10927065
0.51
0.68963884
0.7908


hCV1678682
rs320339
hCV26719232
rs10803158
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV26719233
rs10927067
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV27498250
rs3766673
0.51
0.68963884
0.7611


hCV1678682
rs320339
hCV29542869
rs7534117
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV29560960
rs7519673
0.51
0.68963884
0.7908


hCV1678682
rs320339
hCV29994467
rs6694738
0.51
0.68963884
0.801


hCV1678682
rs320339
hCV30084348
rs9287269
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV30372886
rs9782883
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV31523557
rs10754807
0.51
0.68963884
0.8715


hCV1678682
rs320339
hCV31523563
rs10927051
0.51
0.68963884
0.7601


hCV1678682
rs320339
hCV31523638
rs12037013
0.51
0.68963884
0.8604


hCV1678682
rs320339
hCV31523639
rs12034588
0.51
0.68963884
0.8649


hCV1678682
rs320339
hCV31523643
rs6671475
0.51
0.68963884
0.8081


hCV1678682
rs320339
hCV31523650
rs12048930
0.51
0.68963884
0.7003


hCV1678682
rs320339
hCV31523658
rs12047209
0.51
0.68963884
0.732


hCV1678682
rs320339
hCV31523688
rs12049228
0.51
0.68963884
0.8652


hCV1678682
rs320339
hCV31523691
rs12021907
0.51
0.68963884
0.7908


hCV1678682
rs320339
hCV31523707
rs10803152
0.51
0.68963884
0.8529


hCV1678682
rs320339
hCV31523710
rs10927059
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV31523723
rs12140040
0.51
0.68963884
0.8585


hCV1678682
rs320339
hCV31523736
rs12124113
0.51
0.68963884
0.7903


hCV1678682
rs320339
hCV31523740
rs12032342
0.51
0.68963884
0.8718


hCV1678682
rs320339
hCV31523744
rs12031994
0.51
0.68963884
0.7908


hCV1678682
rs320339
hCV804126
rs320320
0.51
0.68963884
0.8718


hCV1678682
rs320339
hDV71836703
rs6429433
0.51
0.68963884
0.801


hCV1825046
rs2069952
hCV11189130
rs2065979
0.51
0.410917063
1


hCV1825046
rs2069952
hCV11189164
rs3746427
0.51
0.410917063
1


hCV1825046
rs2069952
hCV11189240
rs2038504
0.51
0.410917063
0.7662


hCV1825046
rs2069952
hCV11189332
rs2273683
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV11656979
rs2065108
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV1207887
rs959829
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV1207902
rs2295352
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV1265082
rs6088575
0.51
0.410917063
0.4377


hCV1825046
rs2069952
hCV1265086
rs2378251
0.51
0.410917063
0.4377


hCV1825046
rs2069952
hCV1265087
rs2889855
0.51
0.410917063
0.4377


hCV1825046
rs2069952
hCV1265092
rs6088578
0.51
0.410917063
0.4683


hCV1825046
rs2069952
hCV1271671
rs2093058
0.51
0.410917063
1


hCV1825046
rs2069952
hCV1271676
rs1577924
0.51
0.410917063
1


hCV1825046
rs2069952
hCV1271685
rs663550
0.51
0.410917063
0.9658


hCV1825046
rs2069952
hCV1271688
rs6058202
0.51
0.410917063
1


hCV1825046
rs2069952
hCV1347930
rs3736802
0.51
0.410917063
0.5132


hCV1825046
rs2069952
hCV1347963
rs13042358
0.51
0.410917063
0.7677


hCV1825046
rs2069952
hCV1348023
rs6087677
0.51
0.410917063
0.4741


hCV1825046
rs2069952
hCV1361223
rs3746450
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV15860322
rs2069948
0.51
0.410917063
1


hCV1825046
rs2069952
hCV16013581
rs2253484
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV16013594
rs2424999
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV16076405
rs2145557
0.51
0.410917063
0.4122


hCV1825046
rs2069952
hCV16179579
rs2273684
0.51
0.410917063
0.4255


hCV1825046
rs2069952
hCV16179908
rs2273805
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV16191203
rs2295887
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV1825004
rs1415771
0.51
0.410917063
0.7327


hCV1825046
rs2069952
hCV1825005
rs945959
0.51
0.410917063
0.7327


hCV1825046
rs2069952
hCV1825006
rs1124511
0.51
0.410917063
0.7327


hCV1825046
rs2069952
hCV1825047
rs9574
0.51
0.410917063
1


hCV1825046
rs2069952
hCV1825056
rs6060285
0.51
0.410917063
1


hCV1825046
rs2069952
hCV2142560
rs4911449
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV2142561
rs4911450
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV2142562
rs4911451
0.51
0.410917063
0.5486


hCV1825046
rs2069952
hCV2142566
rs6088650
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV2142567
rs725521
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV2142576
rs2236271
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV2142578
rs6088655
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV2142584
rs3761144
0.51
0.410917063
0.6325


hCV1825046
rs2069952
hCV2142586
rs6060130
0.51
0.410917063
0.6325


hCV1825046
rs2069952
hCV2142587
rs6088664
0.51
0.410917063
0.6283


hCV1825046
rs2069952
hCV2142597
rs6120778
0.51
0.410917063
0.7713


hCV1825046
rs2069952
hCV2142599
rs6060140
0.51
0.410917063
0.6158


hCV1825046
rs2069952
hCV2142611
rs1885114
0.51
0.410917063
0.7713


hCV1825046
rs2069952
hCV25619982
rs6120838
0.51
0.410917063
0.5278


hCV1825046
rs2069952
hCV25750225
rs4911163
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV27166987
rs6119542
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV27166995
rs6088618
0.51
0.410917063
0.4255


hCV1825046
rs2069952
hCV27167691
rs2378333
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV27167696
rs6088716
0.51
0.410917063
0.4698


hCV1825046
rs2069952
hCV27486123
rs3803937
0.51
0.410917063
0.4167


hCV1825046
rs2069952
hCV29372811
rs7266550
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV29372820
rs6120739
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV29372834
rs6060001
0.51
0.410917063
0.4255


hCV1825046
rs2069952
hCV29530377
rs6088747
0.51
0.410917063
1


hCV1825046
rs2069952
hCV29620866
rs6088724
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV29693120
rs6060003
0.51
0.410917063
0.4255


hCV1825046
rs2069952
hCV29711231
rs6119536
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV29729418
rs6142294
0.51
0.410917063
0.8242


hCV1825046
rs2069952
hCV29747405
rs6088640
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV29747445
rs6060199
0.51
0.410917063
0.7956


hCV1825046
rs2069952
hCV29837747
rs6088728
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV29837748
rs6088721
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV2988252
rs2425005
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV2988254
rs6060064
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV29909897
rs6142324
0.51
0.410917063
1


hCV1825046
rs2069952
hCV29982073
rs6088580
0.51
0.410917063
0.4112


hCV1825046
rs2069952
hCV3010271
rs2889861
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV30180146
rs6060216
0.51
0.410917063
0.4122


hCV1825046
rs2069952
hCV30342055
rs6088727
0.51
0.410917063
0.4805


hCV1825046
rs2069952
hCV30360331
rs6088568
0.51
0.410917063
0.4377


hCV1825046
rs2069952
hCV30450320
rs4911478
0.51
0.410917063
1


hCV1825046
rs2069952
hCV30450323
rs6058166
0.51
0.410917063
0.4122


hCV1825046
rs2069952
hCV30485907
rs6087653
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV30540259
rs6087664
0.51
0.410917063
0.4215


hCV1825046
rs2069952
hCV30612241
rs6060168
0.51
0.410917063
0.7713


hCV1825046
rs2069952
hCV30630342
rs6141526
0.51
0.410917063
0.7713


hCV1825046
rs2069952
hCV3249260
rs7263157
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249263
rs6088635
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249268
rs6058137
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249269
rs8116657
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249271
rs4911164
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249272
rs6087644
0.51
0.410917063
0.5123


hCV1825046
rs2069952
hCV3249275
rs6088642
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249278
rs6120757
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249280
rs6120758
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249286
rs6088646
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249289
rs2223881
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249290
rs2076667
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV3249293
rs6058154
0.51
0.410917063
0.7713


hCV1825046
rs2069952
hCV599565
rs633198
0.51
0.410917063
1


hCV1825046
rs2069952
hCV7499886
rs1415774
0.51
0.410917063
1


hCV1825046
rs2069952
hCV7593320
rs1060615
0.51
0.410917063
0.5042


hCV1825046
rs2069952
hCV7593321
rs1013677
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hCV7593328
rs1018447
0.51
0.410917063
0.5351


hCV1825046
rs2069952
hDV71833331
rs6142280
0.51
0.410917063
0.7376


hCV1825046
rs2069952
hDV72053898
rs8114671
0.51
0.410917063
1


hCV1834242
rs11712308
hCV11230788
rs7643038
0.51
0.536148259
0.5833


hCV1834242
rs11712308
hCV11232131
rs2698282
0.51
0.536148259
0.6604


hCV1834242
rs11712308
hCV11232160
rs1880041
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV11232163
rs4327424
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV11232169
rs6438542
0.51
0.536148259
0.6604


hCV1834242
rs11712308
hCV114165
rs6807079
0.51
0.536148259
0.6692


hCV1834242
rs11712308
hCV114166
rs6794579
0.51
0.536148259
0.7088


hCV1834242
rs11712308
hCV15882316
rs2276706
0.51
0.536148259
0.5833


hCV1834242
rs11712308
hCV178227
rs13070374
0.51
0.536148259
0.9338


hCV1834242
rs11712308
hCV1834240
rs1581451
0.51
0.536148259
0.5833


hCV1834242
rs11712308
hCV1834252
rs10934498
0.51
0.536148259
0.6039


hCV1834242
rs11712308
hCV1834256
rs2472662
0.51
0.536148259
0.9342


hCV1834242
rs11712308
hCV1969071
rs7633444
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV1969072
rs2670296
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV263841
rs1523127
0.51
0.536148259
0.5486


hCV1834242
rs11712308
hCV26920276
rs13062540
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV26920316
rs2692618
0.51
0.536148259
0.6259


hCV1834242
rs11712308
hCV27498971
rs3772134
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV27504984
rs3814055
0.51
0.536148259
0.5833


hCV1834242
rs11712308
hCV29280454
rs6794484
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV29841665
rs7623217
0.51
0.536148259
0.9666


hCV1834242
rs11712308
hCV30699687
rs11711386
0.51
0.536148259
0.9351


hCV1834242
rs11712308
hCV30747432
rs12488820
0.51
0.536148259
0.6074


hCV1834242
rs11712308
hCV3150918
rs11720605
0.51
0.536148259
0.7467


hCV1834242
rs11712308
hCV31747142
rs7613999
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV8830526
rs940181
0.51
0.536148259
0.7467


hCV1834242
rs11712308
hCV9152783
rs1523130
0.51
0.536148259
0.6039


hCV1834242
rs11712308
hCV965662
rs523476
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV965695
rs552244
0.51
0.536148259
0.6884


hCV1834242
rs11712308
hCV965698
rs571352
0.51
0.536148259
0.6884


hCV1874482
rs2306158
hCV11197524
rs3736947
0.51
0.756211269
0.8979


hCV1874482
rs2306158
hCV1874474
rs2419629
0.51
0.756211269
0.931


hCV1874482
rs2306158
hCV31261952
rs12414780
0.51
0.756211269
1


hCV1874482
rs2306158
hCV31262197
rs11195948
0.51
0.756211269
0.929


hCV1974936
rs4648648
hCV1974933
rs734999
0.51
0.815233071
0.8413


hCV1974936
rs4648648
hCV1974942
rs6671426
0.51
0.815233071
0.8456


hCV1974936
rs4648648
hCV1974943
rs6672381
0.51
0.815233071
0.871


hCV1974936
rs4648648
hCV1974944
rs6667605
0.51
0.815233071
0.8746


hCV1974936
rs4648648
hCV1974957
rs7550231
0.51
0.815233071
0.8456


hCV1974936
rs4648648
hCV31475436
rs4486391
0.51
0.815233071
0.8728


hCV1974936
rs4648648
hCV31475439
rs10797434
0.51
0.815233071
0.8723


hCV1974936
rs4648648
hDV68598166
rs10797432
0.51
0.815233071
0.8456


hCV2288095
rs378815
hCV11780206
rs5931656
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV11780209
rs5930009
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV11780214
rs7878061
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV26011954
rs4620439
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV26011955
rs5930013
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV26016182
rs11796672
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV26016183
rs9887617
0.51
0.721860657
0.9162


hCV2288095
rs378815
hCV27904396
rs4829996
0.51
0.721860657
0.9459


hCV2288095
rs378815
hCV28962605
rs5930005
0.51
0.721860657
0.9576


hCV2288095
rs378815
hCV29515877
rs5930015
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV29732937
rs5931647
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV29967889
rs5931645
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV30130033
rs5931646
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV30201992
rs5931641
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV30291634
rs5931666
0.51
0.721860657
0.9562


hCV2288095
rs378815
hCV30700232
rs12687091
0.51
0.721860657
0.9579


hCV2288095
rs378815
hCV596663
rs411017
0.51
0.721860657
1


hCV2288095
rs378815
hCV596665
rs401597
0.51
0.721860657
0.9459


hCV2288095
rs378815
hDV77022847
rs4598407
0.51
0.721860657
0.9579


hCV2288095
rs378815
hDV77148131
rs5931661
0.51
0.721860657
0.9116


hCV2288095
rs378815
hDV77150953
rs5976389
0.51
0.721860657
0.9579


hCV233148
rs1417121
hCV12073840
rs14403
0.51
0.50633557
0.8697


hCV233148
rs1417121
hCV15760229
rs3006939
0.51
0.50633557
0.6544


hCV233148
rs1417121
hCV15760238
rs3006936
0.51
0.50633557
0.6656


hCV233148
rs1417121
hCV15760239
rs3006923
0.51
0.50633557
0.7142


hCV233148
rs1417121
hCV26034157
rs2994329
0.51
0.50633557
0.5147


hCV233148
rs1417121
hCV26034158
rs4515770
0.51
0.50633557
0.7064


hCV233148
rs1417121
hCV26034160
rs2994327
0.51
0.50633557
0.7442


hCV233148
rs1417121
hCV26719121
rs10927041
0.51
0.50633557
0.5615


hCV233148
rs1417121
hCV29210363
rs6656918
0.51
0.50633557
0.656


hCV233148
rs1417121
hCV30690778
rs12140414
0.51
0.50633557
0.5904


hCV233148
rs1417121
hCV30690780
rs10737888
0.51
0.50633557
0.6656


hCV233148
rs1417121
hCV30690784
rs4658574
0.51
0.50633557
0.7442


hCV233148
rs1417121
hCV8688079
rs884808
0.51
0.50633557
0.7442


hCV233148
rs1417121
hCV8688080
rs884328
0.51
0.50633557
0.7429


hCV233148
rs1417121
hCV8688111
rs1578275
0.51
0.50633557
0.5904


hCV233148
rs1417121
hCV9493081
rs1058304
0.51
0.50633557
1


hCV233148
rs1417121
hCV97631
rs1538773
0.51
0.50633557
0.6656


hCV2456747
rs3820059
hCV11341869
rs2176473
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV11341876
rs1980198
0.51
0.699341435
0.8561


hCV2456747
rs3820059
hCV11341878
rs4656670
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV11341882
rs12024897
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV11341886
rs7539415
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV11341887
rs3766095
0.51
0.699341435
1


hCV2456747
rs3820059
hCV11341898
rs12563090
0.51
0.699341435
0.8681


hCV2456747
rs3820059
hCV11975148
rs2037250
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV11975152
rs1856303
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV15878582
rs2275299
0.51
0.699341435
0.8709


hCV2456747
rs3820059
hCV221700
rs6677410
0.51
0.699341435
0.8709


hCV2456747
rs3820059
hCV2456730
rs961404
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV2456741
rs6696810
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV2456753
rs7528375
0.51
0.699341435
0.8688


hCV2456747
rs3820059
hCV2456767
rs2014061
0.51
0.699341435
0.8709


hCV2456747
rs3820059
hCV2456768
rs6427186
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV2456776
rs6669741
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV2456780
rs7534737
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV2520836
rs10753786
0.51
0.699341435
0.7613


hCV2456747
rs3820059
hCV2520851
rs10919132
0.51
0.699341435
0.7555


hCV2456747
rs3820059
hCV2520854
rs2300158
0.51
0.699341435
0.7635


hCV2456747
rs3820059
hCV2520874
rs1591733
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV25616192
rs10919168
0.51
0.699341435
0.7266


hCV2456747
rs3820059
hCV27242011
rs1200083
0.51
0.699341435
0.7855


hCV2456747
rs3820059
hCV27242515
rs3818844
0.51
0.699341435
0.8681


hCV2456747
rs3820059
hCV27242533
rs2138898
0.51
0.699341435
0.903


hCV2456747
rs3820059
hCV27242578
rs6427187
0.51
0.699341435
0.9662


hCV2456747
rs3820059
hCV27242639
rs7544221
0.51
0.699341435
1


hCV2456747
rs3820059
hCV27242642
rs10919167
0.51
0.699341435
0.9656


hCV2456747
rs3820059
hCV27242694
rs6673326
0.51
0.699341435
1


hCV2456747
rs3820059
hCV27480801
rs3766057
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV27496192
rs3753303
0.51
0.699341435
0.8786


hCV2456747
rs3820059
hCV27928246
rs4656672
0.51
0.699341435
1


hCV2456747
rs3820059
hCV279320
rs10800441
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV29397237
rs6427185
0.51
0.699341435
1


hCV2456747
rs3820059
hCV29397241
rs4656183
0.51
0.699341435
0.9662


hCV2456747
rs3820059
hCV2986550
rs10919124
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV30126929
rs10429893
0.51
0.699341435
1


hCV2456747
rs3820059
hCV30180981
rs7415756
0.51
0.699341435
0.8709


hCV2456747
rs3820059
hCV30415180
rs7533257
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV30523079
rs10489189
0.51
0.699341435
1


hCV2456747
rs3820059
hCV30577322
rs7516248
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV32141055
rs10800408
0.51
0.699341435
0.7821


hCV2456747
rs3820059
hCV32141218
rs10800424
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV32141221
rs10800425
0.51
0.699341435
0.7794


hCV2456747
rs3820059
hCV32141272
rs4264046
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV32141290
rs10800435
0.51
0.699341435
0.8071


hCV2456747
rs3820059
hCV32141293
rs10800438
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV32141297
rs10800440
0.51
0.699341435
0.8703


hCV2456747
rs3820059
hCV32141333
rs10800446
0.51
0.699341435
0.8715


hCV2456747
rs3820059
hCV32141337
rs10919164
0.51
0.699341435
0.8391


hCV2456747
rs3820059
hCV32141359
rs12022776
0.51
0.699341435
0.8715


hCV2456747
rs3820059
hCV459880
rs10800439
0.51
0.699341435
0.7543


hCV2456747
rs3820059
hCV8688930
rs3905328
0.51
0.699341435
1


hCV2456747
rs3820059
hCV8690976
rs1124843
0.51
0.699341435
1


hCV2456747
rs3820059
hCV8697018
rs932301
0.51
0.699341435
1


hCV2456747
rs3820059
hCV8697031
rs1400836
0.51
0.699341435
1


hCV2456747
rs3820059
hCV8697038
rs961403
0.51
0.699341435
0.873


hCV2456747
rs3820059
hCV8919256
rs1200085
0.51
0.699341435
0.7829


hCV2456747
rs3820059
hCV8919302
rs1208370
0.51
0.699341435
0.7802


hCV2456747
rs3820059
hCV8919303
rs1018831
0.51
0.699341435
0.7895


hCV2456747
rs3820059
hCV8919327
rs1208377
0.51
0.699341435
0.7895


hCV25474414
rs4253399
hCV27477533
rs3756008
0.51
0.838310492
0.8606


hCV25474414
rs4253399
hCV3230025
rs3756009
0.51
0.838310492
0.9593


hCV25474414
rs4253399
hCV8241630
rs925451
0.51
0.838310492
0.9185


hCV263841
rs1523127
hCV105917
rs9289134
0.51
0.347046958
0.561


hCV263841
rs1523127
hCV11230788
rs7643038
0.51
0.347046958
0.966


hCV263841
rs1523127
hCV11232111
rs17203235
0.51
0.347046958
0.3567


hCV263841
rs1523127
hCV134275
rs9847068
0.51
0.347046958
0.5453


hCV263841
rs1523127
hCV15882316
rs2276706
0.51
0.347046958
0.966


hCV263841
rs1523127
hCV178227
rs13070374
0.51
0.347046958
0.5595


hCV263841
rs1523127
hCV178228
rs4687882
0.51
0.347046958
0.5543


hCV263841
rs1523127
hCV1833991
rs11926554
0.51
0.347046958
0.5548


hCV263841
rs1523127
hCV1834237
rs9865270
0.51
0.347046958
0.561


hCV263841
rs1523127
hCV1834240
rs1581451
0.51
0.347046958
0.966


hCV263841
rs1523127
hCV1834242
rs11712308
0.51
0.347046958
0.5486


hCV263841
rs1523127
hCV1834243
rs9682652
0.51
0.347046958
0.5966


hCV263841
rs1523127
hCV1834252
rs10934498
0.51
0.347046958
0.932


hCV263841
rs1523127
hCV1834256
rs2472662
0.51
0.347046958
0.5585


hCV263841
rs1523127
hCV1834260
rs4688033
0.51
0.347046958
0.5966


hCV263841
rs1523127
hCV192027
rs9821892
0.51
0.347046958
0.561


hCV263841
rs1523127
hCV255886
rs10511394
0.51
0.347046958
0.5966


hCV263841
rs1523127
hCV27504984
rs3814055
0.51
0.347046958
0.966


hCV263841
rs1523127
hCV278948
rs1464599
0.51
0.347046958
0.5908


hCV263841
rs1523127
hCV29841665
rs7623217
0.51
0.347046958
0.5633


hCV263841
rs1523127
hCV30562884
rs9815093
0.51
0.347046958
0.561


hCV263841
rs1523127
hCV30699687
rs11711386
0.51
0.347046958
0.5647


hCV263841
rs1523127
hCV30747432
rs12488820
0.51
0.347046958
0.9217


hCV263841
rs1523127
hCV3150918
rs11720605
0.51
0.347046958
0.3489


hCV263841
rs1523127
hCV8830526
rs940181
0.51
0.347046958
0.3489


hCV263841
rs1523127
hCV9151800
rs6803814
0.51
0.347046958
0.3494


hCV263841
rs1523127
hCV9152783
rs1523130
0.51
0.347046958
0.932


hCV26719108
rs10927035
hCV12073160
rs1973284
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV12073167
rs2034915
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV12073172
rs971285
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV12073180
rs1870272
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV15776869
rs2345994
0.51
0.558010019
0.6674


hCV26719108
rs10927035
hCV15823033
rs2125231
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV15885435
rs2290753
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV15965328
rs2291409
0.51
0.558010019
0.717


hCV26719108
rs10927035
hCV1678668
rs1379700
0.51
0.558010019
0.5985


hCV26719108
rs10927035
hCV1678723
rs1486472
0.51
0.558010019
0.5777


hCV26719108
rs10927035
hCV26719086
rs4658585
0.51
0.558010019
0.6417


hCV26719108
rs10927035
hCV26719087
rs4658401
0.51
0.558010019
0.6722


hCV26719108
rs10927035
hCV26719102
rs10927056
0.51
0.558010019
0.6269


hCV26719108
rs10927035
hCV26719114
rs7549780
0.51
0.558010019
0.6768


hCV26719108
rs10927035
hCV26719117
rs12144559
0.51
0.558010019
0.6768


hCV26719108
rs10927035
hCV26719171
rs10927075
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV26719179
rs6672195
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV26719194
rs10927081
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV26719197
rs4590656
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV26719215
rs12144546
0.51
0.558010019
0.6768


hCV26719108
rs10927035
hCV26719225
rs11586029
0.51
0.558010019
0.6832


hCV26719108
rs10927035
hCV29210367
rs4518884
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV29633221
rs10157763
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV29795761
rs7528450
0.51
0.558010019
0.697


hCV26719108
rs10927035
hCV30012351
rs10158245
0.51
0.558010019
0.6929


hCV26719108
rs10927035
hCV31523552
rs12739344
0.51
0.558010019
0.7439


hCV26719108
rs10927035
hCV31523555
rs12749316
0.51
0.558010019
0.6452


hCV26719108
rs10927035
hCV31523573
rs11589907
0.51
0.558010019
0.6768


hCV26719108
rs10927035
hCV31523576
rs12691548
0.51
0.558010019
0.6458


hCV26719108
rs10927035
hCV31523608
rs12744297
0.51
0.558010019
0.7086


hCV26719108
rs10927035
hCV31523624
rs10927044
0.51
0.558010019
0.717


hCV26719108
rs10927035
hCV31523725
rs10927060
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV8688098
rs1531244
0.51
0.558010019
0.6835


hCV26719108
rs10927035
hCV8689016
rs897959
0.51
0.558010019
0.6861


hCV26719108
rs10927035
hCV9115290
rs1352162
0.51
0.558010019
0.717


hCV26719113
rs7517340
hCV15823024
rs2125230
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV15885425
rs2290754
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV15965338
rs2291410
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV16082410
rs2881275
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV1678656
rs1458024
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV1678674
rs1458023
0.51
0.678279305
0.721


hCV26719113
rs7517340
hCV1678682
rs320339
0.51
0.678279305
0.7898


hCV26719113
rs7517340
hCV26719082
rs10927046
0.51
0.678279305
0.7893


hCV26719113
rs7517340
hCV26719085
rs10927047
0.51
0.678279305
0.8571


hCV26719113
rs7517340
hCV26719107
rs7538011
0.51
0.678279305
0.7303


hCV26719113
rs7517340
hCV26719116
rs10927039
0.51
0.678279305
0.7983


hCV26719113
rs7517340
hCV26719120
rs10927040
0.51
0.678279305
0.9236


hCV26719113
rs7517340
hCV26719121
rs10927041
0.51
0.678279305
0.7465


hCV26719113
rs7517340
hCV26719149
rs6675851
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV26719162
rs4132509
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV26719176
rs10927076
0.51
0.678279305
1


hCV26719113
rs7517340
hCV26719192
rs10803161
0.51
0.678279305
0.9278


hCV26719113
rs7517340
hCV26719201
rs4478795
0.51
0.678279305
0.7268


hCV26719113
rs7517340
hCV26719219
rs9782958
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV26719222
rs4553169
0.51
0.678279305
0.9314


hCV26719113
rs7517340
hCV26719227
rs10927065
0.51
0.678279305
0.721


hCV26719113
rs7517340
hCV26719232
rs10803158
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV26719233
rs10927067
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV27498250
rs3766673
0.51
0.678279305
0.8652


hCV26719113
rs7517340
hCV29542869
rs7534117
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV29560960
rs7519673
0.51
0.678279305
0.721


hCV26719113
rs7517340
hCV29741723
rs7517921
0.51
0.678279305
0.7448


hCV26719113
rs7517340
hCV29994467
rs6694738
0.51
0.678279305
0.7303


hCV26719113
rs7517340
hCV30084348
rs9287269
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV30372886
rs9782883
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV31523557
rs10754807
0.51
0.678279305
0.9316


hCV26719113
rs7517340
hCV31523563
rs10927051
0.51
0.678279305
0.8299


hCV26719113
rs7517340
hCV31523638
rs12037013
0.51
0.678279305
0.7893


hCV26719113
rs7517340
hCV31523639
rs12034588
0.51
0.678279305
0.9278


hCV26719113
rs7517340
hCV31523643
rs6671475
0.51
0.678279305
0.8638


hCV26719113
rs7517340
hCV31523650
rs12048930
0.51
0.678279305
0.7467


hCV26719113
rs7517340
hCV31523658
rs12047209
0.51
0.678279305
0.721


hCV26719113
rs7517340
hCV31523688
rs12049228
0.51
0.678279305
0.928


hCV26719113
rs7517340
hCV31523691
rs12021907
0.51
0.678279305
0.721


hCV26719113
rs7517340
hCV31523707
rs10803152
0.51
0.678279305
0.7778


hCV26719113
rs7517340
hCV31523710
rs10927059
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV31523736
rs12124113
0.51
0.678279305
0.7203


hCV26719113
rs7517340
hCV31523740
rs12032342
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hCV31523744
rs12031994
0.51
0.678279305
0.721


hCV26719113
rs7517340
hCV804126
rs320320
0.51
0.678279305
0.9318


hCV26719113
rs7517340
hDV71836703
rs6429433
0.51
0.678279305
0.86


hCV26719121
rs10927041
hCV15760229
rs3006939
0.51
0.636443944
0.7427


hCV26719121
rs10927041
hCV15760238
rs3006936
0.51
0.636443944
0.7525


hCV26719121
rs10927041
hCV15823024
rs2125230
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV15885425
rs2290754
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV15965338
rs2291410
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV16082410
rs2881275
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV1678656
rs1458024
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV1678674
rs1458023
0.51
0.636443944
0.6431


hCV26719121
rs10927041
hCV1678682
rs320339
0.51
0.636443944
0.7003


hCV26719121
rs10927041
hCV26034158
rs4515770
0.51
0.636443944
0.7555


hCV26719121
rs10927041
hCV26719082
rs10927046
0.51
0.636443944
0.6995


hCV26719121
rs10927041
hCV26719085
rs10927047
0.51
0.636443944
0.685


hCV26719121
rs10927041
hCV26719107
rs7538011
0.51
0.636443944
0.7586


hCV26719121
rs10927041
hCV26719113
rs7517340
0.51
0.636443944
0.7465


hCV26719121
rs10927041
hCV26719116
rs10927039
0.51
0.636443944
0.9349


hCV26719121
rs10927041
hCV26719120
rs10927040
0.51
0.636443944
0.8595


hCV26719121
rs10927041
hCV26719149
rs6675851
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV26719162
rs4132509
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV26719176
rs10927076
0.51
0.636443944
0.7883


hCV26719121
rs10927041
hCV26719192
rs10803161
0.51
0.636443944
0.8086


hCV26719121
rs10927041
hCV26719219
rs9782958
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV26719222
rs4553169
0.51
0.636443944
0.817


hCV26719121
rs10927041
hCV26719227
rs10927065
0.51
0.636443944
0.6431


hCV26719121
rs10927041
hCV26719232
rs10803158
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV26719233
rs10927067
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV27498250
rs3766673
0.51
0.636443944
0.7692


hCV26719121
rs10927041
hCV29210363
rs6656918
0.51
0.636443944
0.7435


hCV26719121
rs10927041
hCV29542869
rs7534117
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV29560960
rs7519673
0.51
0.636443944
0.6431


hCV26719121
rs10927041
hCV29994467
rs6694738
0.51
0.636443944
0.7586


hCV26719121
rs10927041
hCV30084348
rs9287269
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV30372886
rs9782883
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV30690780
rs10737888
0.51
0.636443944
0.7525


hCV26719121
rs10927041
hCV31523557
rs10754807
0.51
0.636443944
0.8175


hCV26719121
rs10927041
hCV31523563
rs10927051
0.51
0.636443944
0.8556


hCV26719121
rs10927041
hCV31523638
rs12037013
0.51
0.636443944
0.6995


hCV26719121
rs10927041
hCV31523639
rs12034588
0.51
0.636443944
0.8088


hCV26719121
rs10927041
hCV31523643
rs6671475
0.51
0.636443944
0.872


hCV26719121
rs10927041
hCV31523650
rs12048930
0.51
0.636443944
0.6588


hCV26719121
rs10927041
hCV31523688
rs12049228
0.51
0.636443944
0.8095


hCV26719121
rs10927041
hCV31523691
rs12021907
0.51
0.636443944
0.6431


hCV26719121
rs10927041
hCV31523707
rs10803152
0.51
0.636443944
0.6861


hCV26719121
rs10927041
hCV31523710
rs10927059
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV31523736
rs12124113
0.51
0.636443944
0.6422


hCV26719121
rs10927041
hCV31523740
rs12032342
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV31523744
rs12031994
0.51
0.636443944
0.6431


hCV26719121
rs10927041
hCV804126
rs320320
0.51
0.636443944
0.8181


hCV26719121
rs10927041
hCV97631
rs1538773
0.51
0.636443944
0.7525


hCV26719121
rs10927041
hDV71836703
rs6429433
0.51
0.636443944
0.6481


hCV27020269
rs7659613
hCV15860433
rs2070006
0.51
0.923124202
1


hCV27020269
rs7659613
hCV2892870
rs2070011
0.51
0.923124202
0.9647


hCV27102953
rs4648360
hCV16000557
rs2377041
0.51
0.602141599
0.8987


hCV27102953
rs4648360
hCV1642008
rs1563471
0.51
0.602141599
0.8842


hCV27102953
rs4648360
hCV27102978
rs7537581
0.51
0.602141599
0.9332


hCV27102953
rs4648360
hCV27103080
rs4648459
0.51
0.602141599
0.9004


hCV27102953
rs4648360
hCV27103144
rs11584658
0.51
0.602141599
0.9666


hCV27102953
rs4648360
hCV27103182
rs4609377
0.51
0.602141599
0.8748


hCV27102953
rs4648360
hCV27103185
rs10797389
0.51
0.602141599
0.9636


hCV27102953
rs4648360
hCV27103186
rs4648481
0.51
0.602141599
0.967


hCV27102953
rs4648360
hCV27103188
rs7511879
0.51
0.602141599
0.8714


hCV27102953
rs4648360
hCV27103189
rs12031493
0.51
0.602141599
0.8097


hCV27102953
rs4648360
hCV27103192
rs6680471
0.51
0.602141599
0.7499


hCV27102953
rs4648360
hCV27103207
rs6424062
0.51
0.602141599
0.9021


hCV27102953
rs4648360
hCV31965210
rs10909880
0.51
0.602141599
0.967


hCV27102953
rs4648360
hCV31965333
rs10797390
0.51
0.602141599
0.7827


hCV27102953
rs4648360
hCV788647
rs729045
0.51
0.602141599
0.6831


hCV27102978
rs7537581
hCV11448257
rs1886730
0.51
0.333611682
0.4384


hCV27102978
rs7537581
hCV11612179
rs10752748
0.51
0.333611682
0.4033


hCV27102978
rs7537581
hCV15976797
rs2843401
0.51
0.333611682
0.42


hCV27102978
rs7537581
hCV15976807
rs2843402
0.51
0.333611682
0.4103


hCV27102978
rs7537581
hCV16000557
rs2377041
0.51
0.333611682
0.8288


hCV27102978
rs7537581
hCV16186317
rs2764841
0.51
0.333611682
0.3895


hCV27102978
rs7537581
hCV16186318
rs2985859
0.51
0.333611682
0.413


hCV27102978
rs7537581
hCV1642008
rs1563471
0.51
0.333611682
0.8774


hCV27102978
rs7537581
hCV1974927
rs3748816
0.51
0.333611682
0.386


hCV27102978
rs7537581
hCV1974928
rs3748819
0.51
0.333611682
0.42


hCV27102978
rs7537581
hCV1974930
rs10752747
0.51
0.333611682
0.42


hCV27102978
rs7537581
hCV1974933
rs734999
0.51
0.333611682
0.4443


hCV27102978
rs7537581
hCV1974936
rs4648648
0.51
0.333611682
0.3435


hCV27102978
rs7537581
hCV1974940
rs4310388
0.51
0.333611682
0.3553


hCV27102978
rs7537581
hCV1974942
rs6671426
0.51
0.333611682
0.44


hCV27102978
rs7537581
hCV1974943
rs6672381
0.51
0.333611682
0.4185


hCV27102978
rs7537581
hCV1974944
rs6667605
0.51
0.333611682
0.4135


hCV27102978
rs7537581
hCV1974949
rs2257763
0.51
0.333611682
0.4443


hCV27102978
rs7537581
hCV1974950
rs2281852
0.51
0.333611682
0.4149


hCV27102978
rs7537581
hCV1974951
rs2234161
0.51
0.333611682
0.44


hCV27102978
rs7537581
hCV1974957
rs7550231
0.51
0.333611682
0.3936


hCV27102978
rs7537581
hCV1974967
rs2147905
0.51
0.333611682
0.4342


hCV27102978
rs7537581
hCV25602566
rs3748817
0.51
0.333611682
0.4034


hCV27102978
rs7537581
hCV25981574
rs7535528
0.51
0.333611682
0.3816


hCV27102978
rs7537581
hCV26678889
rs3890745
0.51
0.333611682
0.3962


hCV27102978
rs7537581
hCV27102953
rs4648360
0.51
0.333611682
0.9332


hCV27102978
rs7537581
hCV27103080
rs4648459
0.51
0.333611682
0.8317


hCV27102978
rs7537581
hCV27103144
rs11584658
0.51
0.333611682
0.8974


hCV27102978
rs7537581
hCV27103182
rs4609377
0.51
0.333611682
0.8676


hCV27102978
rs7537581
hCV27103185
rs10797389
0.51
0.333611682
0.8871


hCV27102978
rs7537581
hCV27103186
rs4648481
0.51
0.333611682
0.8992


hCV27102978
rs7537581
hCV27103187
rs4648482
0.51
0.333611682
0.4675


hCV27102978
rs7537581
hCV27103188
rs7511879
0.51
0.333611682
0.8664


hCV27102978
rs7537581
hCV27103189
rs12031493
0.51
0.333611682
0.7384


hCV27102978
rs7537581
hCV27103192
rs6680471
0.51
0.333611682
0.7416


hCV27102978
rs7537581
hCV27103201
rs12049543
0.51
0.333611682
0.3576


hCV27102978
rs7537581
hCV27103202
rs6424081
0.51
0.333611682
0.3576


hCV27102978
rs7537581
hCV27103207
rs6424062
0.51
0.333611682
0.8345


hCV27102978
rs7537581
hCV27103209
rs7529000
0.51
0.333611682
0.3816


hCV27102978
rs7537581
hCV27972176
rs4648356
0.51
0.333611682
0.3962


hCV27102978
rs7537581
hCV28001111
rs4648384
0.51
0.333611682
0.3739


hCV27102978
rs7537581
hCV29511345
rs7548023
0.51
0.333611682
0.3739


hCV27102978
rs7537581
hCV30497685
rs6684865
0.51
0.333611682
0.4033


hCV27102978
rs7537581
hCV31475405
rs10797441
0.51
0.333611682
0.4033


hCV27102978
rs7537581
hCV31475409
rs10910111
0.51
0.333611682
0.407


hCV27102978
rs7537581
hCV31475429
rs10910099
0.51
0.333611682
0.42


hCV27102978
rs7537581
hCV31475436
rs4486391
0.51
0.333611682
0.4262


hCV27102978
rs7537581
hCV31475439
rs10797434
0.51
0.333611682
0.4006


hCV27102978
rs7537581
hCV31965210
rs10909880
0.51
0.333611682
0.8992


hCV27102978
rs7537581
hCV31965333
rs10797390
0.51
0.333611682
0.7038


hCV27102978
rs7537581
hCV31965380
rs12409348
0.51
0.333611682
0.3859


hCV27102978
rs7537581
hCV403768
rs10797440
0.51
0.333611682
0.3723


hCV27102978
rs7537581
hCV403772
rs10797437
0.51
0.333611682
0.3692


hCV27102978
rs7537581
hCV441460
rs4474198
0.51
0.333611682
0.4033


hCV27102978
rs7537581
hCV788647
rs729045
0.51
0.333611682
0.6657


hCV27102978
rs7537581
hCV8725809
rs897628
0.51
0.333611682
0.4133


hCV27102978
rs7537581
hCV8725828
rs1456461
0.51
0.333611682
0.4358


hCV27102978
rs7537581
hCV8725829
rs1456460
0.51
0.333611682
0.36


hCV27102978
rs7537581
hCV9688194
rs6673993
0.51
0.333611682
0.3692


hCV27102978
rs7537581
hDV68598166
rs10797432
0.51
0.333611682
0.44


hCV27102978
rs7537581
hDV76957636
rs4073286
0.51
0.333611682
0.3692


hCV27103080
rs4648459
hCV16000557
rs2377041
0.51
0.540557472
1


hCV27103080
rs4648459
hCV1642008
rs1563471
0.51
0.540557472
0.8395


hCV27103080
rs4648459
hCV27102953
rs4648360
0.51
0.540557472
0.9004


hCV27103080
rs4648459
hCV27102978
rs7537581
0.51
0.540557472
0.8317


hCV27103080
rs4648459
hCV27103144
rs11584658
0.51
0.540557472
0.8659


hCV27103080
rs4648459
hCV27103182
rs4609377
0.51
0.540557472
0.7778


hCV27103080
rs4648459
hCV27103185
rs10797389
0.51
0.540557472
0.8532


hCV27103080
rs4648459
hCV27103186
rs4648481
0.51
0.540557472
0.8681


hCV27103080
rs4648459
hCV27103188
rs7511879
0.51
0.540557472
0.7756


hCV27103080
rs4648459
hCV27103189
rs12031493
0.51
0.540557472
0.7422


hCV27103080
rs4648459
hCV27103192
rs6680471
0.51
0.540557472
0.6587


hCV27103080
rs4648459
hCV27103207
rs6424062
0.51
0.540557472
1


hCV27103080
rs4648459
hCV31965210
rs10909880
0.51
0.540557472
0.8681


hCV27103080
rs4648459
hCV31965333
rs10797390
0.51
0.540557472
0.7405


hCV27103080
rs4648459
hCV788647
rs729045
0.51
0.540557472
0.5916


hCV27103080
rs4648459
hCV8725828
rs1456461
0.51
0.540557472
0.5874


hCV27103182
rs4609377
hCV11448257
rs1886730
0.51
0.384835006
0.5438


hCV27103182
rs4609377
hCV15976797
rs2843401
0.51
0.384835006
0.3989


hCV27103182
rs4609377
hCV15976807
rs2843402
0.51
0.384835006
0.3863


hCV27103182
rs4609377
hCV16000557
rs2377041
0.51
0.384835006
0.7742


hCV27103182
rs4609377
hCV16186318
rs2985859
0.51
0.384835006
0.3915


hCV27103182
rs4609377
hCV1642008
rs1563471
0.51
0.384835006
0.8794


hCV27103182
rs4609377
hCV1974928
rs3748819
0.51
0.384835006
0.3989


hCV27103182
rs4609377
hCV1974930
rs10752747
0.51
0.384835006
0.3989


hCV27103182
rs4609377
hCV1974933
rs734999
0.51
0.384835006
0.5303


hCV27103182
rs4609377
hCV1974936
rs4648648
0.51
0.384835006
0.4201


hCV27103182
rs4609377
hCV1974940
rs4310388
0.51
0.384835006
0.3854


hCV27103182
rs4609377
hCV1974942
rs6671426
0.51
0.384835006
0.5447


hCV27103182
rs4609377
hCV1974943
rs6672381
0.51
0.384835006
0.5265


hCV27103182
rs4609377
hCV1974944
rs6667605
0.51
0.384835006
0.517


hCV27103182
rs4609377
hCV1974949
rs2257763
0.51
0.384835006
0.5303


hCV27103182
rs4609377
hCV1974950
rs2281852
0.51
0.384835006
0.5413


hCV27103182
rs4609377
hCV1974951
rs2234161
0.51
0.384835006
0.5447


hCV27103182
rs4609377
hCV1974957
rs7550231
0.51
0.384835006
0.4949


hCV27103182
rs4609377
hCV1974967
rs2147905
0.51
0.384835006
0.4889


hCV27103182
rs4609377
hCV27102953
rs4648360
0.51
0.384835006
0.8748


hCV27103182
rs4609377
hCV27102978
rs7537581
0.51
0.384835006
0.8676


hCV27103182
rs4609377
hCV27103080
rs4648459
0.51
0.384835006
0.7778


hCV27103182
rs4609377
hCV27103144
rs11584658
0.51
0.384835006
0.9032


hCV27103182
rs4609377
hCV27103185
rs10797389
0.51
0.384835006
0.8944


hCV27103182
rs4609377
hCV27103186
rs4648481
0.51
0.384835006
0.9047


hCV27103182
rs4609377
hCV27103187
rs4648482
0.51
0.384835006
0.4791


hCV27103182
rs4609377
hCV27103188
rs7511879
0.51
0.384835006
0.8718


hCV27103182
rs4609377
hCV27103189
rs12031493
0.51
0.384835006
0.7457


hCV27103182
rs4609377
hCV27103192
rs6680471
0.51
0.384835006
0.7506


hCV27103182
rs4609377
hCV27103207
rs6424062
0.51
0.384835006
0.7813


hCV27103182
rs4609377
hCV27103209
rs7529000
0.51
0.384835006
0.4041


hCV27103182
rs4609377
hCV28001111
rs4648384
0.51
0.384835006
0.3889


hCV27103182
rs4609377
hCV29511345
rs7548023
0.51
0.384835006
0.3889


hCV27103182
rs4609377
hCV30497685
rs6684865
0.51
0.384835006
0.3915


hCV27103182
rs4609377
hCV31475409
rs10910111
0.51
0.384835006
0.3884


hCV27103182
rs4609377
hCV31475429
rs10910099
0.51
0.384835006
0.3989


hCV27103182
rs4609377
hCV31475436
rs4486391
0.51
0.384835006
0.533


hCV27103182
rs4609377
hCV31475439
rs10797434
0.51
0.384835006
0.5069


hCV27103182
rs4609377
hCV31965210
rs10909880
0.51
0.384835006
0.9047


hCV27103182
rs4609377
hCV31965333
rs10797390
0.51
0.384835006
0.7768


hCV27103182
rs4609377
hCV31965380
rs12409348
0.51
0.384835006
0.4098


hCV27103182
rs4609377
hCV788647
rs729045
0.51
0.384835006
0.7268


hCV27103182
rs4609377
hCV8725809
rs897628
0.51
0.384835006
0.3908


hCV27103182
rs4609377
hCV8725828
rs1456461
0.51
0.384835006
0.4541


hCV27103182
rs4609377
hDV68598166
rs10797432
0.51
0.384835006
0.5447


hCV27103188
rs7511879
hCV16000557
rs2377041
0.51
0.52983896
0.7719


hCV27103188
rs7511879
hCV1642008
rs1563471
0.51
0.52983896
0.9211


hCV27103188
rs7511879
hCV27102953
rs4648360
0.51
0.52983896
0.8714


hCV27103188
rs7511879
hCV27102978
rs7537581
0.51
0.52983896
0.8664


hCV27103188
rs7511879
hCV27103080
rs4648459
0.51
0.52983896
0.7756


hCV27103188
rs7511879
hCV27103144
rs11584658
0.51
0.52983896
0.9007


hCV27103188
rs7511879
hCV27103182
rs4609377
0.51
0.52983896
0.8718


hCV27103188
rs7511879
hCV27103185
rs10797389
0.51
0.52983896
0.9269


hCV27103188
rs7511879
hCV27103186
rs4648481
0.51
0.52983896
0.9023


hCV27103188
rs7511879
hCV27103189
rs12031493
0.51
0.52983896
0.807


hCV27103188
rs7511879
hCV27103192
rs6680471
0.51
0.52983896
0.809


hCV27103188
rs7511879
hCV27103207
rs6424062
0.51
0.52983896
0.7791


hCV27103188
rs7511879
hCV31965210
rs10909880
0.51
0.52983896
0.9023


hCV27103188
rs7511879
hCV31965333
rs10797390
0.51
0.52983896
0.7786


hCV27103188
rs7511879
hCV788647
rs729045
0.51
0.52983896
0.7328


hCV27103189
rs12031493
hCV16000557
rs2377041
0.51
0.635618245
0.738


hCV27103189
rs12031493
hCV1642008
rs1563471
0.51
0.635618245
0.8028


hCV27103189
rs12031493
hCV27102953
rs4648360
0.51
0.635618245
0.8097


hCV27103189
rs12031493
hCV27102978
rs7537581
0.51
0.635618245
0.7384


hCV27103189
rs12031493
hCV27103080
rs4648459
0.51
0.635618245
0.7422


hCV27103189
rs12031493
hCV27103144
rs11584658
0.51
0.635618245
0.8365


hCV27103189
rs12031493
hCV27103182
rs4609377
0.51
0.635618245
0.7457


hCV27103189
rs12031493
hCV27103185
rs10797389
0.51
0.635618245
0.855


hCV27103189
rs12031493
hCV27103186
rs4648481
0.51
0.635618245
0.8391


hCV27103189
rs12031493
hCV27103188
rs7511879
0.51
0.635618245
0.807


hCV27103189
rs12031493
hCV27103192
rs6680471
0.51
0.635618245
0.8695


hCV27103189
rs12031493
hCV27103207
rs6424062
0.51
0.635618245
0.7463


hCV27103189
rs12031493
hCV31965210
rs10909880
0.51
0.635618245
0.8391


hCV27103189
rs12031493
hCV31965333
rs10797390
0.51
0.635618245
0.8473


hCV27103189
rs12031493
hCV788647
rs729045
0.51
0.635618245
0.7823


hCV27103207
rs6424062
hCV16000557
rs2377041
0.51
0.53997951
1


hCV27103207
rs6424062
hCV1642008
rs1563471
0.51
0.53997951
0.8426


hCV27103207
rs6424062
hCV27102953
rs4648360
0.51
0.53997951
0.9021


hCV27103207
rs6424062
hCV27102978
rs7537581
0.51
0.53997951
0.8345


hCV27103207
rs6424062
hCV27103080
rs4648459
0.51
0.53997951
1


hCV27103207
rs6424062
hCV27103144
rs11584658
0.51
0.53997951
0.8681


hCV27103207
rs6424062
hCV27103182
rs4609377
0.51
0.53997951
0.7813


hCV27103207
rs6424062
hCV27103185
rs10797389
0.51
0.53997951
0.8559


hCV27103207
rs6424062
hCV27103186
rs4648481
0.51
0.53997951
0.8703


hCV27103207
rs6424062
hCV27103188
rs7511879
0.51
0.53997951
0.7791


hCV27103207
rs6424062
hCV27103189
rs12031493
0.51
0.53997951
0.7463


hCV27103207
rs6424062
hCV27103192
rs6680471
0.51
0.53997951
0.6639


hCV27103207
rs6424062
hCV31965210
rs10909880
0.51
0.53997951
0.8703


hCV27103207
rs6424062
hCV31965333
rs10797390
0.51
0.53997951
0.7449


hCV27103207
rs6424062
hCV788647
rs729045
0.51
0.53997951
0.5975


hCV27103207
rs6424062
hCV8725828
rs1456461
0.51
0.53997951
0.5653


hCV2744023
rs369328
hCV11420034
rs9351219
0.51
0.447364409
0.4799


hCV2744023
rs369328
hCV11569192
rs2585018
0.51
0.447364409
1


hCV2744023
rs369328
hCV11569204
rs9344968
0.51
0.447364409
0.4599


hCV2744023
rs369328
hCV15840762
rs2180140
0.51
0.447364409
0.4889


hCV2744023
rs369328
hCV2012677
rs1470263
0.51
0.447364409
0.4746


hCV2744023
rs369328
hCV2012681
rs6918308
0.51
0.447364409
0.8995


hCV2744023
rs369328
hCV2012686
rs9362676
0.51
0.447364409
0.4746


hCV2744023
rs369328
hCV2012692
rs4707565
0.51
0.447364409
0.4741


hCV2744023
rs369328
hCV2012696
rs4142648
0.51
0.447364409
0.4746


hCV2744023
rs369328
hCV26081278
rs2585008
0.51
0.447364409
1


hCV2744023
rs369328
hCV27392140
rs12661693
0.51
0.447364409
1


hCV2744023
rs369328
hCV28980044
rs6923604
0.51
0.447364409
0.8995


hCV2744023
rs369328
hCV2950250
rs292259
0.51
0.447364409
0.5535


hCV2744023
rs369328
hCV2956500
rs11755610
0.51
0.447364409
0.493


hCV2744023
rs369328
hCV29986476
rs9451269
0.51
0.447364409
0.8669


hCV2744023
rs369328
hCV30238224
rs6910277
0.51
0.447364409
0.8959


hCV2744023
rs369328
hCV30454683
rs9351210
0.51
0.447364409
0.4746


hCV2744023
rs369328
hCV30562928
rs9342209
0.51
0.447364409
0.4746


hCV2744023
rs369328
hCV30580828
rs9344964
0.51
0.447364409
0.4792


hCV2744023
rs369328
hCV30749435
rs7762262
0.51
0.447364409
0.4643


hCV2744023
rs369328
hCV30749473
rs12661230
0.51
0.447364409
0.4599


hCV2744023
rs369328
hCV3180831
rs456671
0.51
0.447364409
0.5535


hCV2744023
rs369328
hCV3180835
rs292222
0.51
0.447364409
1


hCV2744023
rs369328
hCV996140
rs457665
0.51
0.447364409
0.57


hCV2744023
rs369328
hCV996141
rs409320
0.51
0.447364409
1


hCV27474895
rs3756011
hCV32291269
rs4253417
0.51
0.912197135
0.9319


hCV27474895
rs3756011
hCV3230038
rs2289252
0.51
0.912197135
1


hCV27477533
rs3756008
hCV3230025
rs3756009
0.51
0.89567049
1


hCV27477533
rs3756008
hCV8241630
rs925451
0.51
0.89567049
0.9185


hCV2852784
rs743572
hCV11201601
rs3781287
0.51
0.919963603
0.931


hCV2852784
rs743572
hCV12119916
rs6163
0.51
0.919963603
1


hCV2852784
rs743572
hCV12119917
rs6162
0.51
0.919963603
0.931


hCV2852784
rs743572
hCV25761532
rs3740397
0.51
0.919963603
1


hCV2852784
rs743572
hCV27433651
rs10883785
0.51
0.919963603
1


hCV2852784
rs743572
hCV31979198
rs4290163
0.51
0.919963603
0.931


hCV2852784
rs743572
hCV31979199
rs7096475
0.51
0.919963603
0.931


hCV2852784
rs743572
hCV3284571
rs7097872
0.51
0.919963603
0.9301


hCV2852784
rs743572
hCV3284577
rs10786712
0.51
0.919963603
1


hCV2892855
rs6536024
hCV2892858
rs12648395
0.51
0.436203746
0.5717


hCV2892855
rs6536024
hCV2892863
rs1049636
0.51
0.436203746
0.5596


hCV2892855
rs6536024
hCV2892923
rs13435192
0.51
0.436203746
0.5707


hCV2892855
rs6536024
hCV2892924
rs13435101
0.51
0.436203746
0.5658


hCV2892855
rs6536024
hCV2892925
rs7689945
0.51
0.436203746
0.5091


hCV2892855
rs6536024
hCV2892927
rs13123551
0.51
0.436203746
0.5235


hCV2892855
rs6536024
hCV7429782
rs1118823
0.51
0.436203746
0.5717


hCV2892869
rs13109457
hCV11503414
rs2066865
0.51
0.696732032
0.9571


hCV2892869
rs13109457
hCV11503416
rs2066864
0.51
0.696732032
0.9571


hCV2892869
rs13109457
hCV11503431
rs2066861
0.51
0.696732032
0.9571


hCV2892869
rs13109457
hCV11853483
rs12644950
0.51
0.696732032
0.9537


hCV2892869
rs13109457
hCV11853489
rs7681423
0.51
0.696732032
0.9571


hCV2892869
rs13109457
hCV11853496
rs7654093
0.51
0.696732032
0.9568


hCV2892869
rs13109457
hCV27020277
rs6825454
0.51
0.696732032
0.9556


hCV2892869
rs13109457
hCV2892859
rs13130318
0.51
0.696732032
0.869


hCV2892869
rs13109457
hCV2892877
rs6050
0.51
0.696732032
0.9571


hCV2892869
rs13109457
hCV31863982
rs7659024
0.51
0.696732032
0.9571


hCV2892927
rs13123551
hCV2892923
rs13435192
0.51
0.957904963
1


hCV2892927
rs13123551
hCV2892925
rs7689945
0.51
0.957904963
1


hCV29210363
rs6656918
hCV12073840
rs14403
0.51
0.470215497
0.5134


hCV29210363
rs6656918
hCV15760229
rs3006939
0.51
0.470215497
1


hCV29210363
rs6656918
hCV15760238
rs3006936
0.51
0.470215497
1


hCV29210363
rs6656918
hCV15823024
rs2125230
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV15885425
rs2290754
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV15965338
rs2291410
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV16082410
rs2881275
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV1678656
rs1458024
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV1678674
rs1458023
0.51
0.470215497
0.556


hCV29210363
rs6656918
hCV1678682
rs320339
0.51
0.470215497
0.6015


hCV29210363
rs6656918
hCV233148
rs1417121
0.51
0.470215497
0.656


hCV29210363
rs6656918
hCV26034158
rs4515770
0.51
0.470215497
1


hCV29210363
rs6656918
hCV26034160
rs2994327
0.51
0.470215497
0.4867


hCV29210363
rs6656918
hCV26719082
rs10927046
0.51
0.470215497
0.6005


hCV29210363
rs6656918
hCV26719085
rs10927047
0.51
0.470215497
0.5855


hCV29210363
rs6656918
hCV26719107
rs7538011
0.51
0.470215497
0.6479


hCV29210363
rs6656918
hCV26719113
rs7517340
0.51
0.470215497
0.6336


hCV29210363
rs6656918
hCV26719116
rs10927039
0.51
0.470215497
0.7848


hCV29210363
rs6656918
hCV26719120
rs10927040
0.51
0.470215497
0.7569


hCV29210363
rs6656918
hCV26719121
rs10927041
0.51
0.470215497
0.7435


hCV29210363
rs6656918
hCV26719149
rs6675851
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV26719162
rs4132509
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV26719176
rs10927076
0.51
0.470215497
0.6562


hCV29210363
rs6656918
hCV26719192
rs10803161
0.51
0.470215497
0.723


hCV29210363
rs6656918
hCV26719219
rs9782958
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV26719222
rs4553169
0.51
0.470215497
0.6934


hCV29210363
rs6656918
hCV26719227
rs10927065
0.51
0.470215497
0.556


hCV29210363
rs6656918
hCV26719232
rs10803158
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV26719233
rs10927067
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV27498250
rs3766673
0.51
0.470215497
0.5812


hCV29210363
rs6656918
hCV29542869
rs7534117
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV29560960
rs7519673
0.51
0.470215497
0.556


hCV29210363
rs6656918
hCV29741723
rs7517921
0.51
0.470215497
0.6407


hCV29210363
rs6656918
hCV29994467
rs6694738
0.51
0.470215497
0.6479


hCV29210363
rs6656918
hCV30084348
rs9287269
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV30372886
rs9782883
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV30690778
rs12140414
0.51
0.470215497
0.8942


hCV29210363
rs6656918
hCV30690780
rs10737888
0.51
0.470215497
1


hCV29210363
rs6656918
hCV30690784
rs4658574
0.51
0.470215497
0.4867


hCV29210363
rs6656918
hCV31523557
rs10754807
0.51
0.470215497
0.6943


hCV29210363
rs6656918
hCV31523563
rs10927051
0.51
0.470215497
0.6381


hCV29210363
rs6656918
hCV31523638
rs12037013
0.51
0.470215497
0.6005


hCV29210363
rs6656918
hCV31523639
rs12034588
0.51
0.470215497
0.6943


hCV29210363
rs6656918
hCV31523643
rs6671475
0.51
0.470215497
0.7754


hCV29210363
rs6656918
hCV31523650
rs12048930
0.51
0.470215497
0.6433


hCV29210363
rs6656918
hCV31523658
rs12047209
0.51
0.470215497
0.5048


hCV29210363
rs6656918
hCV31523688
rs12049228
0.51
0.470215497
0.6836


hCV29210363
rs6656918
hCV31523691
rs12021907
0.51
0.470215497
0.556


hCV29210363
rs6656918
hCV31523707
rs10803152
0.51
0.470215497
0.5865


hCV29210363
rs6656918
hCV31523710
rs10927059
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV31523723
rs12140040
0.51
0.470215497
0.5114


hCV29210363
rs6656918
hCV31523736
rs12124113
0.51
0.470215497
0.555


hCV29210363
rs6656918
hCV31523740
rs12032342
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV31523744
rs12031994
0.51
0.470215497
0.556


hCV29210363
rs6656918
hCV804126
rs320320
0.51
0.470215497
0.6952


hCV29210363
rs6656918
hCV8688079
rs884808
0.51
0.470215497
0.4867


hCV29210363
rs6656918
hCV8688080
rs884328
0.51
0.470215497
0.4847


hCV29210363
rs6656918
hCV8688111
rs1578275
0.51
0.470215497
0.8942


hCV29210363
rs6656918
hCV9493081
rs1058304
0.51
0.470215497
0.6589


hCV29210363
rs6656918
hCV97631
rs1538773
0.51
0.470215497
1


hCV29210363
rs6656918
hDV71836703
rs6429433
0.51
0.470215497
0.6479


hCV30690780
rs10737888
hCV12073840
rs14403
0.51
0.454920162
0.5283


hCV30690780
rs10737888
hCV15760229
rs3006939
0.51
0.454920162
1


hCV30690780
rs10737888
hCV15760238
rs3006936
0.51
0.454920162
1


hCV30690780
rs10737888
hCV15760239
rs3006923
0.51
0.454920162
0.4865


hCV30690780
rs10737888
hCV15823024
rs2125230
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV15885425
rs2290754
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV15965338
rs2291410
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV16082410
rs2881275
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV1678656
rs1458024
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV1678674
rs1458023
0.51
0.454920162
0.5714


hCV30690780
rs10737888
hCV1678682
rs320339
0.51
0.454920162
0.6154


hCV30690780
rs10737888
hCV233148
rs1417121
0.51
0.454920162
0.6656


hCV30690780
rs10737888
hCV26034158
rs4515770
0.51
0.454920162
1


hCV30690780
rs10737888
hCV26034160
rs2994327
0.51
0.454920162
0.5018


hCV30690780
rs10737888
hCV26719082
rs10927046
0.51
0.454920162
0.6144


hCV30690780
rs10737888
hCV26719085
rs10927047
0.51
0.454920162
0.6005


hCV30690780
rs10737888
hCV26719107
rs7538011
0.51
0.454920162
0.6602


hCV30690780
rs10737888
hCV26719113
rs7517340
0.51
0.454920162
0.647


hCV30690780
rs10737888
hCV26719116
rs10927039
0.51
0.454920162
0.7848


hCV30690780
rs10737888
hCV26719120
rs10927040
0.51
0.454920162
0.7673


hCV30690780
rs10737888
hCV26719121
rs10927041
0.51
0.454920162
0.7525


hCV30690780
rs10737888
hCV26719149
rs6675851
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV26719162
rs4132509
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV26719176
rs10927076
0.51
0.454920162
0.6701


hCV30690780
rs10737888
hCV26719192
rs10803161
0.51
0.454920162
0.7337


hCV30690780
rs10737888
hCV26719201
rs4478795
0.51
0.454920162
0.4789


hCV30690780
rs10737888
hCV26719219
rs9782958
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV26719222
rs4553169
0.51
0.454920162
0.7041


hCV30690780
rs10737888
hCV26719227
rs10927065
0.51
0.454920162
0.5714


hCV30690780
rs10737888
hCV26719232
rs10803158
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV26719233
rs10927067
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV27498250
rs3766673
0.51
0.454920162
0.6075


hCV30690780
rs10737888
hCV29210363
rs6656918
0.51
0.454920162
1


hCV30690780
rs10737888
hCV29542869
rs7534117
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV29560960
rs7519673
0.51
0.454920162
0.5714


hCV30690780
rs10737888
hCV29741723
rs7517921
0.51
0.454920162
0.5624


hCV30690780
rs10737888
hCV29994467
rs6694738
0.51
0.454920162
0.6602


hCV30690780
rs10737888
hCV30084348
rs9287269
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV30372886
rs9782883
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV30690778
rs12140414
0.51
0.454920162
0.898


hCV30690780
rs10737888
hCV30690784
rs4658574
0.51
0.454920162
0.5018


hCV30690780
rs10737888
hCV31523557
rs10754807
0.51
0.454920162
0.705


hCV30690780
rs10737888
hCV31523563
rs10927051
0.51
0.454920162
0.6533


hCV30690780
rs10737888
hCV31523638
rs12037013
0.51
0.454920162
0.6144


hCV30690780
rs10737888
hCV31523639
rs12034588
0.51
0.454920162
0.6943


hCV30690780
rs10737888
hCV31523643
rs6671475
0.51
0.454920162
0.7841


hCV30690780
rs10737888
hCV31523650
rs12048930
0.51
0.454920162
0.566


hCV30690780
rs10737888
hCV31523658
rs12047209
0.51
0.454920162
0.5224


hCV30690780
rs10737888
hCV31523688
rs12049228
0.51
0.454920162
0.6952


hCV30690780
rs10737888
hCV31523691
rs12021907
0.51
0.454920162
0.5714


hCV30690780
rs10737888
hCV31523707
rs10803152
0.51
0.454920162
0.6015


hCV30690780
rs10737888
hCV31523710
rs10927059
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV31523723
rs12140040
0.51
0.454920162
0.5283


hCV30690780
rs10737888
hCV31523736
rs12124113
0.51
0.454920162
0.5704


hCV30690780
rs10737888
hCV31523740
rs12032342
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV31523744
rs12031994
0.51
0.454920162
0.5714


hCV30690780
rs10737888
hCV804126
rs320320
0.51
0.454920162
0.7059


hCV30690780
rs10737888
hCV8688079
rs884808
0.51
0.454920162
0.5018


hCV30690780
rs10737888
hCV8688080
rs884328
0.51
0.454920162
0.4999


hCV30690780
rs10737888
hCV8688111
rs1578275
0.51
0.454920162
0.898


hCV30690780
rs10737888
hCV9493081
rs1058304
0.51
0.454920162
0.6684


hCV30690780
rs10737888
hCV97631
rs1538773
0.51
0.454920162
1


hCV30690780
rs10737888
hDV71836703
rs6429433
0.51
0.454920162
0.6602


hCV31523557
rs10754807
hCV15760229
rs3006939
0.51
0.685954218
0.6934


hCV31523557
rs10754807
hCV15760238
rs3006936
0.51
0.685954218
0.705


hCV31523557
rs10754807
hCV15823024
rs2125230
0.51
0.685954218
1


hCV31523557
rs10754807
hCV15885425
rs2290754
0.51
0.685954218
1


hCV31523557
rs10754807
hCV15965338
rs2291410
0.51
0.685954218
1


hCV31523557
rs10754807
hCV16082410
rs2881275
0.51
0.685954218
1


hCV31523557
rs10754807
hCV1678656
rs1458024
0.51
0.685954218
1


hCV31523557
rs10754807
hCV1678674
rs1458023
0.51
0.685954218
0.8091


hCV31523557
rs10754807
hCV1678682
rs320339
0.51
0.685954218
0.8715


hCV31523557
rs10754807
hCV26034158
rs4515770
0.51
0.685954218
0.6968


hCV31523557
rs10754807
hCV26719082
rs10927046
0.51
0.685954218
0.8715


hCV31523557
rs10754807
hCV26719085
rs10927047
0.51
0.685954218
0.8649


hCV31523557
rs10754807
hCV26719107
rs7538011
0.51
0.685954218
0.8095


hCV31523557
rs10754807
hCV26719113
rs7517340
0.51
0.685954218
0.9316


hCV31523557
rs10754807
hCV26719116
rs10927039
0.51
0.685954218
0.8707


hCV31523557
rs10754807
hCV26719120
rs10927040
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719121
rs10927041
0.51
0.685954218
0.8175


hCV31523557
rs10754807
hCV26719149
rs6675851
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719162
rs4132509
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719176
rs10927076
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719192
rs10803161
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719201
rs4478795
0.51
0.685954218
0.7457


hCV31523557
rs10754807
hCV26719219
rs9782958
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719222
rs4553169
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719227
rs10927065
0.51
0.685954218
0.8091


hCV31523557
rs10754807
hCV26719232
rs10803158
0.51
0.685954218
1


hCV31523557
rs10754807
hCV26719233
rs10927067
0.51
0.685954218
1


hCV31523557
rs10754807
hCV27498250
rs3766673
0.51
0.685954218
0.879


hCV31523557
rs10754807
hCV29210363
rs6656918
0.51
0.685954218
0.6943


hCV31523557
rs10754807
hCV29542869
rs7534117
0.51
0.685954218
1


hCV31523557
rs10754807
hCV29560960
rs7519673
0.51
0.685954218
0.8091


hCV31523557
rs10754807
hCV29741723
rs7517921
0.51
0.685954218
0.7033


hCV31523557
rs10754807
hCV29994467
rs6694738
0.51
0.685954218
0.8095


hCV31523557
rs10754807
hCV30084348
rs9287269
0.51
0.685954218
1


hCV31523557
rs10754807
hCV30372886
rs9782883
0.51
0.685954218
1


hCV31523557
rs10754807
hCV30690780
rs10737888
0.51
0.685954218
0.705


hCV31523557
rs10754807
hCV31523563
rs10927051
0.51
0.685954218
0.923


hCV31523557
rs10754807
hCV31523638
rs12037013
0.51
0.685954218
0.8711


hCV31523557
rs10754807
hCV31523639
rs12034588
0.51
0.685954218
1


hCV31523557
rs10754807
hCV31523643
rs6671475
0.51
0.685954218
0.9345


hCV31523557
rs10754807
hCV31523650
rs12048930
0.51
0.685954218
0.8175


hCV31523557
rs10754807
hCV31523658
rs12047209
0.51
0.685954218
0.7474


hCV31523557
rs10754807
hCV31523688
rs12049228
0.51
0.685954218
1


hCV31523557
rs10754807
hCV31523691
rs12021907
0.51
0.685954218
0.8091


hCV31523557
rs10754807
hCV31523707
rs10803152
0.51
0.685954218
0.8649


hCV31523557
rs10754807
hCV31523710
rs10927059
0.51
0.685954218
1


hCV31523557
rs10754807
hCV31523723
rs12140040
0.51
0.685954218
0.7479


hCV31523557
rs10754807
hCV31523736
rs12124113
0.51
0.685954218
0.8086


hCV31523557
rs10754807
hCV31523740
rs12032342
0.51
0.685954218
1


hCV31523557
rs10754807
hCV31523744
rs12031994
0.51
0.685954218
0.8091


hCV31523557
rs10754807
hCV804126
rs320320
0.51
0.685954218
1


hCV31523557
rs10754807
hCV97631
rs1538773
0.51
0.685954218
0.705


hCV31523557
rs10754807
hDV71836703
rs6429433
0.51
0.685954218
0.8095


hCV31523608
rs12744297
hCV12073160
rs1973284
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV12073167
rs2034915
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV12073172
rs971285
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV12073180
rs1870272
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV15776869
rs2345994
0.51
0.768680874
0.9556


hCV31523608
rs12744297
hCV15823033
rs2125231
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV15885435
rs2290753
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV15965328
rs2291409
0.51
0.768680874
1


hCV31523608
rs12744297
hCV1678668
rs1379700
0.51
0.768680874
0.845


hCV31523608
rs12744297
hCV1678723
rs1486472
0.51
0.768680874
0.7707


hCV31523608
rs12744297
hCV26719086
rs4658585
0.51
0.768680874
0.9197


hCV31523608
rs12744297
hCV26719087
rs4658401
0.51
0.768680874
0.9056


hCV31523608
rs12744297
hCV26719102
rs10927056
0.51
0.768680874
0.8824


hCV31523608
rs12744297
hCV26719114
rs7549780
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV26719117
rs12144559
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV26719171
rs10927075
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV26719179
rs6672195
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV26719194
rs10927081
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV26719197
rs4590656
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV26719215
rs12144546
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV26719225
rs11586029
0.51
0.768680874
0.9596


hCV31523608
rs12744297
hCV29210367
rs4518884
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV29633221
rs10157763
0.51
0.768680874
0.9589


hCV31523608
rs12744297
hCV29795761
rs7528450
0.51
0.768680874
1


hCV31523608
rs12744297
hCV30012351
rs10158245
0.51
0.768680874
0.9568


hCV31523608
rs12744297
hCV31523552
rs12739344
0.51
0.768680874
1


hCV31523608
rs12744297
hCV31523555
rs12749316
0.51
0.768680874
0.9202


hCV31523608
rs12744297
hCV31523573
rs11589907
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV31523576
rs12691548
0.51
0.768680874
0.9207


hCV31523608
rs12744297
hCV31523624
rs10927044
0.51
0.768680874
1


hCV31523608
rs12744297
hCV31523725
rs10927060
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV8688098
rs1531244
0.51
0.768680874
0.9544


hCV31523608
rs12744297
hCV8689016
rs897959
0.51
0.768680874
0.9599


hCV31523608
rs12744297
hCV9115290
rs1352162
0.51
0.768680874
1


hCV31523643
rs6671475
hCV15760229
rs3006939
0.51
0.736259252
0.7747


hCV31523643
rs6671475
hCV15760238
rs3006936
0.51
0.736259252
0.7841


hCV31523643
rs6671475
hCV15823024
rs2125230
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV15885425
rs2290754
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV15965338
rs2291410
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV16082410
rs2881275
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV1678656
rs1458024
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV1678674
rs1458023
0.51
0.736259252
0.7467


hCV31523643
rs6671475
hCV1678682
rs320339
0.51
0.736259252
0.8081


hCV31523643
rs6671475
hCV26034158
rs4515770
0.51
0.736259252
0.7955


hCV31523643
rs6671475
hCV26719082
rs10927046
0.51
0.736259252
0.8076


hCV31523643
rs6671475
hCV26719085
rs10927047
0.51
0.736259252
0.7978


hCV31523643
rs6671475
hCV26719107
rs7538011
0.51
0.736259252
0.8707


hCV31523643
rs6671475
hCV26719113
rs7517340
0.51
0.736259252
0.8638


hCV31523643
rs6671475
hCV26719116
rs10927039
0.51
0.736259252
0.9312


hCV31523643
rs6671475
hCV26719120
rs10927040
0.51
0.736259252
1


hCV31523643
rs6671475
hCV26719121
rs10927041
0.51
0.736259252
0.872


hCV31523643
rs6671475
hCV26719149
rs6675851
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV26719162
rs4132509
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV26719176
rs10927076
0.51
0.736259252
0.9232


hCV31523643
rs6671475
hCV26719192
rs10803161
0.51
0.736259252
0.9345


hCV31523643
rs6671475
hCV26719219
rs9782958
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV26719222
rs4553169
0.51
0.736259252
0.9343


hCV31523643
rs6671475
hCV26719227
rs10927065
0.51
0.736259252
0.7467


hCV31523643
rs6671475
hCV26719232
rs10803158
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV26719233
rs10927067
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV27498250
rs3766673
0.51
0.736259252
1


hCV31523643
rs6671475
hCV29210363
rs6656918
0.51
0.736259252
0.7754


hCV31523643
rs6671475
hCV29542869
rs7534117
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV29560960
rs7519673
0.51
0.736259252
0.7467


hCV31523643
rs6671475
hCV29741723
rs7517921
0.51
0.736259252
0.7503


hCV31523643
rs6671475
hCV29994467
rs6694738
0.51
0.736259252
0.8707


hCV31523643
rs6671475
hCV30084348
rs9287269
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV30372886
rs9782883
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV30690780
rs10737888
0.51
0.736259252
0.7841


hCV31523643
rs6671475
hCV31523557
rs10754807
0.51
0.736259252
0.9345


hCV31523643
rs6671475
hCV31523563
rs10927051
0.51
0.736259252
0.8551


hCV31523643
rs6671475
hCV31523638
rs12037013
0.51
0.736259252
0.8076


hCV31523643
rs6671475
hCV31523639
rs12034588
0.51
0.736259252
0.9312


hCV31523643
rs6671475
hCV31523650
rs12048930
0.51
0.736259252
0.752


hCV31523643
rs6671475
hCV31523688
rs12049228
0.51
0.736259252
0.9314


hCV31523643
rs6671475
hCV31523691
rs12021907
0.51
0.736259252
0.7467


hCV31523643
rs6671475
hCV31523707
rs10803152
0.51
0.736259252
0.7983


hCV31523643
rs6671475
hCV31523710
rs10927059
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV31523736
rs12124113
0.51
0.736259252
0.746


hCV31523643
rs6671475
hCV31523740
rs12032342
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV31523744
rs12031994
0.51
0.736259252
0.7467


hCV31523643
rs6671475
hCV804126
rs320320
0.51
0.736259252
0.9347


hCV31523643
rs6671475
hCV97631
rs1538773
0.51
0.736259252
0.7841


hCV31523643
rs6671475
hDV71836703
rs6429433
0.51
0.736259252
0.8707


hCV31523650
rs12048930
hCV26719120
rs10927040
0.51
0.888920337
0.9316


hCV31523650
rs12048930
hCV31523563
rs10927051
0.51
0.888920337
0.923


hCV31523650
rs12048930
hCV31523639
rs12034588
0.51
0.888920337
0.9349


hCV31863982
rs7659024
hCV11503414
rs2066865
0.51
0.477476354
1


hCV31863982
rs7659024
hCV11503416
rs2066864
0.51
0.477476354
1


hCV31863982
rs7659024
hCV11503431
rs2066861
0.51
0.477476354
1


hCV31863982
rs7659024
hCV11853483
rs12644950
0.51
0.477476354
1


hCV31863982
rs7659024
hCV11853489
rs7681423
0.51
0.477476354
1


hCV31863982
rs7659024
hCV11853496
rs7654093
0.51
0.477476354
1


hCV31863982
rs7659024
hCV15860433
rs2070006
0.51
0.477476354
0.5225


hCV31863982
rs7659024
hCV27020269
rs7659613
0.51
0.477476354
0.5225


hCV31863982
rs7659024
hCV27020277
rs6825454
0.51
0.477476354
0.9115


hCV31863982
rs7659024
hCV2892859
rs13130318
0.51
0.477476354
0.8654


hCV31863982
rs7659024
hCV2892869
rs13109457
0.51
0.477476354
0.9571


hCV31863982
rs7659024
hCV2892877
rs6050
0.51
0.477476354
0.9148


hCV31965333
rs10797390
hCV16000557
rs2377041
0.51
0.676094947
0.7352


hCV31965333
rs10797390
hCV1642008
rs1563471
0.51
0.676094947
0.7255


hCV31965333
rs10797390
hCV27102953
rs4648360
0.51
0.676094947
0.7827


hCV31965333
rs10797390
hCV27102978
rs7537581
0.51
0.676094947
0.7038


hCV31965333
rs10797390
hCV27103080
rs4648459
0.51
0.676094947
0.7405


hCV31965333
rs10797390
hCV27103144
rs11584658
0.51
0.676094947
0.8469


hCV31965333
rs10797390
hCV27103182
rs4609377
0.51
0.676094947
0.7768


hCV31965333
rs10797390
hCV27103185
rs10797389
0.51
0.676094947
0.8326


hCV31965333
rs10797390
hCV27103186
rs4648481
0.51
0.676094947
0.8158


hCV31965333
rs10797390
hCV27103188
rs7511879
0.51
0.676094947
0.7786


hCV31965333
rs10797390
hCV27103189
rs12031493
0.51
0.676094947
0.8473


hCV31965333
rs10797390
hCV27103192
rs6680471
0.51
0.676094947
0.8159


hCV31965333
rs10797390
hCV27103207
rs6424062
0.51
0.676094947
0.7449


hCV31965333
rs10797390
hCV31965210
rs10909880
0.51
0.676094947
0.8158


hCV31965333
rs10797390
hCV788647
rs729045
0.51
0.676094947
0.9244


hCV3216426
rs7315731
hCV1026394
rs35117
0.51
0.727697779
0.9666


hCV3216426
rs7315731
hCV1026396
rs35115
0.51
0.727697779
0.9344


hCV3216426
rs7315731
hCV1026401
rs35122
0.51
0.727697779
0.9318


hCV3216426
rs7315731
hCV1026402
rs247929
0.51
0.727697779
0.9652


hCV3216426
rs7315731
hCV1026405
rs997307
0.51
0.727697779
1


hCV3216426
rs7315731
hCV12058175
rs10880879
0.51
0.727697779
1


hCV3216426
rs7315731
hCV2071465
rs10880884
0.51
0.727697779
0.9664


hCV3216426
rs7315731
hCV2362878
rs247918
0.51
0.727697779
0.888


hCV3216426
rs7315731
hCV26024786
rs7976870
0.51
0.727697779
0.9652


hCV3216426
rs7315731
hCV26173954
rs7308284
0.51
0.727697779
0.7488


hCV3216426
rs7315731
hCV26173968
rs10880880
0.51
0.727697779
1


hCV3216426
rs7315731
hCV26173972
rs1012642
0.51
0.727697779
1


hCV3216426
rs7315731
hCV2773478
rs2193749
0.51
0.727697779
0.9666


hCV3216426
rs7315731
hCV2773479
rs7138997
0.51
0.727697779
0.9344


hCV3216426
rs7315731
hCV2791821
rs2059404
0.51
0.727697779
0.8909


hCV3216426
rs7315731
hCV2791832
rs2408435
0.51
0.727697779
0.9641


hCV3216426
rs7315731
hCV2791836
rs7132422
0.51
0.727697779
0.966


hCV3216426
rs7315731
hCV30311491
rs6582585
0.51
0.727697779
0.7488


hCV3216426
rs7315731
hCV30680015
rs6582574
0.51
0.727697779
0.9658


hCV3216426
rs7315731
hCV30870058
rs11183272
0.51
0.727697779
1


hCV3216426
rs7315731
hCV30870104
rs10880875
0.51
0.727697779
1


hCV3216426
rs7315731
hCV30870137
rs10880871
0.51
0.727697779
1


hCV3216426
rs7315731
hCV31416750
rs10880855
0.51
0.727697779
0.9666


hCV3216426
rs7315731
hCV31416763
rs12319077
0.51
0.727697779
0.9329


hCV3216426
rs7315731
hCV31416770
rs11183201
0.51
0.727697779
0.9661


hCV3216426
rs7315731
hCV3201166
rs11183243
0.51
0.727697779
1


hCV3216426
rs7315731
hCV3216410
rs247930
0.51
0.727697779
0.9666


hCV3216426
rs7315731
hCV3216415
rs247920
0.51
0.727697779
0.9344


hCV3216426
rs7315731
hCV3216418
rs35125
0.51
0.727697779
0.9666


hCV3216426
rs7315731
hCV3216425
rs1366024
0.51
0.727697779
0.9666


hCV3216426
rs7315731
hCV3216427
rs724909
0.51
0.727697779
1


hCV3216426
rs7315731
hCV3216433
rs7306229
0.51
0.727697779
1


hCV3216426
rs7315731
hCV345121
rs10748432
0.51
0.727697779
0.9578


hCV3216426
rs7315731
hCV389695
rs2408461
0.51
0.727697779
0.7488


hCV491830
rs3087546
hCV11280343
rs12222447
0.51
0.804397523
0.8924


hCV596326
rs398101
hCV596330
rs422187
0.51
0.794342915
0.8217


hCV596326
rs398101
hCV596331
rs6048
0.51
0.794342915
0.8216


hCV596331
rs6048
hCV596330
rs422187
0.51
0.959456195
1


hCV596663
rs411017
hCV11780206
rs5931656
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV11780209
rs5930009
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV11780214
rs7878061
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV2288095
rs378815
0.51
0.674917535
1


hCV596663
rs411017
hCV26011954
rs4620439
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV26011955
rs5930013
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV26016182
rs11796672
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV26016183
rs9887617
0.51
0.674917535
0.9162


hCV596663
rs411017
hCV27904396
rs4829996
0.51
0.674917535
0.9459


hCV596663
rs411017
hCV28962605
rs5930005
0.51
0.674917535
0.9576


hCV596663
rs411017
hCV29515877
rs5930015
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV29732937
rs5931647
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV29967889
rs5931645
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV30130033
rs5931646
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV30201992
rs5931641
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV30291634
rs5931666
0.51
0.674917535
0.9562


hCV596663
rs411017
hCV30700232
rs12687091
0.51
0.674917535
0.9579


hCV596663
rs411017
hCV596665
rs401597
0.51
0.674917535
0.9459


hCV596663
rs411017
hDV77022847
rs4598407
0.51
0.674917535
0.9579


hCV596663
rs411017
hDV77148131
rs5931661
0.51
0.674917535
0.9116


hCV596663
rs411017
hDV77150953
rs5976389
0.51
0.674917535
0.9579


hCV788647
rs729045
hCV31965333
rs10797390
0.51
0.862222906
0.9244


hCV8361354
rs1138800
hCV16176508
rs2949857
0.51
0.697573042
0.7785


hCV8361354
rs1138800
hCV16176534
rs2949863
0.51
0.697573042
0.7785


hCV8361354
rs1138800
hCV204260
rs4753535
0.51
0.697573042
0.743


hCV8361354
rs1138800
hCV260722
rs4073615
0.51
0.697573042
0.8988


hCV8361354
rs1138800
hCV26487026
rs4753543
0.51
0.697573042
0.808


hCV8361354
rs1138800
hCV29137668
rs7108501
0.51
0.697573042
0.7385


hCV8361354
rs1138800
hCV29137679
rs6483293
0.51
0.697573042
0.8651


hCV8361354
rs1138800
hCV31252427
rs4625415
0.51
0.697573042
0.7785


hCV8361354
rs1138800
hCV31252429
rs12222234
0.51
0.697573042
0.755


hCV8361354
rs1138800
hCV389113
rs7927016
0.51
0.697573042
0.7785


hCV8361354
rs1138800
hCV389115
rs4531426
0.51
0.697573042
0.7785


hCV8361354
rs1138800
hCV389118
rs10437575
0.51
0.697573042
0.7385


hCV8361354
rs1138800
hCV389119
rs7925817
0.51
0.697573042
0.738


hCV8361354
rs1138800
hCV89001
rs2949858
0.51
0.697573042
0.75


hCV8598986
rs4832233
hCV2105930
rs2083168
0.51
0.996752219
1


hCV8598986
rs4832233
hCV2105934
rs2099616
0.51
0.996752219
1


hCV8598986
rs4832233
hCV2105935
rs3937593
0.51
0.996752219
1


hCV8598986
rs4832233
hCV2105948
rs6547655
0.51
0.996752219
1


hCV8598986
rs4832233
hCV29665700
rs10173155
0.51
0.996752219
1


hCV8598986
rs4832233
hCV31173526
rs6547654
0.51
0.996752219
1


hCV8688111
rs1578275
hCV30690778
rs12140414
0.51
0.973078677
1


hCV9102827
rs3795733
hCV31431621
rs11576266
0.51
0.983113922
1


hCV9493081
rs1058304
hCV12073840
rs14403
0.51
0.513841921
0.871


hCV9493081
rs1058304
hCV15760229
rs3006939
0.51
0.513841921
0.6575


hCV9493081
rs1058304
hCV15760238
rs3006936
0.51
0.513841921
0.6684


hCV9493081
rs1058304
hCV15760239
rs3006923
0.51
0.513841921
0.718


hCV9493081
rs1058304
hCV233148
rs1417121
0.51
0.513841921
1


hCV9493081
rs1058304
hCV26034157
rs2994329
0.51
0.513841921
0.5193


hCV9493081
rs1058304
hCV26034158
rs4515770
0.51
0.513841921
0.7088


hCV9493081
rs1058304
hCV26034160
rs2994327
0.51
0.513841921
0.7471


hCV9493081
rs1058304
hCV26719121
rs10927041
0.51
0.513841921
0.5644


hCV9493081
rs1058304
hCV29210363
rs6656918
0.51
0.513841921
0.6589


hCV9493081
rs1058304
hCV30690778
rs12140414
0.51
0.513841921
0.5936


hCV9493081
rs1058304
hCV30690780
rs10737888
0.51
0.513841921
0.6684


hCV9493081
rs1058304
hCV30690784
rs4658574
0.51
0.513841921
0.7471


hCV9493081
rs1058304
hCV8688079
rs884808
0.51
0.513841921
0.7471


hCV9493081
rs1058304
hCV8688080
rs884328
0.51
0.513841921
0.7459


hCV9493081
rs1058304
hCV8688111
rs1578275
0.51
0.513841921
0.5936


hCV9493081
rs1058304
hCV97631
rs1538773
0.51
0.513841921
0.6684


hCV97631
rs1538773
hCV12073840
rs14403
0.51
0.521807277
0.5283


hCV97631
rs1538773
hCV15760229
rs3006939
0.51
0.521807277
1


hCV97631
rs1538773
hCV15760238
rs3006936
0.51
0.521807277
1


hCV97631
rs1538773
hCV15823024
rs2125230
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV15885425
rs2290754
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV15965338
rs2291410
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV16082410
rs2881275
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV1678656
rs1458024
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV1678674
rs1458023
0.51
0.521807277
0.5714


hCV97631
rs1538773
hCV1678682
rs320339
0.51
0.521807277
0.6154


hCV97631
rs1538773
hCV233148
rs1417121
0.51
0.521807277
0.6656


hCV97631
rs1538773
hCV26034158
rs4515770
0.51
0.521807277
1


hCV97631
rs1538773
hCV26719082
rs10927046
0.51
0.521807277
0.6144


hCV97631
rs1538773
hCV26719085
rs10927047
0.51
0.521807277
0.6005


hCV97631
rs1538773
hCV26719107
rs7538011
0.51
0.521807277
0.6602


hCV97631
rs1538773
hCV26719113
rs7517340
0.51
0.521807277
0.647


hCV97631
rs1538773
hCV26719116
rs10927039
0.51
0.521807277
0.7848


hCV97631
rs1538773
hCV26719120
rs10927040
0.51
0.521807277
0.7673


hCV97631
rs1538773
hCV26719121
rs10927041
0.51
0.521807277
0.7525


hCV97631
rs1538773
hCV26719149
rs6675851
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV26719162
rs4132509
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV26719176
rs10927076
0.51
0.521807277
0.6701


hCV97631
rs1538773
hCV26719192
rs10803161
0.51
0.521807277
0.7337


hCV97631
rs1538773
hCV26719219
rs9782958
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV26719222
rs4553169
0.51
0.521807277
0.7041


hCV97631
rs1538773
hCV26719227
rs10927065
0.51
0.521807277
0.5714


hCV97631
rs1538773
hCV26719232
rs10803158
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV26719233
rs10927067
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV27498250
rs3766673
0.51
0.521807277
0.6075


hCV97631
rs1538773
hCV29210363
rs6656918
0.51
0.521807277
1


hCV97631
rs1538773
hCV29542869
rs7534117
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV29560960
rs7519673
0.51
0.521807277
0.5714


hCV97631
rs1538773
hCV29741723
rs7517921
0.51
0.521807277
0.5624


hCV97631
rs1538773
hCV29994467
rs6694738
0.51
0.521807277
0.6602


hCV97631
rs1538773
hCV30084348
rs9287269
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV30372886
rs9782883
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV30690778
rs12140414
0.51
0.521807277
0.898


hCV97631
rs1538773
hCV30690780
rs10737888
0.51
0.521807277
1


hCV97631
rs1538773
hCV31523557
rs10754807
0.51
0.521807277
0.705


hCV97631
rs1538773
hCV31523563
rs10927051
0.51
0.521807277
0.6533


hCV97631
rs1538773
hCV31523638
rs12037013
0.51
0.521807277
0.6144


hCV97631
rs1538773
hCV31523639
rs12034588
0.51
0.521807277
0.6943


hCV97631
rs1538773
hCV31523643
rs6671475
0.51
0.521807277
0.7841


hCV97631
rs1538773
hCV31523650
rs12048930
0.51
0.521807277
0.566


hCV97631
rs1538773
hCV31523658
rs12047209
0.51
0.521807277
0.5224


hCV97631
rs1538773
hCV31523688
rs12049228
0.51
0.521807277
0.6952


hCV97631
rs1538773
hCV31523691
rs12021907
0.51
0.521807277
0.5714


hCV97631
rs1538773
hCV31523707
rs10803152
0.51
0.521807277
0.6015


hCV97631
rs1538773
hCV31523710
rs10927059
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV31523723
rs12140040
0.51
0.521807277
0.5283


hCV97631
rs1538773
hCV31523736
rs12124113
0.51
0.521807277
0.5704


hCV97631
rs1538773
hCV31523740
rs12032342
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV31523744
rs12031994
0.51
0.521807277
0.5714


hCV97631
rs1538773
hCV804126
rs320320
0.51
0.521807277
0.7059


hCV97631
rs1538773
hCV8688111
rs1578275
0.51
0.521807277
0.898


hCV97631
rs1538773
hCV9493081
rs1058304
0.51
0.521807277
0.6684


hCV97631
rs1538773
hDV71836703
rs6429433
0.51
0.521807277
0.6602
















TABLE 20





Unadjusted additive and genotypic association of 149 SNPs with DVT in LETS (p <= 0.1) and MEGA-1 (p <= 0.05)











































CONTROL













Allele


cnt













(CONTROL

CASE cnt
(CONTROL


marker
annot
Endpoint
Model
parameter
P Value
Odds Ratio
OR95l
OR95u
RiskAllele
NonRiskAllele
frq
Genot
(CASE frq
frq)


























hCV505733
(rs11126416)
LETS
Gen
AA_vs_GG
0.062
1.48
0.98
2.24
A
G
A (0.3642
A A
71
(0.1603)
54
(0.1192)




MEGA1
Gen
AA_vs_GG
0.006
1.36
1.09
1.69
A
G
A (0.3489
A A
210
(0.1514)
213
(0.1212)




LETS
Gen
AA_vs_GG
0.062
1.48
0.98
2.24
A
G
A (0.3642
A A
71
(0.1603)
54
(0.1192)





Gen
AG_vs_GG
0.546
1.09
0.82
1.45
A
G
A (0.3642
A A
71
(0.1603)
54
(0.1192)




MEGA1
Gen
AA_vs_GG
0.006
1.36
1.09
1.69
A
G
A (0.3489
A A
210
(0.1514)
213
(0.1212)





Gen
AG_vs_GG
0.232
1.1
0.94
1.28
A
G
A (0.3489
A A
210
(0.1514)
213
(0.1212)


hCV2879752
(rs1244565)
LETS
add
G_vs_A
0.028
1.23
1.02
1.48
G
A
G (0.4658
G G
115
(0.2608)
104
(0.2296)




MEGA1
add
G_vs_A
0.036
1.11
1.01
1.23
G
A
G (0.4692
G G
341
(0.2498)
379
(0.2163)




LETS
Gen
GA_vs_AA
0.024
1.45
1.05
1.99
G
A
G (0.4658
G G
115
(0.2608)
104
(0.2296)





Gen
GG_vs_AA
0.03
1.51
1.04
2.19
G
A
G (0.4658
G G
115
(0.2608)
104
(0.2296)




MEGA1
Gen
GA_vs_AA
0.578
1.05
0.89
1.24
G
A
G (0.4692
G G
341
(0.2498)
379
(0.2163)





Gen
GG_vs_AA
0.032
1.24
1.02
1.52
G
A
G (0.4692
G G
341
(0.2498)
379
(0.2163)


hCV11503470
(rs1800788)
MEGA1
add
T_vs_C
0.007
1.17
1.04
1.32
T
C
T (0.2163
T T
85
(0.0613)
107
(0.0611)




LETS
add
T_vs_C
0.014
1.32
1.06
1.65
T
C
T (0.1969
T T
31
(0.07)
17
(0.0376)




LETS
Gen
TC_vs_CC
0.148
1.23
0.93
1.63
T
C
T (0.1969
T T
31
(0.07)
17
(0.0376)





Gen
TT_vs_CC
0.02
2.07
1.12
3.83
T
C
T (0.1969
T T
31
(0.07)
17
(0.0376)




MEGA1
Gen
TC_vs_CC
4E−04
1.31
1.13
1.53
T
C
T (0.2163
T T
85
(0.0613)
107
(0.0611)





Gen
TT_vs_CC
0.505
1.11
0.82
1.49
T
C
T (0.2163
T T
85
(0.0613)
107
(0.0611)


hCV15860433
(rs2070006)
MEGA1
add
T_vs_C
2E−05
1.24
1.13
1.37
T
C
T (0.4067
T T
296
(0.2129)
297
(0.1694)




LETS
add
T_vs_C
0.024
1.24
1.03
1.5
T
C
T (0.4011
T T
95
(0.2154)
72
(0.16)




LETS
Gen
TC_vs_CC
0.328
1.16
0.86
1.56
T
C
T (0.4011
T T
95
(0.2154)
72
(0.16)





Gen
TT_vs_CC
0.02
1.57
1.07
2.31
T
C
T (0.4011
T T
95
(0.2154)
72
(0.16)




MEGA1
Gen
TC_vs_CC
0.003
1.28
1.09
1.5
T
C
T (0.4067
T T
296
(0.2129)
297
(0.1694)





Gen
TT_vs_CC
4E−05
1.54
1.25
1.88
T
C
T (0.4067
T T
296
(0.2129)
297
(0.1694)


hCV2744023
(rs369328)
LETS
add
A_vs_G
0.002
1.35
1.11
1.63
A
G
A (0.4491
A A
116
(0.2619)
87
(0.1925)




MEGA1
add
A_vs_G
0.018
1.13
1.02
1.24
A
G
A (0.4784
A A
370
(0.265)
404
(0.2301)




LETS
Gen
AA_vs_GG
0.002
1.81
1.24
2.65
A
G
A (0.4491
A A
116
(0.2619)
87
(0.1925)





Gen
AG_vs_GG
0.072
1.34
0.97
1.84
A
G
A (0.4491
A A
116
(0.2619)
87
(0.1925)




MEGA1
Gen
AA_vs_GG
0.017
1.27
1.04
1.55
A
G
A (0.4784
A A
370
(0.265)
404
(0.2301)





Gen
AG_vs_GG
0.367
1.08
0.91
1.28
A
G
A (0.4784
A A
370
(0.265)
404
(0.2301)


hCV27477533
(rs3756008)
MEGA1
add
T_vs_A
1E−06
1.28
1.16
1.42
T
A
T (0.4064
T T
307
(0.2201)
296
(0.1689)




LETS
add
T_vs_A
0.031
1.22
1.02
1.46
T
A
T (0.4159
T T
101
(0.2285)
88
(0.1947)




LETS
Gen
TA_vs_AA
0.052
1.35
1
1.82
T
A
T (0.4159
T T
101
(0.2285)
88
(0.1947)





Gen
TT_vs_AA
0.044
1.46
1.01
2.11
T
A
T (0.4159
T T
101
(0.2285)
88
(0.1947)




MEGA1
Gen
TA_vs_AA
0.001
1.31
1.11
1.53
T
A
T (0.4064
T T
307
(0.2201)
296
(0.1689)





Gen
TT_vs_AA
2E−06
1.63
1.33
2
T
A
T (0.4064
T T
307
(0.2201)
296
(0.1689)


hCV949676
(rs480802)
MEGA1
Gen
CC_vs_TT
0.027
1.44
1.04
1.99
C
T
C (0.2049
C C
83
(0.0615)
77
(0.0443)




LETS
Gen
CC_vs_TT
0.049
1.86
1
3.47
C
T
C (0.1914
C C
29
(0.0662)
17
(0.0376)




LETS
Gen
CC_vs_TT
0.049
1.86
1
3.47
C
T
C (0.1914
C C
29
(0.0662)
17
(0.0376)





Gen
CT_vs_TT
0.581
1.08
0.81
1.45
C
T
C (0.1914
C C
29
(0.0662)
17
(0.0376)




MEGA1
Gen
CC_vs_TT
0.027
1.44
1.04
1.99
C
T
C (0.2049
C C
83
(0.0615)
77
(0.0443)





Gen
CT_vs_TT
0.519
1.05
0.9
1.23
C
T
C (0.2049
C C
83
(0.0615)
77
(0.0443)


hCV27904396
(rs4829996)
LETS
rec
GG_vs_GA + AA
0.041
1.32
1.01
1.73
G
A
A (0.2969
A A
64
(0.1448)
79
(0.1744)




MEGA1
Gen
GA_vs_AA
0.049
1.26
1
1.58
G
A
A (0.2903
A A
231
(0.1662)
335
(0.1914)




LETS
Gen
GA_vs_AA
0.917
1.02
0.67
1.57
G
A
A (0.2969
A A
64
(0.1448)
79
(0.1744)





Gen
GG_vs_AA
0.119
1.34
0.93
1.94
G
A
A (0.2969
A A
64
(0.1448)
79
(0.1744)




MEGA1
Gen
GA_vs_AA
0.049
1.26
1
1.58
G
A
A (0.2903
A A
231
(0.1662)
335
(0.1914)





Gen
GG_vs_AA
0.115
1.17
0.96
1.41
G
A
A (0.2903
A A
231
(0.1662)
335
(0.1914)


hCV837462
(rs528088)
LETS
Gen
CC_vs_AA
0.071
4.2
0.89
19.9
C
A
C (0.0796
C C
8
(0.0181)
2
(0.0044)




MEGA1
dom
AA + AC_vs_CC
0.027
3.05
1.14
8.18
A
C
C (0.0785
C C
5
(0.0036)
19
(0.0109)




LETS
Gen
CA_vs_AA
0.677
1.08
0.75
1.55
C
A
C (0.0796
C C
8
(0.0181)
2
(0.0044)





Gen
CC_vs_AA
0.071
4.2
0.89
19.9
C
A
C (0.0796
C C
8
(0.0181)
2
(0.0044)




MEGA1
Gen
AA_vs_CC
0.027
3.04
1.13
8.16
A
C
C (0.0785
C C
5
(0.0036)
19
(0.0109)





Gen
AC_vs_CC
0.027
3.09
1.14
8.43
A
C
C (0.0785
C C
5
(0.0036)
19
(0.0109)


hCV30440155
(rs6699146)
LETS
add
C_vs_G
0.062
1.19
0.99
1.43
C
G
C (0.4148
C C
100
(0.2278)
84
(0.1858)




MEGA1
add
C_vs_G
0.003
1.16
1.05
1.28
C
G
C (0.4445
C C
321
(0.2394)
344
(0.1969)




LETS
Gen
CC_vs_GG
0.063
1.42
0.98
2.05
C
G
C (0.4148
C C
100
(0.2278)
84
(0.1858)





Gen
CG_vs_GG
0.29
1.18
0.87
1.59
C
G
C (0.4148
C C
100
(0.2278)
84
(0.1858)




MEGA1
Gen
CC_vs_GG
0.003
1.36
1.11
1.66
C
G
C (0.4445
C C
321
(0.2394)
344
(0.1969)





Gen
CG_vs_GG
0.276
1.1
0.93
1.3
C
G
C (0.4445
C C
321
(0.2394)
344
(0.1969)


hCV28960679
(rs6844764)
LETS
rec
GG_vs_GC + CC
0.072
1.29
0.98
1.71
G
C
C (0.4403
C C
74
(0.1674)
82
(0.1814)




MEGA1
dom
GG + GC_vs_CC
0.007
1.28
1.07
1.54
G
C
C (0.4389
C C
233
(0.1676)
358
(0.2054)




LETS
Gen
GC_vs_CC
0.976
0.99
0.69
1.43
G
C
C (0.4403
C C
74
(0.1674)
82
(0.1814)





Gen
GG_vs_CC
0.203
1.29
0.87
1.9
G
C
C (0.4403
C C
74
(0.1674)
82
(0.1814)




MEGA1
Gen
GC_vs_CC
0.007
1.3
1.07
1.58
G
C
C (0.4389
C C
233
(0.1676)
358
(0.2054)





Gen
GG_vs_CC
0.029
1.26
1.02
1.54
G
C
C (0.4389
C C
233
(0.1676)
358
(0.2054)


hCV1952126
(rs7223784)
LETS
add
A_vs_C
0.026
1.26
1.03
1.55
A
C
C (0.3031
C C
31
(0.07)
43
(0.0951)




MEGA1
add
A_vs_C
0.035
1.13
1.01
1.26
A
C
C (0.2801
C C
91
(0.0658)
147
(0.0839)




LETS
Gen
AA_vs_CC
0.08
1.56
0.95
2.56
A
C
C (0.3031
C C
31
(0.07)
43
(0.0951)





Gen
AC_vs_CC
0.461
1.21
0.73
2.01
A
C
C (0.3031
C C
31
(0.07)
43
(0.0951)




MEGA1
Gen
AA_vs_CC
0.036
1.35
1.02
1.78
A
C
C (0.2801
C C
91
(0.0658)
147
(0.0839)





Gen
AC_vs_CC
0.143
1.24
0.93
1.65
A
C
C (0.2801
C C
91
(0.0658)
147
(0.0839)


hCV31749285
(rs8178591)
LETS
rec
CC_vs_CT + TT
0.069
1.28
0.98
1.66
C
T
T (0.2914
T T
40
(0.0903)
32
(0.0706)




MEGA1
rec
CC_vs_CT + TT
0.013
1.2
1.04
1.38
C
T
T (0.2781
T T
86
(0.0618)
126
(0.072)




LETS
Gen
CC_vs_TT
0.615
0.88
0.53
1.45
C
T
T (0.2914
T T
40
(0.0903)
32
(0.0706)





Gen
CT_vs_TT
0.086
0.64
0.38
1.06
C
T
T (0.2914
T T
40
(0.0903)
32
(0.0706)




MEGA1
Gen
CC_vs_TT
0.114
1.26
0.95
1.69
C
T
T (0.2781
T T
86
(0.0618)
126
(0.072)





Gen
CT_vs_TT
0.666
1.07
0.79
1.44
C
T
T (0.2781
T T
86
(0.0618)
126
(0.072)


hCV3187716
AGTR1
LETS
dom
CC + CA_vs_AA
0.096
1.25
0.96
1.63
C
A
C (0.2931
C C
44
(0.1005)
39
(0.0872)



(rs5186)
MEGA1
add
A_vs_C
0.002
1.19
1.06
1.33
A
C
C (0.3088
C C
102
(0.0759)
165
(0.0942)




LETS
Gen
AA_vs_CC
0.292
0.77
0.48
1.25
A
C
C (0.2931
C C
44
(0.1005)
39
(0.0872)





Gen
AC_vs_CC
0.782
0.93
0.58
1.51
A
C
C (0.2931
C C
44
(0.1005)
39
(0.0872)




MEGA1
Gen
AA_vs_CC
0.018
1.38
1.06
1.8
A
C
C (0.3088
C C
102
(0.0759)
165
(0.0942)





Gen
AC_vs_CC
0.343
1.14
0.87
1.49
A
C
C (0.3088
C C
102
(0.0759)
165
(0.0942)


hCV9493081
AKT3
LETS
add
T_vs_C
4E−04
1.45
1.18
1.78
T
C
T (0.2639
T T
50
(0.1131)
32
(0.071)



(rs1058304)
MEGA1
add
T_vs_C
0.008
1.16
1.04
1.29
T
C
T (0.286
T T
152
(0.1126)
128
(0.0729)




LETS
Gen
TC_vs_CC
0.004
1.5
1.13
1.98
T
C
T (0.2639
T T
50
(0.1131)
32
(0.071)





Gen
TT_vs_CC
0.004
2.01
1.24
3.26
T
C
T (0.2639
T T
50
(0.1131)
32
(0.071)




MEGA1
Gen
TC_vs_CC
0.922
1.01
0.87
1.17
T
C
T (0.286
T T
152
(0.1126)
128
(0.0729)





Gen
TT_vs_CC
2E−04
1.62
1.25
2.09
T
C
T (0.286
T T
152
(0.1126)
128
(0.0729)


hCV30690780
AKT3
LETS
add
C_vs_A
4E−05
1.58
1.27
1.96
C
A
C (0.204
C C
39
(0.0888)
21
(0.0466)



(rs10737888)
MEGA1
add
C_vs_A
0.001
1.21
1.08
1.36
C
A
C (0.2294
C C
114
(0.0845)
89
(0.051)




LETS
Gen
CA_vs_AA
9E−04
1.61
1.21
2.13
C
A
C (0.204
C C
39
(0.0888)
21
(0.0466)





Gen
CC_vs_AA
0.002
2.4
1.37
4.19
C
A
C (0.204
C C
39
(0.0888)
21
(0.0466)




MEGA1
Gen
CA_vs_AA
0.256
1.09
0.94
1.27
C
A
C (0.2294
C C
114
(0.0845)
89
(0.051)





Gen
CC_vs_AA
1E−04
1.78
1.33
2.38
C
A
C (0.2294
C C
114
(0.0845)
89
(0.051)


hCV31523557
AKT3
LETS
add
A_vs_G
2E−04
1.57
1.24
1.98
A
G
A (0.1667
A A
24
(0.0544)
15
(0.0333)



(rs10754807)
MEGA1
add
A_vs_G
0.002
1.21
1.07
1.36
A
G
A (0.1935
A A
74
(0.0548)
74
(0.0421)




LETS
Gen
AA_vs_GG
0.044
1.98
1.02
3.86
A
G
A (0.1667
A A
24
(0.0544)
15
(0.0333)





Gen
AG_vs_GG
4E−04
1.68
1.26
2.25
A
G
A (0.1667
A A
24
(0.0544)
15
(0.0333)




MEGA1
Gen
AA_vs_GG
0.043
1.41
1.01
1.97
A
G
A (0.1935
A A
74
(0.0548)
74
(0.0421)





Gen
AG_vs_GG
0.01
1.22
1.05
1.43
A
G
A (0.1935
A A
74
(0.0548)
74
(0.0421)


hCV26719108
AKT3
LETS
add
C_vs_T
0.002
1.36
1.12
1.66
C
T
C (0.3319
C C
70
(0.1584)
49
(0.1084)



(rs10927035)
MEGA1
add
C_vs_T
0.002
1.18
1.06
1.3
C
T
C (0.3579
C C
222
(0.1649)
225
(0.1292)




LETS
Gen
CC_vs_TT
0.004
1.84
1.21
2.8
C
T
C (0.3319
C C
70
(0.1584)
49
(0.1084)





Gen
CT_vs_TT
0.027
1.38
1.04
1.83
C
T
C (0.3319
C C
70
(0.1584)
49
(0.1084)




MEGA1
Gen
CC_vs_TT
0.002
1.42
1.14
1.77
C
T
C (0.3579
C C
222
(0.1649)
225
(0.1292)





Gen
CT_vs_TT
0.129
1.13
0.97
1.32
C
T
C (0.3579
C C
222
(0.1649)
225
(0.1292)


hCV26719121
AKT3
LETS
add
C_vs_T
1E−04
1.59
1.26
2
C
T
C (0.167
C C
25
(0.0566)
15
(0.0332)



(rs10927041)
MEGA1
add
C_vs_T
0.007
1.18
1.05
1.34
C
T
C (0.1929
C C
72
(0.0534)
73
(0.0416)




LETS
Gen
CC_vs_TT
0.03
2.08
1.07
4.03
C
T
C (0.167
C C
25
(0.0566)
15
(0.0332)





Gen
CT_vs_TT
3E−04
1.69
1.27
2.26
C
T
C (0.167
C C
25
(0.0566)
15
(0.0332)




MEGA1
Gen
CC_vs_TT
0.063
1.38
0.98
1.93
C
T
C (0.1929
C C
72
(0.0534)
73
(0.0416)





Gen
CT_vs_TT
0.026
1.19
1.02
1.39
C
T
C (0.1929
C C
72
(0.0534)
73
(0.0416)


hCV26719227
AKT3
LETS
add
A_vs_C
0.01
1.4
1.08
1.8
A
C
A (0.147
A A
12
(0.0271)
10
(0.0223)



(rs10927065)
MEGA1
add
A_vs_C
0.013
1.18
1.04
1.34
A
C
A (0.1654
A A
52
(0.0385)
51
(0.0291)




LETS
Gen
AA_vs_CC
0.458
1.38
0.59
3.25
A
C
A (0.147
A A
12
(0.0271)
10
(0.0223)





Gen
AC_vs_CC
0.007
1.5
1.12
2.01
A
C
A (0.147
A A
12
(0.0271)
10
(0.0223)




MEGA1
Gen
AA_vs_CC
0.093
1.4
0.94
2.09
A
C
A (0.1654
A A
52
(0.0385)
51
(0.0291)





Gen
AC_vs_CC
0.042
1.18
1.01
1.38
A
C
A (0.1654
A A
52
(0.0385)
51
(0.0291)


hCV31523638
AKT3
LETS
add
A_vs_G
0.003
1.49
1.15
1.93
A
G
A (0.1294
A A
12
(0.0273)
9
(0.0199)



(rs12037013)
MEGA1
add
A_vs_G
0.021
1.18
1.02
1.35
A
G
A (0.1502
A A
40
(0.0296)
36
(0.0205)




LETS
Gen
AA_vs_GG
0.317
1.57
0.65
3.77
A
G
A (0.1294
A A
12
(0.0273)
9
(0.0199)





Gen
AG_vs_GG
0.002
1.6
1.18
2.17
A
G
A (0.1294
A A
12
(0.0273)
9
(0.0199)




MEGA1
Gen
AA_vs_GG
0.075
1.52
0.96
2.4
A
G
A (0.1502
A A
40
(0.0296)
36
(0.0205)





Gen
AG_vs_GG
0.085
1.15
0.98
1.35
A
G
A (0.1502
A A
40
(0.0296)
36
(0.0205)


hCV30690777
AKT3
MEGA1
add
A_vs_G
0.002
1.25
1.08
1.43
A
G
A (0.1439
A A
36
(0.0267)
27
(0.0154)



(rs12045585)
LETS
add
A_vs_G
0.035
1.32
1.02
1.72
A
G
A (0.1396
A A
11
(0.0253)
8
(0.018)




LETS
Gen
AA_vs_GG
0.36
1.54
0.61
3.88
A
G
A (0.1396
A A
11
(0.0253)
8
(0.018)





Gen
AG_vs_GG
0.045
1.36
1.01
1.83
A
G
A (0.1396
A A
11
(0.0253)
8
(0.018)




MEGA1
Gen
AA_vs_GG
0.017
1.85
1.12
3.07
A
G
A (0.1439
A A
36
(0.0267)
27
(0.0154)





Gen
AG_vs_GG
0.021
1.21
1.03
1.42
A
G
A (0.1439
A A
36
(0.0267)
27
(0.0154)


hCV31523650
AKT3
LETS
add
T_vs_C
1E−03
1.47
1.17
1.86
T
C
T (0.18
T T
25
(0.0571)
16
(0.0356)



(rs12048930)
MEGA1
add
T_vs_C
0.026
1.15
1.02
1.29
T
C
T (0.2011
T T
74
(0.0536)
82
(0.0468)




LETS
Gen
TC_vs_CC
0.003
1.55
1.17
2.06
T
C
T (0.18
T T
25
(0.0571)
16
(0.0356)





Gen
TT_vs_CC
0.053
1.9
0.99
3.64
T
C
T (0.18
T T
25
(0.0571)
16
(0.0356)




MEGA1
Gen
TC_vs_CC
0.032
1.18
1.01
1.38
T
C
T (0.2011
T T
74
(0.0536)
82
(0.0468)





Gen
TT_vs_CC
0.228
1.22
0.88
1.7
T
C
T (0.2011
T T
74
(0.0536)
82
(0.0468)


hCV30690778
AKT3
LETS
add
C_vs_T
0.003
1.44
1.14
1.82
C
T
C (0.1718
C C
19
(0.0433)
15
(0.0333)



(rs12140414)
MEGA1
add
C_vs_T
0.04
1.14
1.01
1.3
C
T
C (0.1872
C C
59
(0.0437)
52
(0.0296)




LETS
Gen
CC_vs_TT
0.23
1.53
0.76
3.08
C
T
C (0.1718
C C
19
(0.0433)
15
(0.0333)





Gen
CT_vs_TT
0.002
1.58
1.19
2.1
C
T
C (0.1718
C C
19
(0.0433)
15
(0.0333)




MEGA1
Gen
CC_vs_TT
0.027
1.54
1.05
2.26
C
T
C (0.1872
C C
59
(0.0437)
52
(0.0296)





Gen
CT_vs_TT
0.283
1.09
0.93
1.27
C
T
C (0.1872
C C
59
(0.0437)
52
(0.0296)


hCV31523608
AKT3
MEGA1
add
G_vs_A
0.001
1.19
1.07
1.32
G
A
G (0.3236
G G
186
(0.138)
197
(0.1124)



(rs12744297)
LETS
add
G_vs_A
0.006
1.32
1.08
1.61
G
A
G (0.296
G G
57
(0.1293)
43
(0.0953)




LETS
Gen
GA_vs_AA
0.021
1.39
1.05
1.84
G
A
G (0.296
G G
57
(0.1293)
43
(0.0953)





Gen
GG_vs_AA
0.026
1.65
1.06
2.57
G
A
G (0.296
G G
57
(0.1293)
43
(0.0953)




MEGA1
Gen
GA_vs_AA
0.013
1.21
1.04
1.41
G
A
G (0.3236
G G
186
(0.138)
197
(0.1124)





Gen
GG_vs_AA
0.004
1.39
1.11
1.75
G
A
G (0.3236
G G
186
(0.138)
197
(0.1124)


hCV233148
AKT3
LETS
add
C_vs_G
3E−04
1.45
1.18
1.78
C
G
C (0.2627
C C
50
(0.1129)
32
(0.0706)



(rs1417121)
MEGA1
add
C_vs_G
0.001
1.2
1.08
1.33
C
G
C (0.2854
C C
163
(0.1174)
129
(0.0734)




LETS
Gen
CC_vs_GG
0.004
2.02
1.25
3.27
C
G
C (0.2627
C C
50
(0.1129)
32
(0.0706)





Gen
CG_vs_GG
0.004
1.5
1.14
1.98
C
G
C (0.2627
C C
50
(0.1129)
32
(0.0706)




MEGA1
Gen
CC_vs_GG
3E−05
1.71
1.33
2.2
C
G
C (0.2854
C C
163
(0.1174)
129
(0.0734)





Gen
CG_vs_GG
0.591
1.04
0.9
1.21
C
G
C (0.2854
C C
163
(0.1174)
129
(0.0734)


hCV12073840
AKT3
LETS
Gen
TC_vs_CC
0.004
1.5
1.14
1.98
T
C
T (0.2228
T T
29
(0.0664)
24
(0.0532)



(rs14403)
MEGA1
Gen
TT_vs_CC
0.028
1.42
1.04
1.93
T
C
T (0.2392
T T
90
(0.0668)
85
(0.0484)




LETS
Gen
TC_vs_CC
0.004
1.5
1.14
1.98
T
C
T (0.2228
T T
29
(0.0664)
24
(0.0532)





Gen
TT_vs_CC
0.169
1.49
0.84
2.63
T
C
T (0.2228
T T
29
(0.0664)
24
(0.0532)




MEGA1
Gen
TC_vs_CC
0.808
1.02
0.88
1.18
T
C
T (0.2392
T T
90
(0.0668)
85
(0.0484)





Gen
TT_vs_CC
0.028
1.42
1.04
1.93
T
C
T (0.2392
T T
90
(0.0668)
85
(0.0484)


hCV1678674
AKT3
LETS
add
C_vs_T
4E−04
1.5
1.2
1.88
C
T
C (0.1808
C C
31
(0.0711)
18
(0.0402)



(rs1458023)
MEGA1
add
C_vs_T
0.006
1.18
1.05
1.33
C
T
C (0.2008
C C
80
(0.0593)
82
(0.0468)




LETS
Gen
CC_vs_TT
0.015
2.12
1.16
3.88
C
T
C (0.1808
C C
31
(0.0711)
18
(0.0402)





Gen
CT_vs_TT
0.003
1.54
1.16
2.06
C
T
C (0.1808
C C
31
(0.0711)
18
(0.0402)




MEGA1
Gen
CC_vs_TT
0.057
1.37
0.99
1.88
C
T
C (0.2008
C C
80
(0.0593)
82
(0.0468)





Gen
CT_vs_TT
0.021
1.2
1.03
1.4
C
T
C (0.2008
C C
80
(0.0593)
82
(0.0468)


hCV97631
AKT3
LETS
add
G_vs_T
1E−04
1.55
1.24
1.92
G
T
G (0.2051
G G
35
(0.0794)
21
(0.0466)



(rs1538773)
MEGA1
add
G_vs_T
0.006
1.18
1.05
1.32
G
T
G (0.2279
G G
102
(0.0756)
89
(0.0508)




LETS
Gen
GG_vs_TT
0.009
2.14
1.21
3.77
G
T
G (0.2051
G G
35
(0.0794)
21
(0.0466)





Gen
GT_vs_TT
6E−04
1.63
1.23
2.16
G
T
G (0.2051
G G
35
(0.0794)
21
(0.0466)




MEGA1
Gen
GG_vs_TT
0.003
1.59
1.18
2.14
G
T
G (0.2279
G G
102
(0.0756)
89
(0.0508)





Gen
GT_vs_TT
0.224
1.1
0.94
1.28
G
T
G (0.2279
G G
102
(0.0756)
89
(0.0508)


hCV8688111
AKT3
LETS
add
C_vs_G
0.001
1.49
1.17
1.89
C
G
C (0.167
C C
20
(0.0459)
12
(0.0269)



(rs1578275)
MEGA1
add
C_vs_G
0.047
1.14
1
1.29
C
G
C (0.1846
C C
58
(0.0432)
52
(0.0298)




LETS
Gen
CC_vs_GG
0.064
2
0.96
4.18
C
G
C (0.167
C C
20
(0.0459)
12
(0.0269)





Gen
CG_vs_GG
0.004
1.53
1.15
2.04
C
G
C (0.167
C C
20
(0.0459)
12
(0.0269)




MEGA1
Gen
CC_vs_GG
0.036
1.51
1.03
2.22
C
G
C (0.1846
C C
58
(0.0432)
52
(0.0298)





Gen
CG_vs_GG
0.291
1.09
0.93
1.27
C
G
C (0.1846
C C
58
(0.0432)
52
(0.0298)


hCV15885425
AKT3
LETS
add
C_vs_A
1E−04
1.57
1.24
1.97
C
A
C (0.1726
C C
27
(0.0615)
15
(0.0332)



(rs2290754)
MEGA1
add
C_vs_A
0.019
1.15
1.02
1.3
C
A
C (0.199
C C
76
(0.0564)
85
(0.0485)




LETS
Gen
CA_vs_AA
0.001
1.62
1.21
2.15
C
A
C (0.1726
C C
27
(0.0615)
15
(0.0332)





Gen
CC_vs_AA
0.015
2.25
1.17
4.32
C
A
C (0.1726
C C
27
(0.0615)
15
(0.0332)




MEGA1
Gen
CA_vs_AA
0.026
1.19
1.02
1.39
C
A
C (0.199
C C
76
(0.0564)
85
(0.0485)





Gen
CC_vs_AA
0.184
1.24
0.9
1.72
C
A
C (0.199
C C
76
(0.0564)
85
(0.0485)


hCV1678682
AKT3
LETS
add
T_vs_G
3E−04
1.51
1.21
1.9
T
G
T (0.1752
T T
30
(0.0683)
18
(0.0402)



(rs320339)
MEGA1
add
T_vs_G
0.002
1.21
1.07
1.37
T
G
T (0.1945
T T
84
(0.0624)
75
(0.0428)




LETS
Gen
TG_vs_GG
0.002
1.59
1.19
2.13
T
G
T (0.1752
T T
30
(0.0683)
18
(0.0402)





Gen
TT_vs_GG
0.021
2.04
1.11
3.75
T
G
T (0.1752
T T
30
(0.0683)
18
(0.0402)




MEGA1
Gen
TG_vs_GG
0.04
1.18
1.01
1.37
T
G
T (0.1945
T T
84
(0.0624)
75
(0.0428)





Gen
TT_vs_GG
0.006
1.57
1.14
2.17
T
G
T (0.1945
T T
84
(0.0624)
75
(0.0428)


hCV29210363
AKT3
LETS
add
G_vs_A
5E−05
1.56
1.26
1.94
G
A
G (0.2062
G G
38
(0.0868)
22
(0.0488)



(rs6656918)
MEGA1
add
G_vs_A
0.003
1.19
1.06
1.34
G
A
G (0.2303
G G
111
(0.0823)
91
(0.0519)




LETS
Gen
GA_vs_AA
6E−04
1.64
1.24
2.17
G
A
G (0.2062
G G
38
(0.0868)
22
(0.0488)





Gen
GG_vs_AA
0.004
2.24
1.29
3.9
G
A
G (0.2062
G G
38
(0.0868)
22
(0.0488)




MEGA1
Gen
GA_vs_AA
0.289
1.09
0.93
1.26
G
A
G (0.2303
G G
111
(0.0823)
91
(0.0519)





Gen
GG_vs_AA
4E−04
1.69
1.26
2.27
G
A
G (0.2303
G G
111
(0.0823)
91
(0.0519)


hCV31523643
AKT3
LETS
add
G_vs_A
4E−04
1.52
1.21
1.91
G
A
G (0.1737
G G
27
(0.0611)
15
(0.0332)



(rs6671475)
MEGA1
add
G_vs_A
0.014
1.16
1.03
1.31
G
A
G (0.198
G G
76
(0.0563)
80
(0.0457)




LETS
Gen
GA_vs_AA
0.003
1.55
1.16
2.06
G
A
G (0.1737
G G
27
(0.0611)
15
(0.0332)





Gen
GG_vs_AA
0.018
2.2
1.14
4.22
G
A
G (0.1737
G G
27
(0.0611)
15
(0.0332)




MEGA1
Gen
GA_vs_AA
0.038
1.18
1.01
1.37
G
A
G (0.198
G G
76
(0.0563)
80
(0.0457)





Gen
GG_vs_AA
0.1
1.32
0.95
1.82
G
A
G (0.198
G G
76
(0.0563)
80
(0.0457)


hCV26719113
AKT3
LETS
add
T_vs_C
2E−04
1.58
1.24
2
T
C
T (0.1602
T T
24
(0.0557)
16
(0.0364)



(rs7517340)
MEGA1
add
T_vs_C
0.003
1.2
1.07
1.36
T
C
T (0.1871
T T
78
(0.058)
67
(0.0384)




LETS
Gen
TC_vs_CC
2E−04
1.76
1.31
2.36
T
C
T (0.1602
T T
24
(0.0557)
16
(0.0364)





Gen
TT_vs_CC
0.061
1.87
0.97
3.59
T
C
T (0.1602
T T
24
(0.0557)
16
(0.0364)




MEGA1
Gen
TC_vs_CC
0.074
1.15
0.99
1.35
T
C
T (0.1871
T T
78
(0.058)
67
(0.0384)





Gen
TT_vs_CC
0.005
1.62
1.15
2.27
T
C
T (0.1871
T T
78
(0.058)
67
(0.0384)


hCV26034142
AKT3
LETS
add
C_vs_T
0.025
1.23
1.03
1.47
C
T
C (0.4347
C C
112
(0.2534)
96
(0.2124)



(rs9428576)
MEGA1
rec
CC_vs_CT + TT
0.01
1.26
1.06
1.49
C
T
C (0.4504
C C
318
(0.2359)
346
(0.1974)




LETS
Gen
CC_vs_TT
0.029
1.49
1.04
2.15
C
T
C (0.4347
C C
112
(0.2534)
96
(0.2124)





Gen
CT_vs_TT
0.067
1.33
0.98
1.81
C
T
C (0.4347
C C
112
(0.2534)
96
(0.2124)




MEGA1
Gen
CC_vs_TT
0.066
1.21
0.99
1.48
C
T
C (0.4504
C C
318
(0.2359)
346
(0.1974)





Gen
CT_vs_TT
0.454
0.94
0.8
1.11
C
T
C (0.4504
C C
318
(0.2359)
346
(0.1974)


hCV2303891
APOH
MEGA1
add
C_vs_G
0.007
1.38
1.09
1.76
C
G
G (0.0555
G G
4
(0.0029)
3
(0.0017)



(rs1801690)
LETS
add
C_vs_G
0.042
1.65
1.02
2.68
C
G
G (0.0512
G G
0
(0)
1
(0.0022)




LETS
Gen
CC_vs_GG
0.969
291630
####
####
C
G
G (0.0512
G G
0
(0)
1
(0.0022)





Gen
CG_vs_GG
0.97
188937
####
####
C
G
G (0.0512
G G
0
(0)
1
(0.0022)




MEGA1
Gen
CC_vs_GG
0.528
0.62
0.14
2.76
C
G
G (0.0555
G G
4
(0.0029)
3
(0.0017)





Gen
CG_vs_GG
0.263
0.42
0.09
1.92
C
G
G (0.0555
G G
4
(0.0029)
3
(0.0017)


hCV2456747
C1orf114
MEGA1
add
A_vs_G
1E−04
1.22
1.1
1.35
A
G
A (0.3342
A A
212
(0.152)
215
(0.1229)



(rs3820059)
LETS
add
A_vs_G
0.004
1.34
1.1
1.64
A
G
A (0.2969
A A
55
(0.1244)
44
(0.0971)




LETS
Gen
AA_vs_GG
0.035
1.61
1.03
2.51
A
G
A (0.2969
A A
55
(0.1244)
44
(0.0971)





Gen
AG_vs_GG
0.005
1.49
1.13
1.98
A
G
A (0.2969
A A
55
(0.1244)
44
(0.0971)




MEGA1
Gen
AA_vs_GG
1E−03
1.45
1.16
1.8
A
G
A (0.3342
A A
212
(0.152)
215
(0.1229)





Gen
AG_vs_GG
0.002
1.27
1.09
1.48
A
G
A (0.3342
A A
212
(0.152)
215
(0.1229)


hCV2403368
C1QTNF6
LETS
rec
GG_vs_GC + CC
0.02
1.37
1.05
1.79
G
C
C (0.2594
C C
25
(0.0566)
26
(0.0574)



(rs229526)
MEGA1
rec
GG_vs_GC + CC
0.033
1.17
1.01
1.35
G
C
C (0.2484
C C
78
(0.056)
106
(0.0604)




LETS
Gen
GC_vs_CC
0.521
0.82
0.46
1.49
G
C
C (0.2594
C C
25
(0.0566)
26
(0.0574)





Gen
GG_vs_CC
0.615
1.16
0.65
2.06
G
C
C (0.2594
C C
25
(0.0566)
26
(0.0574)




MEGA1
Gen
GC_vs_CC
0.911
0.98
0.72
1.35
G
C
C (0.2484
C C
78
(0.056)
106
(0.0604)





Gen
GG_vs_CC
0.371
1.15
0.85
1.56
G
C
C (0.2484
C C
78
(0.056)
106
(0.0604)


hCV7574127
C6orf167
LETS
add
A_vs_G
0.091
1.18
0.97
1.43
A
G
G (0.4746
G G
80
(0.181)
97
(0.2141)



(rs1737145)
MEGA1
add
A_vs_G
0.009
1.14
1.03
1.26
A
G
G (0.4837
G G
292
(0.2108)
424
(0.242)




LETS
Gen
AA_vs_GG
0.097
1.38
0.94
2.03
A
G
G (0.4746
G G
80
(0.181)
97
(0.2141)





Gen
AG_vs_GG
0.414
1.16
0.82
1.64
A
G
G (0.4746
G G
80
(0.181)
97
(0.2141)




MEGA1
Gen
AA_vs_GG
0.01
1.3
1.07
1.58
A
G
G (0.4837
G G
292
(0.2108)
424
(0.242)





Gen
AG_vs_GG
0.164
1.14
0.95
1.36
A
G
G (0.4837
G G
292
(0.2108)
424
(0.242)


hCV25959498
C7orf46
LETS
add
G_vs_A
0.034
1.48
1.03
2.14
G
A
A (0.083
A A
1
(0.0023)
6
(0.0133)



(rs34518648)
MEGA1
add
G_vs_A
0.038
1.22
1.01
1.47
G
A
A (0.0843
A A
6
(0.0043)
17
(0.0097)




LETS
Gen
GA_vs_AA
0.166
4.57
0.53
39.2
G
A
A (0.083
A A
1
(0.0023)
6
(0.0133)





Gen
GG_vs_AA
0.093
6.16
0.74
51.3
G
A
A (0.083
A A
1
(0.0023)
6
(0.0133)




MEGA1
Gen
GA_vs_AA
0.159
1.98
0.77
5.12
G
A
A (0.0843
A A
6
(0.0043)
17
(0.0097)





Gen
GG_vs_AA
0.079
2.31
0.91
5.88
G
A
A (0.0843
A A
6
(0.0043)
17
(0.0097)


hCV25959466
C7orf46
MEGA1
add
T_vs_C
0.03
1.23
1.02
1.48
T
C
C (0.0854
C C
7
(0.005)
18
(0.0103)



(rs35495590)
LETS
add
T_vs_C
0.048
1.45
1
2.1
T
C
C (0.0808
C C
1
(0.0023)
5
(0.0111)




LETS
Gen
TC_vs_CC
0.229
3.81
0.43
33.7
T
C
C (0.0808
C C
1
(0.0023)
5
(0.0111)





Gen
TT_vs_CC
0.137
5.12
0.6
44
T
C
C (0.0808
C C
1
(0.0023)
5
(0.0111)




MEGA1
Gen
TC_vs_CC
0.206
1.78
0.73
4.35
T
C
C (0.0854
C C
7
(0.005)
18
(0.0103)





Gen
TT_vs_CC
0.096
2.11
0.88
5.06
T
C
C (0.0854
C C
7
(0.005)
18
(0.0103)


hCV25768636
CCDC36
MEGA1
rec
AA_vs_AG + GG
0.033
1.26
1.02
1.56
A
G
A (0.3444
A A
188
(0.1356)
194
(0.1105)



(rs4279134)
LETS
rec
AA_vs_AG + GG
0.036
1.53
1.03
2.27
A
G
A (0.3271
A A
68
(0.1538)
48
(0.1064)




LETS
Gen
AA_vs_GG
0.022
1.63
1.07
2.49
A
G
A (0.3271
A A
68
(0.1538)
48
(0.1064)





Gen
AG_vs_GG
0.359
1.14
0.86
1.51
A
G
A (0.3271
A A
68
(0.1538)
48
(0.1064)




MEGA1
Gen
AA_vs_GG
0.033
1.28
1.02
1.61
A
G
A (0.3444
A A
188
(0.1356)
194
(0.1105)





Gen
AG_vs_GG
0.698
1.03
0.89
1.2
A
G
A (0.3444
A A
188
(0.1356)
194
(0.1105)


hCV25991132
CCDC41 ( )
MEGA1
rec
GG_vs_GA + AA
0.018
1.26
1.04
1.53
G
A
A (0.0924
A A
13
(0.0094)
6
(0.0034)




LETS
rec
GG_vs_GA + AA
0.041
1.46
1.02
2.1
G
A
A (0.0971
A A
1
(0.0023)
5
(0.011)




LETS
Gen
GA_vs_AA
0.236
3.72
0.42
32.7
G
A
A (0.0971
A A
1
(0.0023)
5
(0.011)





Gen
GG_vs_AA
0.134
5.19
0.6
44.6
G
A
A (0.0971
A A
1
(0.0023)
5
(0.011)




MEGA1
Gen
GA_vs_AA
0.013
0.29
0.11
0.77
G
A
A (0.0924
A A
13
(0.0094)
6
(0.0034)





Gen
GG_vs_AA
0.052
0.38
0.14
1.01
G
A
A (0.0924
A A
13
(0.0094)
6
(0.0034)


hCV3164397
CMYA5
LETS
rec
CC_vs_CT + TT
0.004
1.55
1.15
2.08
C
T
T (0.1678
T T
9
(0.0204)
8
(0.0177)



(rs10043986)
MEGA1
dom
CC + CT_vs_TT
0.015
2.28
1.18
4.42
C
T
T (0.1359
T T
12
(0.0086)
34
(0.0194)




LETS
Gen
CC_vs_TT
0.959
0.98
0.37
2.56
C
T
T (0.1678
T T
9
(0.0204)
8
(0.0177)





Gen
CT_vs_TT
0.323
0.61
0.23
1.63
C
T
T (0.1678
T T
9
(0.0204)
8
(0.0177)




MEGA1
Gen
CC_vs_TT
0.017
2.24
1.16
4.35
C
T
T (0.1359
T T
12
(0.0086)
34
(0.0194)





Gen
CT_vs_TT
0.01
2.41
1.23
4.73
C
T
T (0.1359
T T
12
(0.0086)
34
(0.0194)


hCV3230083
CYP4V2
MEGA1
Gen
AC_vs_CC
4E−04
1.35
1.14
1.59
A
C
A (0.4278
A A
282
(0.2098)
329
(0.1877)



(rs10013653)
LETS
Gen
AC_vs_CC
0.048
1.37
1
1.86
A
C
A (0.4533
A A
97
(0.2195)
100
(0.2222)




LETS
Gen
AA_vs_CC
0.342
1.2
0.83
1.74
A
C
A (0.4533
A A
97
(0.2195)
100
(0.2222)





Gen
AC_vs_CC
0.048
1.37
1
1.86
A
C
A (0.4533
A A
97
(0.2195)
100
(0.2222)




MEGA1
Gen
AA_vs_CC
0.002
1.39
1.13
1.7
A
C
A (0.4278
A A
282
(0.2098)
329
(0.1877)





Gen
AC_vs_CC
4E−04
1.35
1.14
1.59
A
C
A (0.4278
A A
282
(0.2098)
329
(0.1877)


hCV25990131
CYP4V2
MEGA1
add
A_vs_C
0.001
1.19
1.07
1.32
A
C
C (0.36
C C
149
(0.1067)
229
(0.1306)



(rs13146272)
LETS
add
A_vs_C
0.049
1.22
1
1.49
A
C
C (0.3492
C C
32
(0.0726)
63
(0.1397)




LETS
Gen
AA_vs_CC
0.003
2.03
1.27
3.24
A
C
C (0.3492
C C
32
(0.0726)
63
(0.1397)





Gen
AC_vs_CC
0.001
2.18
1.36
3.48
A
C
C (0.3492
C C
32
(0.0726)
63
(0.1397)




MEGA1
Gen
AA_vs_CC
0.006
1.38
1.1
1.74
A
C
C (0.36
C C
149
(0.1067)
229
(0.1306)





Gen
AC_vs_CC
0.251
1.15
0.91
1.44
A
C
C (0.36
C C
149
(0.1067)
229
(0.1306)


hCV15968043
CYP4V2
MEGA1
dom
AA + AT_vs_TT
2E−04
1.33
1.14
1.55
A
T
A (0.4126
A A
292
(0.2108)
300
(0.172)



(rs2292423)
LETS
dom
AA + AT_vs_TT
0.043
1.34
1.01
1.78
A
T
A (0.4327
A A
97
(0.219)
92
(0.2031)




LETS
Gen
AA_vs_TT
0.14
1.32
0.91
1.92
A
T
A (0.4327
A A
97
(0.219)
92
(0.2031)





Gen
AT_vs_TT
0.052
1.35
1
1.83
A
T
A (0.4327
A A
97
(0.219)
92
(0.2031)




MEGA1
Gen
AA_vs_TT
1E−04
1.49
1.21
1.83
A
T
A (0.4126
A A
292
(0.2108)
300
(0.172)





Gen
AT_vs_TT
0.003
1.27
1.08
1.5
A
T
A (0.4126
A A
292
(0.2108)
300
(0.172)


hCV3230096
CYP4V2
LETS
dom
TT + TC_vs_CC
0.058
1.32
0.99
1.76
T
C
T (0.4369
T T
95
(0.2149)
92
(0.2035)



(rs3817184)
MEGA1
dom
TT + TC_vs_CC
0.003
1.26
1.08
1.47
T
C
T (0.4164
T T
301
(0.2165)
309
(0.1776)




LETS
Gen
TC_vs_CC
0.063
1.34
0.98
1.81
T
C
T (0.4369
T T
95
(0.2149)
92
(0.2035)





Gen
TT_vs_CC
0.193
1.28
0.88
1.86
T
C
T (0.4369
T T
95
(0.2149)
92
(0.2035)




MEGA1
Gen
TC_vs_CC
0.027
1.2
1.02
1.41
T
C
T (0.4164
T T
301
(0.2165)
309
(0.1776)





Gen
TT_vs_CC
5E−04
1.43
1.17
1.75
T
C
T (0.4164
T T
301
(0.2165)
309
(0.1776)


hCV11786147
CYP4V2
LETS
dom
TT + TG_vs_GG
0.052
1.33
1
1.77
T
G
T (0.433
T T
94
(0.2151)
90
(0.2009)



(rs4862662)
MEGA1
dom
TT + TG_vs_GG
0.003
1.26
1.09
1.47
T
G
T (0.4111
T T
278
(0.2065)
303
(0.1731)




LETS
Gen
TG_vs_GG
0.06
1.34
0.99
1.82
T
G
T (0.433
T T
94
(0.2151)
90
(0.2009)





Gen
TT_vs_GG
0.164
1.31
0.9
1.9
T
G
T (0.433
T T
94
(0.2151)
90
(0.2009)




MEGA1
Gen
TG_vs_GG
0.018
1.22
1.03
1.43
T
G
T (0.4111
T T
278
(0.2065)
303
(0.1731)





Gen
TT_vs_GG
0.001
1.4
1.14
1.72
T
G
T (0.4111
T T
278
(0.2065)
303
(0.1731)


hCV3230084
CYP4V2
MEGA1
Gen
TC_vs_CC
0.002
1.29
1.1
1.51
T
C
T (0.3945
T T
247
(0.1839)
288
(0.1648)



(rs7682918)
LETS
Gen
TC_vs_CC
0.031
1.39
1.03
1.88
T
C
T (0.4257
T T
75
(0.1705)
87
(0.1929)




LETS
Gen
TC_vs_CC
0.031
1.39
1.03
1.88
T
C
T (0.4257
T T
75
(0.1705)
87
(0.1929)





Gen
TT_vs_CC
0.792
1.05
0.71
1.55
T
C
T (0.4257
T T
75
(0.1705)
87
(0.1929)




MEGA1
Gen
TC_vs_CC
0.002
1.29
1.1
1.51
T
C
T (0.3945
T T
247
(0.1839)
288
(0.1648)





Gen
TT_vs_CC
0.009
1.32
1.07
1.63
T
C
T (0.3945
T T
247
(0.1839)
288
(0.1648)


hCV26265231
CYP4V2
MEGA1
dom
AA + AG_vs_GG
8E−04
1.32
1.12
1.55
A
G
A (0.459
A A
335
(0.2496)
373
(0.2141)



(rs7684025)
LETS
dom
AA + AG_vs_GG
0.017
1.44
1.07
1.95
A
G
A (0.4812
A A
116
(0.2619)
116
(0.2561)




LETS
Gen
AA_vs_GG
0.114
1.34
0.93
1.94
A
G
A (0.4812
A A
116
(0.2619)
116
(0.2561)





Gen
AG_vs_GG
0.013
1.5
1.09
2.07
A
G
A (0.4812
A A
116
(0.2619)
116
(0.2561)




MEGA1
Gen
AA_vs_GG
6E−04
1.43
1.16
1.75
A
G
A (0.459
A A
335
(0.2496)
373
(0.2141)





Gen
AG_vs_GG
0.006
1.27
1.07
1.51
A
G
A (0.459
A A
335
(0.2496)
373
(0.2141)


hCV9860072
DHX38
LETS
Gen
AC_vs_CC
0.013
1.43
1.08
1.91
A
C
A (0.3521
A A
62
(0.14)
62
(0.1369)



(rs1050362)
MEGA1
Gen
AA_vs_CC
0.042
1.26
1.01
1.57
A
C
A (0.354
A A
205
(0.1488)
220
(0.1259)




LETS
Gen
AA_vs_CC
0.289
1.25
0.83
1.88
A
C
A (0.3521
A A
62
(0.14)
62
(0.1369)





Gen
AC_vs_CC
0.013
1.43
1.08
1.91
A
C
A (0.3521
A A
62
(0.14)
62
(0.1369)




MEGA1
Gen
AA_vs_CC
0.042
1.26
1.01
1.57
A
C
A (0.354
A A
205
(0.1488)
220
(0.1259)





Gen
AC_vs_CC
0.385
1.07
0.92
1.25
A
C
A (0.354
A A
205
(0.1488)
220
(0.1259)


hCV2103346
DKFZP564J102
LETS
rec
CC_vs_CT + TT
0.016
1.5
1.08
2.08
C
T
C (0.4257
C C
104
(0.2358)
77
(0.1707)



(rs11733307)
MEGA1
dom
CC + CT_vs_TT
0.021
1.2
1.03
1.4
C
T
C (0.4422
C C
301
(0.2231)
359
(0.2046)




LETS
Gen
CC_vs_TT
0.108
1.36
0.94
1.98
C
T
C (0.4257
C C
104
(0.2358)
77
(0.1707)





Gen
CT_vs_TT
0.286
0.85
0.63
1.15
C
T
C (0.4257
C C
104
(0.2358)
77
(0.1707)




MEGA1
Gen
CC_vs_TT
0.036
1.24
1.01
1.52
C
T
C (0.4422
C C
301
(0.2231)
359
(0.2046)





Gen
CT_vs_TT
0.045
1.18
1
1.4
C
T
C (0.4422
C C
301
(0.2231)
359
(0.2046)


hCV12086148
DKFZP564J102
LETS
rec
GG_vs_GA + AA
0.065
1.29
0.98
1.69
G
A
A (0.2417
A A
24
(0.0544)
25
(0.0554)



(rs1877321)
MEGA1
Gen
GG_vs_AA
0.027
1.47
1.04
2.06
G
A
A (0.2363
A A
56
(0.0404)
100
(0.0573)




LETS
Gen
GA_vs_AA
0.613
0.86
0.47
1.56
G
A
A (0.2417
A A
24
(0.0544)
25
(0.0554)





Gen
GG_vs_AA
0.69
1.13
0.63
2.02
G
A
A (0.2417
A A
24
(0.0544)
25
(0.0554)




MEGA1
Gen
GA_vs_AA
0.056
1.4
0.99
1.99
G
A
A (0.2363
A A
56
(0.0404)
100
(0.0573)





Gen
GG_vs_AA
0.027
1.47
1.04
2.06
G
A
A (0.2363
A A
56
(0.0404)
100
(0.0573)


hCV25473516
DUSP11
LETS
Gen
TT_vs_CC
0.074
1.46
0.96
2.22
T
C
T (0.365
T T
70
(0.1584)
53
(0.1173)



(rs2272051)
MEGA1
Gen
TT_vs_CC
0.011
1.33
1.07
1.67
T
C
T (0.3501
T T
206
(0.1483)
209
(0.1194)




LETS
Gen
TC_vs_CC
0.698
1.06
0.8
1.41
T
C
T (0.365
T T
70
(0.1584)
53
(0.1173)





Gen
TT_vs_CC
0.074
1.46
0.96
2.22
T
C
T (0.365
T T
70
(0.1584)
53
(0.1173)




MEGA1
Gen
TC_vs_CC
0.355
1.07
0.92
1.25
T
C
T (0.3501
T T
206
(0.1483)
209
(0.1194)





Gen
TT_vs_CC
0.011
1.33
1.07
1.67
T
C
T (0.3501
T T
206
(0.1483)
209
(0.1194)


hCV15871021
EBF1
LETS
rec
GG_vs_GA + AA
0.013
1.41
1.08
1.86
G
A
A (0.4084
A A
70
(0.1584)
66
(0.1457)



(rs2072495)
MEGA1
dom
GG + GA_vs_AA
0.007
1.33
1.08
1.63
G
A
A (0.3927
A A
168
(0.1206)
269
(0.154)




LETS
Gen
GA_vs_AA
0.157
0.76
0.51
1.11
G
A
A (0.4084
A A
70
(0.1584)
66
(0.1457)





Gen
GG_vs_AA
0.506
1.15
0.77
1.71
G
A
A (0.4084
A A
70
(0.1584)
66
(0.1457)




MEGA1
Gen
GA_vs_AA
0.008
1.34
1.08
1.67
G
A
A (0.3927
A A
168
(0.1206)
269
(0.154)





Gen
GG_vs_AA
0.019
1.31
1.04
1.64
G
A
A (0.3927
A A
168
(0.1206)
269
(0.154)


hCV491830
EPS8L2
LETS
add
T_vs_C
0.018
1.26
1.04
1.52
T
C
C (0.4601
C C
74
(0.1689)
94
(0.2084)



(rs3087546)
MEGA1
add
T_vs_C
0.027
1.12
1.01
1.24
T
C
C (0.4385
C C
236
(0.17)
356
(0.2035)




LETS
Gen
TC_vs_CC
0.437
1.15
0.81
1.65
T
C
C (0.4601
C C
74
(0.1689)
94
(0.2084)





Gen
TT_vs_CC
0.026
1.54
1.05
2.26
T
C
C (0.4601
C C
74
(0.1689)
94
(0.2084)




MEGA1
Gen
TC_vs_CC
0.041
1.22
1.01
1.49
T
C
C (0.4385
C C
236
(0.17)
356
(0.2035)





Gen
TT_vs_CC
0.017
1.28
1.04
1.57
T
C
C (0.4385
C C
236
(0.17)
356
(0.2035)


hCV2017876
EPS8L3
LETS
add
G_vs_A
0.069
1.18
0.99
1.42
G
A
A (0.4889
A A
96
(0.2167)
113
(0.25)



(rs3818562)
MEGA1
add
G_vs_A
0.025
1.12
1.01
1.24
G
A
A (0.4794
A A
282
(0.2049)
394
(0.2254)




LETS
Gen
GA_vs_AA
0.572
1.1
0.79
1.54
G
A
A (0.4889
A A
96
(0.2167)
113
(0.25)





Gen
GG_vs_AA
0.077
1.39
0.97
1.99
G
A
A (0.4889
A A
96
(0.2167)
113
(0.25)




MEGA1
Gen
GA_vs_AA
0.498
1.07
0.89
1.28
G
A
A (0.4794
A A
282
(0.2049)
394
(0.2254)





Gen
GG_vs_AA
0.03
1.25
1.02
1.53
G
A
A (0.4794
A A
282
(0.2049)
394
(0.2254)


hCV12066124
F11
MEGA1
add
C_vs_T
2E−07
1.31
1.18
1.44
C
T
T (0.4786
T T
233
(0.1675)
407
(0.232)



(rs2036914)
LETS
add
C_vs_T
0.013
1.27
1.05
1.53
C
T
T (0.457
T T
69
(0.1558)
99
(0.2185)




LETS
Gen
CC_vs_TT
0.01
1.65
1.13
2.42
C
T
T (0.457
T T
69
(0.1558)
99
(0.2185)





Gen
CT_vs_TT
0.053
1.43
1
2.05
C
T
T (0.457
T T
69
(0.1558)
99
(0.2185)




MEGA1
Gen
CC_vs_TT
2E−07
1.73
1.41
2.12
C
T
T (0.4786
T T
233
(0.1675)
407
(0.232)





Gen
CT_vs_TT
9E−04
1.38
1.14
1.66
C
T
T (0.4786
T T
233
(0.1675)
407
(0.232)


hCV16172935
F11
LETS
rec
AA_vs_AG + GG
0.075
1.27
0.98
1.66
A
G
G (0.3451
G G
52
(0.1176)
46
(0.1018)



(rs2241817)
MEGA1
rec
AA_vs_AG + GG
0.032
1.17
1.01
1.35
A
G
G (0.358
G G
139
(0.1004)
219
(0.1259)




LETS
Gen
AA_vs_GG
0.962
0.99
0.64
1.54
A
G
G (0.3451
G G
52
(0.1176)
46
(0.1018)





Gen
AG_vs_GG
0.167
0.73
0.47
1.14
A
G
G (0.3451
G G
52
(0.1176)
46
(0.1018)




MEGA1
Gen
AA_vs_GG
0.01
1.37
1.08
1.74
A
G
G (0.358
G G
139
(0.1004)
219
(0.1259)





Gen
AG_vs_GG
0.102
1.22
0.96
1.54
A
G
G (0.358
G G
139
(0.1004)
219
(0.1259)


hCV3230038
F11
LETS
add
T_vs_C
0.061
1.19
0.99
1.42
T
C
T (0.4279
T T
107
(0.2426)
93
(0.2062)



(rs2289252)
MEGA1
add
T_vs_C
#####
1.34
1.21
1.48
T
C
T (0.4166
T T
314
(0.2331)
309
(0.1766)




LETS
Gen
TC_vs_CC
0.165
1.24
0.92
1.68
T
C
T (0.4279
T T
107
(0.2426)
93
(0.2062)





Gen
TT_vs_CC
0.069
1.4
0.97
2.01
T
C
T (0.4279
T T
107
(0.2426)
93
(0.2062)




MEGA1
Gen
TC_vs_CC
2E−05
1.43
1.21
1.69
T
C
T (0.4166
T T
314
(0.2331)
309
(0.1766)





Gen
TT_vs_CC
4E−08
1.78
1.45
2.18
T
C
T (0.4166
T T
314
(0.2331)
309
(0.1766)


hCV27474895
F11
MEGA1
add
A_vs_C
#####
1.32
1.19
1.46
A
C
A (0.4182
A A
326
(0.2364)
312
(0.1785)



(rs3756011)
LETS
add
A_vs_C
0.035
1.21
1.01
1.45
A
C
A (0.4248
A A
107
(0.2415)
92
(0.2035)




LETS
Gen
AA_vs_CC
0.043
1.45
1.01
2.09
A
C
A (0.4248
A A
107
(0.2415)
92
(0.2035)





Gen
AC_vs_CC
0.089
1.3
0.96
1.76
A
C
A (0.4248
A A
107
(0.2415)
92
(0.2035)




MEGA1
Gen
AA_vs_CC
1E−07
1.73
1.41
2.12
A
C
A (0.4182
A A
326
(0.2364)
312
(0.1785)





Gen
AC_vs_CC
2E−04
1.37
1.16
1.61
A
C
A (0.4182
A A
326
(0.2364)
312
(0.1785)


hCV25474413
F11
LETS
Gen
CC_vs_AA
0.061
1.42
0.98
2.05
C
A
A (0.4912
A A
91
(0.2054)
116
(0.2561)



(rs3822057)
MEGA1
Gen
CC_vs_AA
2E−06
1.63
1.33
2
C
A
A (0.51
A A
269
(0.1971)
457
(0.2604)




LETS
Gen
CA_vs_AA
0.146
1.28
0.92
1.79
C
A
A (0.4912
A A
91
(0.2054)
116
(0.2561)





Gen
CC_vs_AA
0.061
1.42
0.98
2.05
C
A
A (0.4912
A A
91
(0.2054)
116
(0.2561)




MEGA1
Gen
CA_vs_AA
0.002
1.34
1.12
1.6
C
A
A (0.51
A A
269
(0.1971)
457
(0.2604)





Gen
CC_vs_AA
2E−06
1.63
1.33
2
C
A
A (0.51
A A
269
(0.1971)
457
(0.2604)


hCV27490984
F11
LETS
rec
GG_vs_GA + AA
0.076
1.27
0.98
1.66
G
A
A (0.3462
A A
54
(0.1222)
46
(0.1018)



(rs3822058)
MEGA1
rec
GG_vs_GA + AA
0.022
1.18
1.02
1.36
G
A
A (0.3589
A A
135
(0.097)
219
(0.1254)




LETS
Gen
GA_vs_AA
0.108
0.7
0.45
1.08
G
A
A (0.3462
A A
54
(0.1222)
46
(0.1018)





Gen
GG_vs_AA
0.831
0.95
0.61
1.48
G
A
A (0.3462
A A
54
(0.1222)
46
(0.1018)




MEGA1
Gen
GA_vs_AA
0.059
1.26
0.99
1.6
G
A
A (0.3589
A A
135
(0.097)
219
(0.1254)





Gen
GG_vs_AA
0.004
1.42
1.12
1.81
G
A
A (0.3589
A A
135
(0.097)
219
(0.1254)


hCV25474414
F11
MEGA1
add
G_vs_T
5E−07
1.3
1.17
1.44
G
T
G (0.3872
G G
278
(0.2067)
264
(0.1504)



(rs4253399)
LETS
add
G_vs_T
0.023
1.23
1.03
1.48
G
T
G (0.3902
G G
94
(0.2132)
80
(0.1774)




LETS
Gen
GG_vs_TT
0.038
1.48
1.02
2.15
G
T
G (0.3902
G G
94
(0.2132)
80
(0.1774)





Gen
GT_vs_TT
0.049
1.35
1
1.81
G
T
G (0.3902
G G
94
(0.2132)
80
(0.1774)




MEGA1
Gen
GG_vs_TT
6E−07
1.7
1.38
2.09
G
T
G (0.3872
G G
278
(0.2067)
264
(0.1504)





Gen
GT_vs_TT
0.003
1.28
1.09
1.5
G
T
G (0.3872
G G
278
(0.2067)
264
(0.1504)


hCV26038139
F11
MEGA1
Gen
AG_vs_GG
0.006
1.39
1.1
1.74
A
G
G (0.3744
G G
142
(0.102)
249
(0.1421)



(rs4253405)
LETS
Gen
AG_vs_GG
0.048
0.66
0.43
1
A
G
G (0.3639
G G
63
(0.1429)
52
(0.115)




LETS
Gen
AA_vs_GG
0.767
0.94
0.62
1.43
A
G
G (0.3639
G G
63
(0.1429)
52
(0.115)





Gen
AG_vs_GG
0.048
0.66
0.43
1
A
G
G (0.3639
G G
63
(0.1429)
52
(0.115)




MEGA1
Gen
AA_vs_GG
3E−04
1.54
1.22
1.95
A
G
G (0.3744
G G
142
(0.102)
249
(0.1421)





Gen
AG_vs_GG
0.006
1.39
1.1
1.74
A
G
G (0.3744
G G
142
(0.102)
249
(0.1421)


hCV3230119
F11
LETS
rec
GG_vs_GC + CC
0.052
1.3
1
1.7
G
C
C (0.3518
C C
52
(0.1179)
48
(0.1062)



(rs4253430)
MEGA1
rec
GG_vs_GC + CC
0.038
1.16
1.01
1.34
G
C
C (0.3562
C C
135
(0.0971)
218
(0.1244)




LETS
Gen
GC_vs_CC
0.222
0.76
0.49
1.18
G
C
C (0.3518
C C
52
(0.1179)
48
(0.1062)





Gen
GG_vs_CC
0.845
1.04
0.67
1.62
G
C
C (0.3518
C C
52
(0.1179)
48
(0.1062)




MEGA1
Gen
GC_vs_CC
0.062
1.25
0.99
1.59
G
C
C (0.3562
C C
135
(0.0971)
218
(0.1244)





Gen
GG_vs_CC
0.006
1.4
1.1
1.77
G
C
C (0.3562
C C
135
(0.0971)
218
(0.1244)


hCV8241630
F11
MEGA1
add
A_vs_G
#####
1.32
1.2
1.46
A
G
A (0.3886
A A
289
(0.2128)
272
(0.1554)



(rs925451)
LETS
add
A_vs_G
0.045
1.2
1
1.44
A
G
A (0.4071
A A
95
(0.2154)
87
(0.1925)




LETS
Gen
AA_vs_GG
0.078
1.39
0.96
2.01
A
G
A (0.4071
A A
95
(0.2154)
87
(0.1925)





Gen
AG_vs_GG
0.029
1.39
1.03
1.88
A
G
A (0.4071
A A
95
(0.2154)
87
(0.1925)




MEGA1
Gen
AA_vs_GG
1E−07
1.75
1.42
2.15
A
G
A (0.3886
A A
289
(0.2128)
272
(0.1554)





Gen
AG_vs_GG
3E−04
1.34
1.14
1.57
A
G
A (0.3886
A A
289
(0.2128)
272
(0.1554)


hCV8726802
F2
MEGA1
add
A_vs_G
2E−07
2.85
1.92
4.24
A
G
A (0.0106
A A
0
(0)
0
(0)



(rs1799963)
LETS
add
A_vs_G
0.003
3
1.44
6.26
A
G
A (0.0111
A A
0
(0)
0
(0)




LETS
Gen
AG_vs_GG
0.003
3
1.44
6.26
A
G
G (0.0111
G G
0
(0)
0
(0)




MEGA1
Gen
AG_vs_GG
2E−07
2.85
1.92
4.24
A
G
A (0.0106
A A
0
(0)
0
(0)


hCV27480803
F5
MEGA1
add
C_vs_T
4E−04
1.2
1.08
1.32
C
T
C (0.4411
C C
346
(0.2493)
351
(0.2008)



(rs3766103)
LETS
add
C_vs_T
0.017
1.26
1.04
1.52
C
T
C (0.4062
C C
96
(0.2177)
73
(0.1611)




LETS
Gen
CC_vs_TT
0.015
1.61
1.1
2.36
C
T
C (0.4062
C C
96
(0.2177)
73
(0.1611)





Gen
CT_vs_TT
0.25
1.19
0.88
1.61
C
T
C (0.4062
C C
96
(0.2177)
73
(0.1611)




MEGA1
Gen
CC_vs_TT
3E−04
1.44
1.18
1.75
C
T
C (0.4411
C C
346
(0.2493)
351
(0.2008)





Gen
CT_vs_TT
0.107
1.15
0.97
1.35
C
T
C (0.4411
C C
346
(0.2493)
351
(0.2008)


hCV8919444
F5 (rs4524)
MEGA1
add
T_vs_C
1E−04
1.26
1.12
1.42
T
C
C (0.2553
C C
76
(0.0548)
107
(0.0611)




LETS
add
T_vs_C
0.006
1.36
1.09
1.69
T
C
C (0.2577
C C
24
(0.0542)
32
(0.0708)




LETS
Gen
TC_vs_CC
0.931
1.03
0.58
1.83
T
C
C (0.2577
C C
24
(0.0542)
32
(0.0708)





Gen
TT_vs_CC
0.13
1.54
0.88
2.68
T
C
C (0.2577
C C
24
(0.0542)
32
(0.0708)




MEGA1
Gen
TC_vs_CC
0.565
0.91
0.66
1.25
T
C
C (0.2553
C C
76
(0.0548)
107
(0.0611)





Gen
TT_vs_CC
0.124
1.27
0.94
1.73
T
C
C (0.2553
C C
76
(0.0548)
107
(0.0611)


hCV8919442
F5 (rs4525)
MEGA1
add
T_vs_C
5E−05
1.28
1.14
1.44
T
C
C (0.2558
C C
74
(0.0541)
107
(0.0609)




LETS
add
T_vs_C
0.01
1.33
1.07
1.66
T
C
C (0.2556
C C
25
(0.0568)
31
(0.0689)




LETS
Gen
TC_vs_CC
0.846
0.94
0.53
1.68
T
C
C (0.2556
C C
25
(0.0568)
31
(0.0689)





Gen
TT_vs_CC
0.216
1.42
0.82
2.47
T
C
C (0.2556
C C
25
(0.0568)
31
(0.0689)




MEGA1
Gen
TC_vs_CC
0.562
0.91
0.66
1.25
T
C
C (0.2558
C C
74
(0.0541)
107
(0.0609)





Gen
TT_vs_CC
0.103
1.29
0.95
1.77
T
C
C (0.2558
C C
74
(0.0541)
107
(0.0609)


hCV8919451
F5 (rs6016)
MEGA1
add
G_vs_A
6E−05
1.27
1.13
1.43
G
A
A (0.255
A A
78
(0.0562)
108
(0.0615)




LETS
add
G_vs_A
0.006
1.35
1.09
1.69
G
A
A (0.2578
A A
24
(0.0544)
31
(0.0689)




LETS
Gen
GA_vs_AA
0.967
0.99
0.55
1.76
G
A
A (0.2578
A A
24
(0.0544)
31
(0.0689)





Gen
GG_vs_AA
0.163
1.49
0.85
2.6
G
A
A (0.2578
A A
24
(0.0544)
31
(0.0689)




MEGA1
Gen
GA_vs_AA
0.414
0.88
0.64
1.2
G
A
A (0.255
A A
78
(0.0562)
108
(0.0615)





Gen
GG_vs_AA
0.141
1.26
0.93
1.71
G
A
A (0.255
A A
78
(0.0562)
108
(0.0615)


hCV2288095
F9 (rs378815)
LETS
Gen
CC_vs_TT
0.02
1.5
1.07
2.11
C
T
T (0.3711
T T
80
(0.1814)
107
(0.2378)




MEGA1
Gen
CT_vs_TT
0.048
1.23
1
1.52
C
T
T (0.3545
T T
306
(0.2201)
431
(0.2464)




LETS
Gen
CC_vs_TT
0.02
1.5
1.07
2.11
C
T
T (0.3711
T T
80
(0.1814)
107
(0.2378)





Gen
CT_vs_TT
0.282
1.24
0.84
1.82
C
T
T (0.3711
T T
80
(0.1814)
107
(0.2378)




MEGA1
Gen
CC_vs_TT
0.177
1.13
0.95
1.34
C
T
T (0.3545
T T
306
(0.2201)
431
(0.2464)





Gen
CT_vs_TT
0.048
1.23
1
1.52
C
T
T (0.3545
T T
306
(0.2201)
431
(0.2464)


hCV596326
F9 (rs398101)
LETS
rec
AA_vs_AG + GG
0.006
1.46
1.12
1.9
A
G
G (0.3363
G G
75
(0.1705)
92
(0.2035)




MEGA1
Gen
AG_vs_GG
0.015
1.31
1.05
1.64
A
G
G (0.3174
G G
257
(0.1857)
381
(0.2175)




LETS
Gen
AA_vs_GG
0.06
1.4
0.99
1.99
A
G
G (0.3363
G G
75
(0.1705)
92
(0.2035)





Gen
AG_vs_GG
0.729
0.93
0.62
1.4
A
G
G (0.3363
G G
75
(0.1705)
92
(0.2035)




MEGA1
Gen
AA_vs_GG
0.067
1.19
0.99
1.42
A
G
G (0.3174
G G
257
(0.1857)
381
(0.2175)





Gen
AG_vs_GG
0.015
1.31
1.05
1.64
A
G
G (0.3174
G G
257
(0.1857)
381
(0.2175)


hCV596330
F9 (rs422187)
LETS
add
A_vs_C
0.048
1.19
1
1.41
A
C
C (0.3267
C C
70
(0.1587)
87
(0.1933)




MEGA1
add
A_vs_C
0.049
1.09
1
1.2
A
C
C (0.3178
C C
243
(0.176)
376
(0.2147)




LETS
Gen
AA_vs_CC
0.085
1.37
0.96
1.96
A
C
C (0.3267
C C
70
(0.1587)
87
(0.1933)





Gen
AC_vs_CC
0.757
1.07
0.71
1.61
A
C
C (0.3267
C C
70
(0.1587)
87
(0.1933)




MEGA1
Gen
AA_vs_CC
0.016
1.26
1.04
1.51
A
C
C (0.3178
C C
243
(0.176)
376
(0.2147)





Gen
AC_vs_CC
0.008
1.35
1.08
1.68
A
C
C (0.3178
C C
243
(0.176)
376
(0.2147)


hCV596331
F9 (rs6048)
LETS
rec
AA_vs_AG + GG
0.016
1.39
1.06
1.81
A
G
G (0.3267
G G
70
(0.158)
87
(0.1921)




MEGA1
dom
AA + AG_vs_GG
0.014
1.26
1.05
1.51
A
G
G (0.3043
G G
233
(0.1698)
356
(0.2046)




LETS
Gen
AA_vs_GG
0.069
1.4
0.97
2
A
G
G (0.3267
G G
70
(0.158)
87
(0.1921)





Gen
AG_vs_GG
0.968
1.01
0.67
1.52
A
G
G (0.3267
G G
70
(0.158)
87
(0.1921)




MEGA1
Gen
AA_vs_GG
0.023
1.24
1.03
1.5
A
G
G (0.3043
G G
233
(0.1698)
356
(0.2046)





Gen
AG_vs_GG
0.024
1.3
1.04
1.63
A
G
G (0.3043
G G
233
(0.1698)
356
(0.2046)


hCV2892877
FGA (rs6050)
LETS
add
C_vs_T
0.058
1.29
0.99
1.68
C
T
C (0.2494
C C
0
(0)
0
(0)




MEGA1
add
C_vs_T
5E−07
1.44
1.25
1.66
C
T
C (0.2457
C C
0
(0)
0
(0)




LETS
Gen
CT_vs_TT
0.058
1.29
0.99
1.68
C
T
C (0.2494
C C
0
(0)
0
(0)




MEGA1
Gen
CT_vs_TT
5E−07
1.44
1.25
1.66
C
T
C (0.2457
C C
0
(0)
0
(0)


hCV11503469
FGG
MEGA1
add
A_vs_T
#####
1.41
1.26
1.57
A
T
A (0.2751
A A
174
(0.1251)
139
(0.0792)



(rs2066854)
LETS
add
A_vs_T
2E−04
1.48
1.2
1.83
A
T
A (0.2619
A A
54
(0.1241)
22
(0.0499)




LETS
Gen
AA_vs_TT
5E−05
3.01
1.77
5.11
A
T
A (0.2619
A A
54
(0.1241)
22
(0.0499)





Gen
AT_vs_TT
0.139
1.23
0.93
1.62
A
T
A (0.2619
A A
54
(0.1241)
22
(0.0499)




MEGA1
Gen
AA_vs_TT
8E−08
1.96
1.53
2.5
A
T
A (0.2751
A A
174
(0.1251)
139
(0.0792)





Gen
AT_vs_TT
4E−06
1.42
1.22
1.65
A
T
A (0.2751
A A
174
(0.1251)
139
(0.0792)


hCV11503414
FGG
MEGA1
add
A_vs_G
#####
1.41
1.27
1.57
A
G
A (0.2745
A A
166
(0.1231)
136
(0.0774)



(rs2066865)
LETS
add
A_vs_G
4E−04
1.45
1.18
1.78
A
G
A (0.264
A A
56
(0.1281)
24
(0.0537)




LETS
Gen
AA_vs_GG
8E−05
2.81
1.68
4.7
A
G
A (0.264
A A
56
(0.1281)
24
(0.0537)





Gen
AG_vs_GG
0.215
1.19
0.9
1.57
A
G
A (0.264
A A
56
(0.1281)
24
(0.0537)




MEGA1
Gen
AA_vs_GG
9E−08
1.97
1.54
2.53
A
G
A (0.2745
A A
166
(0.1231)
136
(0.0774)





Gen
AG_vs_GG
5E−06
1.42
1.22
1.65
A
G
A (0.2745
A A
166
(0.1231)
136
(0.0774)


hCV30505633
GNG12
LETS
add
T_vs_C
0.023
1.52
1.06
2.17
T
C
T (0.0596
T T
5
(0.0113)
1
(0.0022)



(rs7530537)
MEGA1
add
T_vs_C
0.047
1.2
1
1.44
T
C
T (0.072
T T
16
(0.0115)
12
(0.0068)




LETS
Gen
TC_vs_CC
0.078
1.42
0.96
2.09
T
C
T (0.0596
T T
5
(0.0113)
1
(0.0022)





Gen
TT_vs_CC
0.124
5.42
0.63
46.6
T
C
T (0.0596
T T
5
(0.0113)
1
(0.0022)




MEGA1
Gen
TC_vs_CC
0.128
1.17
0.96
1.43
T
C
T (0.072
T T
16
(0.0115)
12
(0.0068)





Gen
TT_vs_CC
0.151
1.74
0.82
3.68
T
C
T (0.072
T T
16
(0.0115)
12
(0.0068)


hCV8717873
GP6
MEGA1
add
A_vs_G
0.004
1.21
1.06
1.38
A
G
G (0.193
G G
45
(0.0324)
61
(0.0349)



(rs1613662)
LETS
add
A_vs_G
0.013
1.36
1.07
1.74
A
G
G (0.1998
G G
10
(0.0226)
19
(0.0419)




LETS
Gen
AA_vs_GG
0.07
2.06
0.94
4.51
A
G
G (0.1998
G G
10
(0.0226)
19
(0.0419)





Gen
AG_vs_GG
0.282
1.55
0.7
3.47
A
G
G (0.1998
G G
10
(0.0226)
19
(0.0419)




MEGA1
Gen
AA_vs_GG
0.449
1.16
0.78
1.73
A
G
G (0.193
G G
45
(0.0324)
61
(0.0349)





Gen
AG_vs_GG
0.62
0.9
0.6
1.36
A
G
G (0.193
G G
45
(0.0324)
61
(0.0349)


hCV1376342
GP6
LETS
Gen
TT_vs_CC
0.076
1.81
0.94
3.49
T
C
C (0.2141
C C
15
(0.0339)
26
(0.0574)



(rs1654416)
MEGA1
rec
TT_vs_TC + CC
0.009
1.22
1.05
1.42
T
C
C (0.203
C C
49
(0.0358)
66
(0.0376)




LETS
Gen
TC_vs_CC
0.182
1.59
0.81
3.13
T
C
C (0.2141
C C
15
(0.0339)
26
(0.0574)





Gen
TT_vs_CC
0.076
1.81
0.94
3.49
T
C
C (0.2141
C C
15
(0.0339)
26
(0.0574)




MEGA1
Gen
TC_vs_CC
0.647
0.91
0.62
1.35
T
C
C (0.203
C C
49
(0.0358)
66
(0.0376)





Gen
TT_vs_CC
0.545
1.12
0.77
1.64
T
C
C (0.203
C C
49
(0.0358)
66
(0.0376)


hCV8717893
GP6
LETS
Gen
GG_vs_AA
0.077
1.81
0.94
3.48
G
A
A (0.2141
A A
15
(0.0339)
26
(0.0574)



(rs1671192)
MEGA1
rec
GG_vs_GA + AA
0.004
1.24
1.07
1.44
G
A
A (0.2027
A A
51
(0.0367)
64
(0.0364)




LETS
Gen
GA_vs_AA
0.182
1.59
0.81
3.13
G
A
A (0.2141
A A
15
(0.0339)
26
(0.0574)





Gen
GG_vs_AA
0.077
1.81
0.94
3.48
G
A
A (0.2141
A A
15
(0.0339)
26
(0.0574)




MEGA1
Gen
GA_vs_AA
0.395
0.84
0.57
1.25
G
A
A (0.2027
A A
51
(0.0367)
64
(0.0364)





Gen
GG_vs_AA
0.729
1.07
0.73
1.56
G
A
A (0.2027
A A
51
(0.0367)
64
(0.0364)


hCV2575036
GRB10
LETS
add
A_vs_G
0.007
3.03
1.35
6.81
A
G
G (0.0265
G G
0
(0)
0
(0)



(rs34432772)
MEGA1
add
G_vs_A
0.025
1.49
1.05
2.11
G
A
G (0.0174
G G
1
(0.0007)
0
(0)




LETS
Gen
AG_vs_GG
0.007
0.33
0.15
0.74
A
G
G (0.0265
G G
0
(0)
0
(0)




MEGA1
Gen
GA_vs_AA
0.038
1.45
1.02
2.07
G
A
G (0.0174
G G
1
(0.0007)
0
(0)





Gen
GG_vs_AA
0.952
137573
0
####
G
A
G (0.0174
G G
1
(0.0007)
0
(0)


hCV2699725
GUCY1B2
LETS
Gen
CG_vs_GG
0.037
1.85
1.04
3.31
C
G
C (0.0234
C C
3
(0.0069)
1
(0.0022)



(rs11841997)
MEGA1
Gen
GC_vs_CC
0.048
1.33
1
1.78
G
C
G (0.0307
G G
4
(0.0029)
5
(0.0028)




LETS
Gen
CC_vs_GG
0.314
3.2
0.33
30.9
C
G
C (0.0234
C C
3
(0.0069)
1
(0.0022)





Gen
CG_vs_GG
0.037
1.85
1.04
3.31
C
G
C (0.0234
C C
3
(0.0069)
1
(0.0022)




MEGA1
Gen
GC_vs_CC
0.048
1.33
1
1.78
G
C
G (0.0307
G G
4
(0.0029)
5
(0.0028)





Gen
GG_vs_CC
0.97
1.03
0.27
3.83
G
C
G (0.0307
G G
4
(0.0029)
5
(0.0028)


hCV25995678
hCV25995678
LETS
add
T_vs_C
0.019
1.46
1.06
2
T
C
C (0.1117
C C
4
(0.009)
8
(0.0177)




MEGA1
dom
TT + TC_vs_CC
0.049
2.73
1
7.42
T
C
C (0.0891
C C
5
(0.0036)
17
(0.0097)




LETS
Gen
TC_vs_CC
0.569
1.44
0.41
4.98
T
C
C (0.1117
C C
4
(0.009)
8
(0.0177)





Gen
TT_vs_CC
0.229
2.1
0.63
7.04
T
C
C (0.1117
C C
4
(0.009)
8
(0.0177)




MEGA1
Gen
TC_vs_CC
0.052
2.72
0.99
7.5
T
C
C (0.0891
C C
5
(0.0036)
17
(0.0097)





Gen
TT_vs_CC
0.049
2.73
1
7.42
T
C
C (0.0891
C C
5
(0.0036)
17
(0.0097)


hCV25996277
hCV25996277
LETS
add
A_vs_T
0.024
1.43
1.05
1.96
A
T
T (0.1126
T T
4
(0.009)
8
(0.0177)




MEGA1
Gen
AA_vs_TT
0.021
3.19
1.19
8.51
A
T
T (0.0904
T T
5
(0.0036)
20
(0.0114)




LETS
Gen
AA_vs_TT
0.231
2.09
0.63
7.02
A
T
T (0.1126
T T
4
(0.009)
8
(0.0177)





Gen
AT_vs_TT
0.547
1.47
0.42
5.08
A
T
T (0.1126
T T
4
(0.009)
8
(0.0177)




MEGA1
Gen
AA_vs_TT
0.021
3.19
1.19
8.51
A
T
T (0.0904
T T
5
(0.0036)
20
(0.0114)





Gen
AT_vs_TT
0.025
3.13
1.16
8.48
A
T
T (0.0904
T T
5
(0.0036)
20
(0.0114)


hCV31199195
KCTD10
LETS
dom
CC + CA_vs_AA
0.021
1.4
1.05
1.86
C
A
C (0.1534
C C
12
(0.0271)
14
(0.0309)



(rs10850234)
MEGA1
dom
CC + CA_vs_AA
0.036
1.17
1.01
1.37
C
A
C (0.1683
C C
52
(0.0375)
52
(0.0297)




LETS
Gen
CA_vs_AA
0.013
1.45
1.08
1.95
C
A
C (0.1534
C C
12
(0.0271)
14
(0.0309)





Gen
CC_vs_AA
0.945
0.97
0.44
2.14
C
A
C (0.1534
C C
12
(0.0271)
14
(0.0309)




MEGA1
Gen
CA_vs_AA
0.065
1.16
0.99
1.35
C
A
C (0.1683
C C
52
(0.0375)
52
(0.0297)





Gen
CC_vs_AA
0.155
1.33
0.9
1.97
C
A
C (0.1683
C C
52
(0.0375)
52
(0.0297)


hCV27502514
KLF3
MEGA1
dom
AA + AG_vs_GG
0.026
1.19
1.02
1.38
A
G
A (0.1584
A A
44
(0.0318)
45
(0.0257)



(rs3796533)
LETS
dom
AA + AG_vs_GG
0.038
1.34
1.02
1.77
A
G
A (0.1678
A A
17
(0.0384)
15
(0.0331)




LETS
Gen
AA_vs_GG
0.499
1.28
0.63
2.61
A
G
A (0.1678
A A
17
(0.0384)
15
(0.0331)





Gen
AG_vs_GG
0.042
1.35
1.01
1.8
A
G
A (0.1678
A A
17
(0.0384)
15
(0.0331)




MEGA1
Gen
AA_vs_GG
0.218
1.31
0.85
2
A
G
A (0.1584
A A
44
(0.0318)
45
(0.0257)





Gen
AG_vs_GG
0.042
1.18
1.01
1.38
A
G
A (0.1584
A A
44
(0.0318)
45
(0.0257)


hCV11786258
KLKB1
LETS
Gen
AG_vs_GG
0.069
1.32
0.98
1.78
A
G
A (0.4156
A A
83
(0.1886)
83
(0.1844)



(rs4253303)
MEGA1
Gen
AG_vs_GG
0.003
1.27
1.09
1.49
A
G
A (0.3933
A A
271
(0.1948)
282
(0.1609)




LETS
Gen
AA_vs_GG
0.32
1.21
0.83
1.78
A
G
A (0.4156
A A
83
(0.1886)
83
(0.1844)





Gen
AG_vs_GG
0.069
1.32
0.98
1.78
A
G
A (0.4156
A A
83
(0.1886)
83
(0.1844)




MEGA1
Gen
AA_vs_GG
4E−04
1.45
1.18
1.79
A
G
A (0.3933
A A
271
(0.1948)
282
(0.1609)





Gen
AG_vs_GG
0.003
1.27
1.09
1.49
A
G
A (0.3933
A A
271
(0.1948)
282
(0.1609)


hCV540410
LASP1
LETS
Gen
AT_vs_TT
0.058
1.5
0.99
2.28
A
T
A (0.0552
A A
2
(0.0045)
4
(0.0088)



(rs609529)
MEGA1
Gen
AA_vs_TT
0.009
3.83
1.39
10.6
A
T
A (0.0644
A A
15
(0.0108)
5
(0.0028)




LETS
Gen
AA_vs_TT
0.47
0.53
0.1
2.93
A
T
A (0.0552
A A
2
(0.0045)
4
(0.0088)





Gen
AT_vs_TT
0.058
1.5
0.99
2.28
A
T
A (0.0552
A A
2
(0.0045)
4
(0.0088)




MEGA1
Gen
AA_vs_TT
0.009
3.83
1.39
10.6
A
T
A (0.0644
A A
15
(0.0108)
5
(0.0028)





Gen
AT_vs_TT
0.637
1.05
0.85
1.3
A
T
A (0.0644
A A
15
(0.0108)
5
(0.0028)


hDV70662128
LOC129656
LETS
add
A_vs_G
0.063
1.68
0.97
2.92
A
G
A (0.0243
A A
0
(0)
0
(0)



(rs17043082)
MEGA1
add
A_vs_G
9E−04
1.59
1.21
2.09
A
G
A (0.0259
A A
5
(0.0036)
4
(0.0023)




LETS
Gen
AG_vs_GG
0.063
1.68
0.97
2.92
A
G
A (0.0243
A A
0
(0)
0
(0)




MEGA1
Gen
AA_vs_GG
0.465
1.63
0.44
6.1
A
G
A (0.0259
A A
5
(0.0036)
4
(0.0023)





Gen
AG_vs_GG
9E−04
1.65
1.23
2.23
A
G
A (0.0259
A A
5
(0.0036)
4
(0.0023)


hCV11541681
LOC200420
MEGA1
add
C_vs_G
0.013
1.14
1.03
1.26
C
G
C (0.3707
C C
228
(0.1638)
243
(0.1385)



(rs2001490)
LETS
add
C_vs_G
0.039
1.22
1.01
1.49
C
G
C (0.3841
C C
81
(0.1828)
60
(0.1325)




LETS
Gen
CC_vs_GG
0.028
1.57
1.05
2.35
C
G
C (0.3841
C C
81
(0.1828)
60
(0.1325)





Gen
CG_vs_GG
0.441
1.12
0.84
1.5
C
G
C (0.3841
C C
81
(0.1828)
60
(0.1325)




MEGA1
Gen
CC_vs_GG
0.015
1.3
1.05
1.61
C
G
C (0.3707
C C
228
(0.1638)
243
(0.1385)





Gen
CG_vs_GG
0.126
1.13
0.97
1.32
C
G
C (0.3707
C C
228
(0.1638)
243
(0.1385)


hCV2706410
LOC387646
LETS
Gen
CT_vs_TT
0.015
1.41
1.07
1.87
C
T
C (0.2279
C C
33
(0.0747)
30
(0.0664)



(rs7896532)
MEGA1
Gen
CT_vs_TT
0.04
1.17
1.01
1.36
C
T
C (0.2459
C C
86
(0.0629)
121
(0.0689)




LETS
Gen
CC_vs_TT
0.33
1.3
0.77
2.19
C
T
C (0.2279
C C
33
(0.0747)
30
(0.0664)





Gen
CT_vs_TT
0.015
1.41
1.07
1.87
C
T
C (0.2279
C C
33
(0.0747)
30
(0.0664)




MEGA1
Gen
CC_vs_TT
0.817
0.97
0.72
1.29
C
T
C (0.2459
C C
86
(0.0629)
121
(0.0689)





Gen
CT_vs_TT
0.04
1.17
1.01
1.36
C
T
C (0.2459
C C
86
(0.0629)
121
(0.0689)


hCV1547677
LOC646030
LETS
add
G_vs_A
0.024
2.6
1.13
5.97
G
A
G (0.0089
G G
0
(0)
0
(0)



(rs6505228)
MEGA1
add
G_vs_A
0.044
1.37
1.01
1.87
G
A
G (0.0168
G G
15
(0.011)
6
(0.0034)




LETS
Gen
GA_vs_AA
0.024
2.6
1.13
5.97
G
A
G (0.0089
G G
0
(0)
0
(0)




MEGA1
Gen
GA_vs_AA
0.737
1.08
0.7
1.66
G
A
G (0.0168
G G
15
(0.011)
6
(0.0034)





Gen
GG_vs_AA
0.015
3.24
1.25
8.38
G
A
G (0.0168
G G
15
(0.011)
6
(0.0034)


hCV8827309
LOC728221
LETS
add
T_vs_C
0.006
1.49
1.12
1.98
T
C
T (0.1029
T T
11
(0.0251)
5
(0.0111)



(rs1110796)
MEGA1
add
T_vs_C
0.04
1.17
1.01
1.36
T
C
T (0.1204
T T
21
(0.0152)
24
(0.0139)




LETS
Gen
TC_vs_CC
0.021
1.46
1.06
2.02
T
C
T (0.1029
T T
11
(0.0251)
5
(0.0111)





Gen
TT_vs_CC
0.093
2.49
0.86
7.26
T
C
T (0.1029
T T
11
(0.0251)
5
(0.0111)




MEGA1
Gen
TC_vs_CC
0.031
1.2
1.02
1.42
T
C
T (0.1204
T T
21
(0.0152)
24
(0.0139)





Gen
TT_vs_CC
0.658
1.14
0.63
2.06
T
C
T (0.1204
T T
21
(0.0152)
24
(0.0139)


hCV2103392
LOC728284
LETS
dom
CC + CT_vs_TT
0.097
1.4
0.94
2.07
C
T
T (0.3606
T T
49
(0.1109)
67
(0.1482)



(rs12500826)
MEGA1
dom
CC + CT_vs_TT
0.014
1.31
1.06
1.62
C
T
T (0.3796
T T
153
(0.1138)
252
(0.1438)




LETS
Gen
CC_vs_TT
0.124
1.39
0.91
2.11
C
T
T (0.3606
T T
49
(0.1109)
67
(0.1482)





Gen
CT_vs_TT
0.113
1.4
0.92
2.13
C
T
T (0.3606
T T
49
(0.1109)
67
(0.1482)




MEGA1
Gen
CC_vs_TT
0.005
1.39
1.11
1.75
C
T
T (0.3796
T T
153
(0.1138)
252
(0.1438)





Gen
CT_vs_TT
0.064
1.24
0.99
1.55
C
T
T (0.3796
T T
153
(0.1138)
252
(0.1438)


hCV3230136
LOC728284
MEGA1
rec
GG_vs_GA + AA
0.007
1.21
1.05
1.4
G
A
A (0.2789
A A
75
(0.054)
130
(0.0743)



(rs13116273)
LETS
rec
GG_vs_GA + AA
0.03
1.34
1.03
1.75
G
A
A (0.271
A A
31
(0.0703)
31
(0.0686)




LETS
Gen
GA_vs_AA
0.415
0.8
0.46
1.37
G
A
A (0.271
A A
31
(0.0703)
31
(0.0686)





Gen
GG_vs_AA
0.7
1.11
0.65
1.88
G
A
A (0.271
A A
31
(0.0703)
31
(0.0686)




MEGA1
Gen
GA_vs_AA
0.11
1.28
0.95
1.74
G
A
A (0.2789
A A
75
(0.054)
130
(0.0743)





Gen
GG_vs_AA
0.008
1.51
1.12
2.03
G
A
A (0.2789
A A
75
(0.054)
130
(0.0743)


hCV3230131
LOC728284
LETS
rec
TT_vs_TC + CC
0.05
1.3
1
1.7
T
C
C (0.2705
C C
31
(0.0701)
31
(0.0687)



(rs13136269)
MEGA1
rec
TT_vs_TC + CC
0.003
1.24
1.08
1.43
T
C
C (0.2817
C C
74
(0.0532)
134
(0.0765)




LETS
Gen
TC_vs_CC
0.47
0.82
0.48
1.41
T
C
C (0.2705
C C
31
(0.0701)
31
(0.0687)





Gen
TT_vs_CC
0.721
1.1
0.65
1.87
T
C
C (0.2705
C C
31
(0.0701)
31
(0.0687)




MEGA1
Gen
TC_vs_CC
0.067
1.33
0.98
1.8
T
C
C (0.2817
C C
74
(0.0532)
134
(0.0765)





Gen
TT_vs_CC
0.003
1.59
1.18
2.14
T
C
C (0.2817
C C
74
(0.0532)
134
(0.0765)


hCV29821005
LOC728284
LETS
Gen
TC_vs_CC
0.055
1.31
0.99
1.74
T
C
T (0.2056
T T
20
(0.0455)
19
(0.0422)



(rs6552970)
MEGA1
Gen
TC_vs_CC
0.008
1.23
1.05
1.43
T
C
T (0.1943
T T
62
(0.0461)
77
(0.0439)




LETS
Gen
TC_vs_CC
0.055
1.31
0.99
1.74
T
C
T (0.2056
T T
20
(0.0455)
19
(0.0422)





Gen
TT_vs_CC
0.59
1.2
0.62
2.29
T
C
T (0.2056
T T
20
(0.0455)
19
(0.0422)




MEGA1
Gen
TC_vs_CC
0.008
1.23
1.05
1.43
T
C
T (0.1943
T T
62
(0.0461)
77
(0.0439)





Gen
TT_vs_CC
0.491
1.13
0.8
1.6
T
C
T (0.1943
T T
62
(0.0461)
77
(0.0439)


hCV32209621
LOC728284
LETS
Gen
AG_vs_GG
0.054
1.39
0.99
1.94
A
G
G (0.4766
G G
91
(0.2063)
113
(0.2517)



(rs6552971)
MEGA1
Gen
AA_vs_GG
0.045
1.23
1
1.5
A
G
G (0.4997
G G
305
(0.2261)
450
(0.2564)




LETS
Gen
AA_vs_GG
0.46
1.15
0.79
1.66
A
G
G (0.4766
G G
91
(0.2063)
113
(0.2517)





Gen
AG_vs_GG
0.054
1.39
0.99
1.94
A
G
G (0.4766
G G
91
(0.2063)
113
(0.2517)




MEGA1
Gen
AA_vs_GG
0.045
1.23
1
1.5
A
G
G (0.4997
G G
305
(0.2261)
450
(0.2564)





Gen
AG_vs_GG
0.109
1.16
0.97
1.38
A
G
G (0.4997
G G
305
(0.2261)
450
(0.2564)


hCV32209620
LOC728284
LETS
dom
CC + CT_vs_TT
0.061
1.29
0.99
1.69
C
T
C (0.2073
C C
23
(0.0523)
21
(0.0466)



(rs6552972)
MEGA1
dom
CC + CT_vs_TT
0.011
1.21
1.05
1.4
C
T
C (0.1947
C C
62
(0.0463)
76
(0.0436)




LETS
Gen
CC_vs_TT
0.487
1.24
0.67
2.3
C
T
C (0.2073
C C
23
(0.0523)
21
(0.0466)





Gen
CT_vs_TT
0.066
1.3
0.98
1.72
C
T
C (0.2073
C C
23
(0.0523)
21
(0.0466)




MEGA1
Gen
CC_vs_TT
0.462
1.14
0.81
1.61
C
T
C (0.1947
C C
62
(0.0463)
76
(0.0436)





Gen
CT_vs_TT
0.011
1.22
1.05
1.42
C
T
C (0.1947
C C
62
(0.0463)
76
(0.0436)


hCV916107
LOC729138
LETS
add
C_vs_T
0.018
1.27
1.04
1.54
C
T
T (0.3554
T T
41
(0.0928)
61
(0.1347)



(rs670659)
MEGA1
add
C_vs_T
0.026
1.13
1.01
1.25
C
T
T (0.3571
T T
149
(0.1071)
238
(0.1361)




LETS
Gen
CC_vs_TT
0.022
1.67
1.08
2.6
C
T
T (0.3554
T T
41
(0.0928)
61
(0.1347)





Gen
CT_vs_TT
0.158
1.38
0.88
2.14
C
T
T (0.3554
T T
41
(0.0928)
61
(0.1347)




MEGA1
Gen
CC_vs_TT
0.012
1.35
1.07
1.7
C
T
T (0.3571
T T
149
(0.1071)
238
(0.1361)





Gen
CT_vs_TT
0.035
1.28
1.02
1.61
C
T
T (0.3571
T T
149
(0.1071)
238
(0.1361)


hCV30922162
LOC729672
LETS
add
T_vs_C
0.013
1.3
1.06
1.6
T
C
T (0.287
T T
50
(0.1131)
29
(0.064)



(rs4334028)
MEGA1
add
T_vs_C
0.048
1.12
1
1.25
T
C
T (0.2889
T T
132
(0.0951)
133
(0.0758)




LETS
Gen
TC_vs_CC
0.3
1.16
0.88
1.52
T
C
T (0.287
T T
50
(0.1131)
29
(0.064)





Gen
TT_vs_CC
0.006
2
1.22
3.29
T
C
T (0.287
T T
50
(0.1131)
29
(0.064)




MEGA1
Gen
TC_vs_CC
0.355
1.07
0.92
1.24
T
C
T (0.2889
T T
132
(0.0951)
133
(0.0758)





Gen
TT_vs_CC
0.035
1.32
1.02
1.72
T
C
T (0.2889
T T
132
(0.0951)
133
(0.0758)


hCV7504118
LOC729672
MEGA1
add
G_vs_A
0.022
1.14
1.02
1.27
G
A
G (0.2773
G G
123
(0.0887)
120
(0.0683)



(rs967257)
LETS
add
G_vs_A
0.028
1.26
1.02
1.55
G
A
G (0.2792
G G
44
(0.0995)
29
(0.064)




LETS
Gen
GA_vs_AA
0.222
1.19
0.9
1.56
G
A
G (0.2792
G G
44
(0.0995)
29
(0.064)





Gen
GG_vs_AA
0.029
1.75
1.06
2.91
G
A
G (0.2792
G G
44
(0.0995)
29
(0.064)




MEGA1
Gen
GA_vs_AA
0.229
1.09
0.94
1.27
G
A
G (0.2773
G G
123
(0.0887)
120
(0.0683)





Gen
GG_vs_AA
0.019
1.38
1.06
1.81
G
A
G (0.2773
G G
123
(0.0887)
120
(0.0683)


hCV11633415
LOC730144
MEGA1
add
T_vs_C
0.003
1.34
1.1
1.64
T
C
C (0.0798
C C
6
(0.0043)
11
(0.0063)



(rs4262503)
LETS
add
T_vs_C
0.036
1.49
1.03
2.15
T
C
C (0.083
C C
0
(0)
4
(0.0088)




LETS
Gen
TC_vs_CC
0.974
2E+06
0
Inf
T
C
C (0.083
C C
0
(0)
4
(0.0088)





Gen
TT_vs_CC
0.974
2E+06
0
Inf
T
C
C (0.083
C C
0
(0)
4
(0.0088)




MEGA1
Gen
TC_vs_CC
0.842
1.11
0.4
3.06
T
C
C (0.0798
C C
6
(0.0043)
11
(0.0063)





Gen
TT_vs_CC
0.416
1.51
0.56
4.1
T
C
C (0.0798
C C
6
(0.0043)
11
(0.0063)


hCV2494846
LUZP1
MEGA1
rec
GG_vs_GT + TT
0.029
1.56
1.05
2.33
G
T
G (0.1657
G G
55
(0.0395)
45
(0.0257)



(rs3765407)
LETS
rec
GG_vs_GT + TT
0.043
2.2
1.03
4.74
G
T
G (0.1416
G G
21
(0.0475)
10
(0.0221)




LETS
Gen
GG_vs_TT
0.032
2.32
1.08
5.01
G
T
G (0.1416
G G
21
(0.0475)
10
(0.0221)





Gen
GT_vs_TT
0.202
1.22
0.9
1.65
G
T
G (0.1416
G G
21
(0.0475)
10
(0.0221)




MEGA1
Gen
GG_vs_TT
0.029
1.57
1.05
2.34
G
T
G (0.1657
G G
55
(0.0395)
45
(0.0257)





Gen
GT_vs_TT
0.93
1.01
0.86
1.18
G
T
G (0.1657
G G
55
(0.0395)
45
(0.0257)


hCV25752810
MDN1
MEGA1
add
C_vs_A
0.011
1.49
1.09
2.04
C
A
C (0.0191
C C
7
(0.0051)
4
(0.0023)



(rs4707557)
LETS
add
C_vs_A
0.03
2.01
1.07
3.76
C
A
C (0.0144
C C
3
(0.0068)
1
(0.0022)




LETS
Gen
CA_vs_AA
0.047
2.11
1.01
4.4
C
A
C (0.0144
C C
3
(0.0068)
1
(0.0022)





Gen
CC_vs_AA
0.32
3.16
0.33
30.5
C
A
C (0.0144
C C
3
(0.0068)
1
(0.0022)




MEGA1
Gen
CA_vs_AA
0.03
1.49
1.04
2.12
C
A
C (0.0191
C C
7
(0.0051)
4
(0.0023)





Gen
CC_vs_AA
0.187
2.29
0.67
7.84
C
A
C (0.0191
C C
7
(0.0051)
4
(0.0023)


hCV16170613
MET
MEGA1
add
G_vs_A
0.017
1.38
1.06
1.8
G
A
G (0.0313
G G
3
(0.0022)
1
(0.0006)



(rs2237712)
LETS
add
G_vs_A
0.031
1.68
1.05
2.7
G
A
G (0.0299
G G
4
(0.009)
0
(0)




LETS
Gen
GA_vs_AA
0.155
1.45
0.87
2.43
G
A
G (0.0299
G G
4
(0.009)
0
(0)





Gen
GG_vs_AA
0.974
2E+06
0
Inf
G
A
G (0.0299
G G
4
(0.009)
0
(0)




MEGA1
Gen
GA_vs_AA
0.033
1.35
1.02
1.77
G
A
G (0.0313
G G
3
(0.0022)
1
(0.0006)





Gen
GG_vs_AA
0.242
3.86
0.4
37.1
G
A
G (0.0313
G G
3
(0.0022)
1
(0.0006)


hCV11726971
NFIA
LETS
Gen
GG_vs_AA
0.016
2.55
1.19
5.45
G
A
G (0.1512
G G
23
(0.0519)
10
(0.0221)



(rs2065841)
MEGA1
Gen
GA_vs_AA
0.038
1.18
1.01
1.37
G
A
G (0.1927
G G
51
(0.0369)
75
(0.0428)




LETS
Gen
GA_vs_AA
0.242
1.19
0.89
1.61
G
A
G (0.1512
G G
23
(0.0519)
10
(0.0221)





Gen
GG_vs_AA
0.016
2.55
1.19
5.45
G
A
G (0.1512
G G
23
(0.0519)
10
(0.0221)




MEGA1
Gen
GA_vs_AA
0.038
1.18
1.01
1.37
G
A
G (0.1927
G G
51
(0.0369)
75
(0.0428)





Gen
GG_vs_AA
0.591
0.9
0.63
1.3
G
A
G (0.1927
G G
51
(0.0369)
75
(0.0428)


hCV30747430
NR1I2
MEGA1
add
T_vs_C
0.007
1.19
1.05
1.34
T
C
T (0.1852
T T
76
(0.0563)
65
(0.037)



(rs11712211)
LETS
add
T_vs_C
0.014
1.35
1.06
1.71
T
C
T (0.1519
T T
26
(0.0591)
11
(0.0244)




LETS
Gen
TC_vs_CC
0.277
1.18
0.87
1.59
T
C
T (0.1519
T T
26
(0.0591)
11
(0.0244)





Gen
TT_vs_CC
0.009
2.63
1.28
5.42
T
C
T (0.1519
T T
26
(0.0591)
11
(0.0244)




MEGA1
Gen
TC_vs_CC
0.146
1.12
0.96
1.31
T
C
T (0.1852
T T
76
(0.0563)
65
(0.037)





Gen
TT_vs_CC
0.006
1.61
1.14
2.27
T
C
T (0.1852
T T
76
(0.0563)
65
(0.037)


hCV263841
NR1I2
LETS
add
C_vs_A
1E−04
1.44
1.19
1.73
C
A
C (0.3296
C C
88
(0.2018)
49
(0.1106)



(rs1523127)
MEGA1
add
C_vs_A
0.008
1.15
1.04
1.27
C
A
C (0.3907
C C
250
(0.1788)
261
(0.1485)




LETS
Gen
CA_vs_AA
0.13
1.25
0.94
1.66
C
A
C (0.3296
C C
88
(0.2018)
49
(0.1106)





Gen
CC_vs_AA
7E−05
2.24
1.51
3.34
C
A
C (0.3296
C C
88
(0.2018)
49
(0.1106)




MEGA1
Gen
CA_vs_AA
0.15
1.12
0.96
1.31
C
A
C (0.3907
C C
250
(0.1788)
261
(0.1485)





Gen
CC_vs_AA
0.007
1.33
1.08
1.65
C
A
C (0.3907
C C
250
(0.1788)
261
(0.1485)


hCV4041
NR3C1
MEGA1
dom
TT + TC_vs_CC
0.021
1.41
1.05
1.89
T
C
T (0.0268
T T
4
(0.0029)
1
(0.0006)



(rs6190)
LETS
dom
TT + TC_vs_CC
0.05
1.65
1
2.73
T
C
T (0.031
T T
1
(0.0023)
1
(0.0022)




LETS
Gen
TC_vs_CC
0.047
1.68
1.01
2.79
T
C
T (0.031
T T
1
(0.0023)
1
(0.0022)





Gen
TT_vs_CC
0.966
1.06
0.07
17
T
C
T (0.031
T T
1
(0.0023)
1
(0.0022)




MEGA1
Gen
TC_vs_CC
0.038
1.37
1.02
1.84
T
C
T (0.0268
T T
4
(0.0029)
1
(0.0006)





Gen
TT_vs_CC
0.139
5.24
0.58
46.9
T
C
T (0.0268
T T
4
(0.0029)
1
(0.0006)


hCV2915511
OBSL1
LETS
Gen
CT_vs_TT
0.015
1.95
1.14
3.35
C
T
C (0.0265
C C
3
(0.0068)
1
(0.0022)



(rs627530)
MEGA1
Gen
CC_vs_TT
0.024
3.28
1.17
9.23
C
T
C (0.0387
C C
13
(0.0093)
5
(0.0028)




LETS
Gen
CC_vs_TT
0.311
3.23
0.33
31.1
C
T
C (0.0265
C C
3
(0.0068)
1
(0.0022)





Gen
CT_vs_TT
0.015
1.95
1.14
3.35
C
T
C (0.0265
C C
3
(0.0068)
1
(0.0022)




MEGA1
Gen
CC_vs_TT
0.024
3.28
1.17
9.23
C
T
C (0.0387
C C
13
(0.0093)
5
(0.0028)





Gen
CT_vs_TT
0.564
0.92
0.7
1.22
C
T
C (0.0387
C C
13
(0.0093)
5
(0.0028)


hCV16177220
ODZ1
MEGA1
add
C_vs_T
3E−04
1.22
1.09
1.36
C
T
T (0.2098
T T
125
(0.0899)
214
(0.122)



(rs2266911)
LETS
add
C_vs_T
0.017
1.28
1.05
1.57
C
T
T (0.213
T T
35
(0.079)
54
(0.1192)




LETS
Gen
CC_vs_TT
0.03
1.65
1.05
2.6
C
T
T (0.213
T T
35
(0.079)
54
(0.1192)





Gen
CT_vs_TT
0.321
1.31
0.77
2.22
C
T
T (0.213
T T
35
(0.079)
54
(0.1192)




MEGA1
Gen
CC_vs_TT
0.001
1.46
1.16
1.85
C
T
T (0.2098
T T
125
(0.0899)
214
(0.122)





Gen
CT_vs_TT
0.253
1.18
0.89
1.56
C
T
T (0.2098
T T
125
(0.0899)
214
(0.122)


hCV7584272
OR1B1
LETS
Gen
AG_vs_GG
0.065
1.29
0.98
1.7
A
G
A (0.2367
A A
26
(0.059)
24
(0.0531)



(rs1536929)
MEGA1
dom
AA + AG_vs_GG
0.044
1.16
1
1.33
A
G
A (0.2396
A A
83
(0.0607)
98
(0.0558)




LETS
Gen
AA_vs_GG
0.461
1.24
0.7
2.23
A
G
A (0.2367
A A
26
(0.059)
24
(0.0531)





Gen
AG_vs_GG
0.065
1.29
0.98
1.7
A
G
A (0.2367
A A
26
(0.059)
24
(0.0531)




MEGA1
Gen
AA_vs_GG
0.344
1.16
0.85
1.58
A
G
A (0.2396
A A
83
(0.0607)
98
(0.0558)





Gen
AG_vs_GG
0.054
1.16
1
1.34
A
G
A (0.2396
A A
83
(0.0607)
98
(0.0558)


hCV9327878
OR7G1
MEGA1
add
G_vs_C
0.006
1.16
1.04
1.29
G
C
G (0.3169
G G
180
(0.1316)
190
(0.1082)



(rs2217657)
LETS
add
G_vs_C
0.033
1.24
1.02
1.5
G
C
G (0.3069
G G
61
(0.1386)
45
(0.1004)




LETS
Gen
GC_vs_CC
0.209
1.2
0.9
1.59
G
C
G (0.3069
G G
61
(0.1386)
45
(0.1004)





Gen
GG_vs_CC
0.04
1.57
1.02
2.42
G
C
G (0.3069
G G
61
(0.1386)
45
(0.1004)




MEGA1
Gen
GC_vs_CC
0.055
1.16
1
1.35
G
C
G (0.3169
G G
180
(0.1316)
190
(0.1082)





Gen
GG_vs_CC
0.012
1.34
1.07
1.69
G
C
G (0.3169
G G
180
(0.1316)
190
(0.1082)


hCV15990789
OTOG
MEGA1
rec
GG_vs_GA + AA
0.008
1.22
1.05
1.41
G
A
A (0.4036
A A
220
(0.1614)
279
(0.1592)



(rs2355466)
LETS
rec
GG_vs_GA + AA
0.013
1.43
1.08
1.89
G
A
A (0.4446
A A
75
(0.1697)
80
(0.1774)




LETS
Gen
GA_vs_AA
0.602
0.91
0.63
1.31
G
A
A (0.4446
A A
75
(0.1697)
80
(0.1774)





Gen
GG_vs_AA
0.153
1.33
0.9
1.96
G
A
A (0.4446
A A
75
(0.1697)
80
(0.1774)




MEGA1
Gen
GA_vs_AA
0.256
0.89
0.72
1.09
G
A
A (0.4036
A A
220
(0.1614)
279
(0.1592)





Gen
GG_vs_AA
0.308
1.12
0.9
1.38
G
A
A (0.4036
A A
220
(0.1614)
279
(0.1592)


hCV8361354
PANX1
LETS
Gen
CC_vs_AA
0.01
1.75
1.15
2.67
C
A
A (0.4007
A A
48
(0.1084)
70
(0.1545)



(rs1138800)
MEGA1
Gen
CA_vs_AA
0.038
0.8
0.64
0.99
C
A
A (0.3793
A A
207
(0.1491)
227
(0.1296)




LETS
Gen
CA_vs_AA
0.179
1.33
0.88
2.01
C
A
A (0.4007
A A
48
(0.1084)
70
(0.1545)





Gen
CC_vs_AA
0.01
1.75
1.15
2.67
C
A
A (0.4007
A A
48
(0.1084)
70
(0.1545)




MEGA1
Gen
CA_vs_AA
0.038
0.8
0.64
0.99
C
A
A (0.3793
A A
207
(0.1491)
227
(0.1296)





Gen
CC_vs_AA
0.455
0.92
0.74
1.15
C
A
A (0.3793
A A
207
(0.1491)
227
(0.1296)


hCV30500334
PHACTR3
LETS
add
G_vs_A
0.006
1.31
1.08
1.59
G
A
A (0.4172
A A
59
(0.1332)
74
(0.1634)



(rs6128674)
MEGA1
add
G_vs_A
0.017
1.13
1.02
1.25
G
A
A (0.3969
A A
185
(0.1358)
285
(0.1624)




LETS
Gen
GA_vs_AA
0.758
1.06
0.72
1.57
G
A
A (0.4172
A A
59
(0.1332)
74
(0.1634)





Gen
GG_vs_AA
0.024
1.59
1.06
2.38
G
A
A (0.4172
A A
59
(0.1332)
74
(0.1634)




MEGA1
Gen
GA_vs_AA
0.128
1.18
0.95
1.46
G
A
A (0.3969
A A
185
(0.1358)
285
(0.1624)





Gen
GG_vs_AA
0.017
1.3
1.05
1.62
G
A
A (0.3969
A A
185
(0.1358)
285
(0.1624)


hCV27474984
PIK3R1
MEGA1
add
A_vs_G
0.011
1.14
1.03
1.26
A
G
A (0.4412
A A
293
(0.2108)
362
(0.2067)



(rs3756668)
LETS
add
A_vs_G
0.026
1.24
1.03
1.5
A
G
A (0.449
A A
110
(0.2489)
87
(0.1929)




LETS
Gen
AA_vs_GG
0.025
1.54
1.06
2.25
A
G
A (0.449
A A
110
(0.2489)
87
(0.1929)





Gen
AG_vs_GG
0.305
1.18
0.86
1.61
A
G
A (0.449
A A
110
(0.2489)
87
(0.1929)




MEGA1
Gen
AA_vs_GG
0.029
1.25
1.02
1.53
A
G
A (0.4412
A A
293
(0.2108)
362
(0.2067)





Gen
AG_vs_GG
1E−04
1.38
1.17
1.62
A
G
A (0.4412
A A
293
(0.2108)
362
(0.2067)


hCV7625318
PLEKHG4
LETS
Gen
AG_vs_GG
0.003
1.79
1.22
2.62
A
G
A (0.0629
A A
2
(0.0045)
4
(0.0088)



(rs3868142)
MEGA1
Gen
AG_vs_GG
0.035
1.24
1.02
1.51
A
G
A (0.0764
A A
13
(0.0094)
16
(0.0091)




LETS
Gen
AA_vs_GG
0.497
0.55
0.1
3.04
A
G
A (0.0629
A A
2
(0.0045)
4
(0.0088)





Gen
AG_vs_GG
0.003
1.79
1.22
2.62
A
G
A (0.0629
A A
2
(0.0045)
4
(0.0088)




MEGA1
Gen
AA_vs_GG
0.878
1.06
0.51
2.21
A
G
A (0.0764
A A
13
(0.0094)
16
(0.0091)





Gen
AG_vs_GG
0.035
1.24
1.02
1.51
A
G
A (0.0764
A A
13
(0.0094)
16
(0.0091)


hCV8598986
POLR1A
LETS
rec
CC_vs_CT + TT
0.023
1.36
1.04
1.76
C
T
T (0.3186
T T
28
(0.0633)
45
(0.0996)



(rs4832233)
MEGA1
rec
CC_vs_CT + TT
0.05
1.15
1
1.33
C
T
T (0.2873
T T
119
(0.0858)
154
(0.0882)




LETS
Gen
CC_vs_TT
0.019
1.83
1.1
3.04
C
T
T (0.3186
T T
28
(0.0633)
45
(0.0996)





Gen
CT_vs_TT
0.173
1.43
0.85
2.39
C
T
T (0.3186
T T
28
(0.0633)
45
(0.0996)




MEGA1
Gen
CC_vs_TT
0.478
1.1
0.85
1.42
C
T
T (0.2873
T T
119
(0.0858)
154
(0.0882)





Gen
CT_vs_TT
0.663
0.94
0.72
1.23
C
T
T (0.2873
T T
119
(0.0858)
154
(0.0882)


hCV926518
PPP2R5C
LETS
Gen
GT_vs_TT
0.034
1.45
1.03
2.04
G
T
G (0.0896
G G
4
(0.009)
5
(0.0111)



(rs746781)
MEGA1
Gen
GT_vs_TT
0.05
1.2
1
1.44
G
T
G (0.0994
G G
16
(0.0117)
26
(0.0148)




LETS
Gen
GG_vs_TT
0.842
0.87
0.23
3.28
G
T
G (0.0896
G G
4
(0.009)
5
(0.0111)





Gen
GT_vs_TT
0.034
1.45
1.03
2.04
G
T
G (0.0896
G G
4
(0.009)
5
(0.0111)




MEGA1
Gen
GG_vs_TT
0.525
0.82
0.44
1.53
G
T
G (0.0994
G G
16
(0.0117)
26
(0.0148)





Gen
GT_vs_TT
0.05
1.2
1
1.44
G
T
G (0.0994
G G
16
(0.0117)
26
(0.0148)


hCV1841975
PROC
LETS
Gen
TT_vs_AA
0.064
1.43
0.98
2.08
T
A
T (0.427
T T
100
(0.2262)
81
(0.1792)



(rs1799810)
MEGA1
Gen
TT_vs_AA
0.006
1.33
1.09
1.62
T
A
T (0.4356
T T
323
(0.2327)
329
(0.1883)




LETS
Gen
TA_vs_AA
0.495
1.11
0.82
1.5
T
A
T (0.427
T T
100
(0.2262)
81
(0.1792)





Gen
TT_vs_AA
0.064
1.43
0.98
2.08
T
A
T (0.427
T T
100
(0.2262)
81
(0.1792)




MEGA1
Gen
TA_vs_AA
0.772
1.02
0.87
1.21
T
A
T (0.4356
T T
323
(0.2327)
329
(0.1883)





Gen
TT_vs_AA
0.006
1.33
1.09
1.62
T
A
T (0.4356
T T
323
(0.2327)
329
(0.1883)


hCV8957432
RAC2 (rs6572)
MEGA1
rec
CC_vs_CG + GG
0.031
1.21
1.02
1.44
C
G
C (0.4364
C C
308
(0.2217)
334
(0.1905)




LETS
rec
CC_vs_CG + GG
0.043
1.41
1.01
1.96
C
G
C (0.4458
C C
99
(0.2245)
77
(0.1704)




LETS
Gen
CC_vs_GG
0.102
1.38
0.94
2.04
C
G
C (0.4458
C C
99
(0.2245)
77
(0.1704)





Gen
CG_vs_GG
0.863
0.97
0.71
1.33
C
G
C (0.4458
C C
99
(0.2245)
77
(0.1704)




MEGA1
Gen
CC_vs_GG
0.02
1.27
1.04
1.55
C
G
C (0.4364
C C
308
(0.2217)
334
(0.1905)





Gen
CG_vs_GG
0.363
1.08
0.92
1.27
C
G
C (0.4364
C C
308
(0.2217)
334
(0.1905)


hCV29271569
RDH13
LETS
add
T_vs_C
0.014
1.36
1.06
1.75
T
C
C (0.1954
C C
9
(0.0204)
17
(0.0375)



(rs1626971)
MEGA1
add
T_vs_C
0.031
1.15
1.01
1.32
T
C
C (0.1867
C C
43
(0.031)
60
(0.0342)




LETS
Gen
TC_vs_CC
0.322
1.53
0.66
3.56
T
C
C (0.1954
C C
9
(0.0204)
17
(0.0375)





Gen
TT_vs_CC
0.089
2.04
0.9
4.66
T
C
C (0.1954
C C
9
(0.0204)
17
(0.0375)




MEGA1
Gen
TC_vs_CC
0.906
0.98
0.65
1.47
T
C
C (0.1867
C C
43
(0.031)
60
(0.0342)





Gen
TT_vs_CC
0.445
1.17
0.78
1.75
T
C
C (0.1867
C C
43
(0.031)
60
(0.0342)


hCV8703249
RDH13
LETS
add
G_vs_T
0.052
1.28
1
1.64
G
T
T (0.1898
T T
10
(0.0226)
17
(0.0375)



(rs1654444)
MEGA1
add
G_vs_T
0.02
1.17
1.03
1.33
G
T
T (0.1879
T T
41
(0.0296)
64
(0.0364)




LETS
Gen
GG_vs_TT
0.149
1.8
0.81
3.99
G
T
T (0.1898
T T
10
(0.0226)
17
(0.0375)





Gen
GT_vs_TT
0.382
1.44
0.64
3.27
G
T
T (0.1898
T T
10
(0.0226)
17
(0.0375)




MEGA1
Gen
GG_vs_TT
0.193
1.31
0.87
1.95
G
T
T (0.1879
T T
41
(0.0296)
64
(0.0364)





Gen
GT_vs_TT
0.642
1.1
0.73
1.67
G
T
T (0.1879
T T
41
(0.0296)
64
(0.0364)


hCV8717752
RDH13
LETS
add
G_vs_A
0.024
1.34
1.04
1.72
G
A
A (0.1892
A A
7
(0.0158)
17
(0.0376)



(rs1671217)
MEGA1
rec
GG_vs_GA + AA
0.048
1.17
1
1.36
G
A
A (0.1774
A A
36
(0.026)
52
(0.0297)




LETS
Gen
GA_vs_AA
0.114
2.09
0.84
5.22
G
A
A (0.1892
A A
7
(0.0158)
17
(0.0376)





Gen
GG_vs_AA
0.038
2.58
1.06
6.32
G
A
A (0.1892
A A
7
(0.0158)
17
(0.0376)




MEGA1
Gen
GA_vs_AA
0.9
1.03
0.66
1.61
G
A
A (0.1774
A A
36
(0.026)
52
(0.0297)





Gen
GG_vs_AA
0.414
1.2
0.78
1.85
G
A
A (0.1774
A A
36
(0.026)
52
(0.0297)


hCV11975296
SELP (rs6131)
MEGA1
add
T_vs_C
0.003
1.2
1.06
1.36
T
C
T (0.1818
T T
63
(0.0453)
66
(0.0377)




LETS
add
T_vs_C
0.025
1.29
1.03
1.62
T
C
T (0.1777
T T
27
(0.0611)
20
(0.0442)




LETS
Gen
TC_vs_CC
0.049
1.34
1
1.8
T
C
T (0.1777
T T
27
(0.0611)
20
(0.0442)





Gen
TT_vs_CC
0.157
1.54
0.85
2.81
T
C
T (0.1777
T T
27
(0.0611)
20
(0.0442)




MEGA1
Gen
TC_vs_CC
0.004
1.25
1.07
1.46
T
C
T (0.1818
T T
63
(0.0453)
66
(0.0377)





Gen
TT_vs_CC
0.148
1.3
0.91
1.86
T
C
T (0.1818
T T
63
(0.0453)
66
(0.0377)


hCV9596963
SERPINA5
LETS
dom
AA + AG_vs_GG
0.03
1.61
1.05
2.48
A
G
G (0.3831
G G
38
(0.0874)
60
(0.1336)



(rs6115)
MEGA1
dom
AA + AG_vs_GG
0.038
1.27
1.01
1.6
A
G
G (0.3441
G G
137
(0.0988)
214
(0.1224)




LETS
Gen
AA_vs_GG
0.033
1.65
1.04
2.6
A
G
G (0.3831
G G
38
(0.0874)
60
(0.1336)





Gen
AG_vs_GG
0.043
1.59
1.01
2.48
A
G
G (0.3831
G G
38
(0.0874)
60
(0.1336)




MEGA1
Gen
AA_vs_GG
0.05
1.27
1
1.61
A
G
G (0.3441
G G
137
(0.0988)
214
(0.1224)





Gen
AG_vs_GG
0.047
1.27
1
1.62
A
G
G (0.3441
G G
137
(0.0988)
214
(0.1224)


hCV16180170
SERPINC1
MEGA1
add
T_vs_C
0.01
1.24
1.05
1.47
T
C
T (0.0892
T T
22
(0.0158)
15
(0.0085)



(rs2227589)
LETS
add
T_vs_C
0.026
1.42
1.04
1.94
T
C
T (0.0863
T T
6
(0.0135)
4
(0.0088)




LETS
Gen
TC_vs_CC
0.031
1.46
1.04
2.06
T
C
T (0.0863
T T
6
(0.0135)
4
(0.0088)





Gen
TT_vs_CC
0.442
1.65
0.46
5.89
T
C
T (0.0863
T T
6
(0.0135)
4
(0.0088)




MEGA1
Gen
TC_vs_CC
0.052
1.2
1
1.45
T
C
T (0.0892
T T
22
(0.0158)
15
(0.0085)





Gen
TT_vs_CC
0.052
1.93
1
3.73
T
C
T (0.0892
T T
22
(0.0158)
15
(0.0085)


hCV1650632
SERPINC1
MEGA1
Gen
CC_vs_TT
0.005
1.38
1.1
1.74
C
T
C (0.3391
C C
191
(0.1426)
197
(0.1126)



(rs5878)
LETS
Gen
CT_vs_TT
0.026
1.38
1.04
1.83
C
T
C (0.3213
C C
49
(0.1119)
56
(0.1258)




LETS
Gen
CC_vs_TT
0.92
1.02
0.66
1.57
C
T
C (0.3213
C C
49
(0.1119)
56
(0.1258)





Gen
CT_vs_TT
0.026
1.38
1.04
1.83
C
T
C (0.3213
C C
49
(0.1119)
56
(0.1258)




MEGA1
Gen
CC_vs_TT
0.005
1.38
1.1
1.74
C
T
C (0.3391
C C
191
(0.1426)
197
(0.1126)





Gen
CT_vs_TT
0.191
1.11
0.95
1.29
C
T
C (0.3391
C C
191
(0.1426)
197
(0.1126)


hCV3216426
SFRS2IP
LETS
dom
AA + AT_vs_TT
0.016
1.47
1.07
2.02
A
T
T (0.5022
T T
87
(0.1977)
119
(0.2662)



(rs7315731)
MEGA1
dom
AA + AT_vs_TT
0.02
1.22
1.03
1.44
A
T
T (0.4909
T T
301
(0.2155)
441
(0.251)




LETS
Gen
AA_vs_TT
0.016
1.58
1.09
2.29
A
T
T (0.5022
T T
87
(0.1977)
119
(0.2662)





Gen
AT_vs_TT
0.043
1.41
1.01
1.98
A
T
T (0.5022
T T
87
(0.1977)
119
(0.2662)




MEGA1
Gen
AA_vs_TT
0.066
1.2
0.99
1.47
A
T
T (0.4909
T T
301
(0.2155)
441
(0.251)





Gen
AT_vs_TT
0.023
1.23
1.03
1.47
A
T
T (0.4909
T T
301
(0.2155)
441
(0.251)


hCV25602230
SIRT6
MEGA1
add
G_vs_T
0.008
1.73
1.15
2.58
G
T
G (0.0108
G G
4
(0.0029)
1
(0.0006)



(rs7246235)
LETS
add
G_vs_T
0.012
3.45
1.31
9.07
G
T
G (0.0055
G G
2
(0.0045)
0
(0)




LETS
Gen
GG_vs_TT
0.971
819571
89035
Inf
G
T
G (0.0055
G G
2
(0.0045)
0
(0)





Gen
GT_vs_TT
0.027
3.16
1.14
8.76
G
T
G (0.0055
G G
2
(0.0045)
0
(0)




MEGA1
Gen
GG_vs_TT
0.143
5.14
0.57
46
G
T
G (0.0108
G G
4
(0.0029)
1
(0.0006)





Gen
GT_vs_TT
0.028
1.64
1.05
2.55
G
T
G (0.0108
G G
4
(0.0029)
1
(0.0006)


hCV2086329
SPARC
MEGA1
rec
GG_vs_GA + AA
0.001
1.35
1.13
1.62
G
A
G (0.4219
G G
298
(0.2152)
296
(0.1688)



(rs4958487)
LETS
rec
GG_vs_GA + AA
0.013
1.52
1.09
2.12
G
A
G (0.4183
G G
104
(0.2348)
76
(0.1678)




LETS
Gen
GA_vs_AA
0.943
1.01
0.75
1.36
G
A
G (0.4183
G G
104
(0.2348)
76
(0.1678)





Gen
GG_vs_AA
0.026
1.53
1.05
2.23
G
A
G (0.4183
G G
104
(0.2348)
76
(0.1678)




MEGA1
Gen
GA_vs_AA
0.146
0.89
0.76
1.04
G
A
G (0.4219
G G
298
(0.2152)
296
(0.1688)





Gen
GG_vs_AA
0.026
1.26
1.03
1.54
G
A
G (0.4219
G G
298
(0.2152)
296
(0.1688)


hCV11466393
TACR1 (rs881)
LETS
add
C_vs_G
0.012
1.38
1.07
1.77
C
G
G (0.1953
G G
10
(0.0228)
17
(0.0384)




MEGA1
add
C_vs_G
0.037
1.15
1.01
1.32
C
G
G (0.1746
G G
32
(0.023)
52
(0.0297)




LETS
Gen
CC_vs_GG
0.121
1.88
0.85
4.17
C
G
G (0.1953
G G
10
(0.0228)
17
(0.0384)





Gen
CG_vs_GG
0.465
1.36
0.6
3.08
C
G
G (0.1953
G G
10
(0.0228)
17
(0.0384)




MEGA1
Gen
CC_vs_GG
0.185
1.35
0.86
2.12
C
G
G (0.1746
G G
32
(0.023)
52
(0.0297)





Gen
CG_vs_GG
0.487
1.18
0.74
1.87
C
G
G (0.1746
G G
32
(0.023)
52
(0.0297)


hCV3216649
TAF1B
LETS
dom
AA + AG_vs_GG
0.059
1.29
0.99
1.68
A
G
A (0.2971
A A
50
(0.1134)
47
(0.1042)



(rs1054565)
MEGA1
dom
AA + AG_vs_GG
0.044
1.16
1
1.33
A
G
A (0.3179
A A
160
(0.115)
191
(0.109)




LETS
Gen
AA_vs_GG
0.336
1.24
0.8
1.93
A
G
A (0.2971
A A
50
(0.1134)
47
(0.1042)





Gen
AG_vs_GG
0.064
1.3
0.98
1.72
A
G
A (0.2971
A A
50
(0.1134)
47
(0.1042)




MEGA1
Gen
AA_vs_GG
0.267
1.14
0.9
1.44
A
G
A (0.3179
A A
160
(0.115)
191
(0.109)





Gen
AG_vs_GG
0.051
1.16
1
1.35
A
G
A (0.3179
A A
160
(0.115)
191
(0.109)


hCV470708
THBS2
LETS
add
T_vs_G
0.031
1.25
1.02
1.52
T
G
T (0.2838
T T
50
(0.1131)
38
(0.0843)



(rs10945408)
MEGA1
Gen
TT_vs_GG
0.041
1.29
1.01
1.65
T
G
T (0.3005
T T
152
(0.109)
153
(0.0873)




LETS
Gen
TG_vs_GG
0.108
1.26
0.95
1.66
T
G
T (0.2838
T T
50
(0.1131)
38
(0.0843)





Gen
TT_vs_GG
0.067
1.54
0.97
2.45
T
G
T (0.2838
T T
50
(0.1131)
38
(0.0843)




MEGA1
Gen
TG_vs_GG
0.755
1.02
0.88
1.19
T
G
T (0.3005
T T
152
(0.109)
153
(0.0873)





Gen
TT_vs_GG
0.041
1.29
1.01
1.65
T
G
T (0.3005
T T
152
(0.109)
153
(0.0873)


hCV3272537
TIAM1
LETS
dom
AA + AT_vs_TT
0.078
1.29
0.97
1.71
A
T
A (0.4281
A A
100
(0.2268)
90
(0.1991)



(rs497689)
MEGA1
dom
AA + AT_vs_TT
0.003
1.26
1.08
1.46
A
T
A (0.4287
A A
277
(0.2003)
347
(0.1989)




LETS
Gen
AA_vs_TT
0.106
1.36
0.94
1.96
A
T
A (0.4281
A A
100
(0.2268)
90
(0.1991)





Gen
AT_vs_TT
0.132
1.26
0.93
1.71
A
T
A (0.4281
A A
100
(0.2268)
90
(0.1991)




MEGA1
Gen
AA_vs_TT
0.113
1.18
0.96
1.44
A
T
A (0.4287
A A
277
(0.2003)
347
(0.1989)





Gen
AT_vs_TT
0.002
1.29
1.1
1.52
A
T
A (0.4287
A A
277
(0.2003)
347
(0.1989)


hCV27833944
TNFSF4
LETS
add
C_vs_T
0.061
1.35
0.99
1.85
C
T
C (0.0856
C C
5
(0.0113)
3
(0.0067)



(rs6702339)
MEGA1
add
C_vs_T
0.009
1.24
1.06
1.46
C
T
C (0.0901
C C
25
(0.018)
16
(0.0091)




LETS
Gen
CC_vs_TT
0.423
1.8
0.43
7.59
C
T
C (0.0856
C C
5
(0.0113)
3
(0.0067)





Gen
CT_vs_TT
0.084
1.35
0.96
1.91
C
T
C (0.0856
C C
5
(0.0113)
3
(0.0067)




MEGA1
Gen
CC_vs_TT
0.025
2.06
1.09
3.87
C
T
C (0.0901
C C
25
(0.018)
16
(0.0091)





Gen
CT_vs_TT
0.072
1.19
0.98
1.43
C
T
C (0.0901
C C
25
(0.018)
16
(0.0091)


hCV1723643
UMODL1
LETS
rec
AA_vs_AC + CC
0.056
1.3
0.99
1.7
A
C
C (0.2406
C C
19
(0.0431)
22
(0.0488)



(rs220130)
MEGA1
rec
AA_vs_AC + CC
0.019
1.19
1.03
1.38
A
C
C (0.2246
C C
59
(0.0426)
95
(0.0542)




LETS
Gen
AA_vs_CC
0.481
1.26
0.67
2.38
A
C
C (0.2406
C C
19
(0.0431)
22
(0.0488)





Gen
AC_vs_CC
0.912
0.96
0.5
1.85
A
C
C (0.2406
C C
19
(0.0431)
22
(0.0488)




MEGA1
Gen
AA_vs_CC
0.075
1.36
0.97
1.9
A
C
C (0.2246
C C
59
(0.0426)
95
(0.0542)





Gen
AC_vs_CC
0.396
1.16
0.82
1.65
A
C
C (0.2246
C C
59
(0.0426)
95
(0.0542)


hCV7581501
USP45
LETS
Gen
CG_vs_GG
0.016
1.51
1.08
2.11
C
G
C (0.096
C C
9
(0.0203)
7
(0.0155)



(rs1323717)
MEGA1
Gen
CC_vs_GG
0.034
1.94
1.05
3.6
C
G
C (0.1142
C C
26
(0.0187)
17
(0.0097)




LETS
Gen
CC_vs_GG
0.481
1.43
0.53
3.89
C
G
C (0.096
C C
9
(0.0203)
7
(0.0155)





Gen
CG_vs_GG
0.016
1.51
1.08
2.11
C
G
C (0.096
C C
9
(0.0203)
7
(0.0155)




MEGA1
Gen
CC_vs_GG
0.034
1.94
1.05
3.6
C
G
C (0.1142
C C
26
(0.0187)
17
(0.0097)





Gen
CG_vs_GG
0.949
0.99
0.84
1.18
C
G
C (0.1142
C C
26
(0.0187)
17
(0.0097)


hCV15949414
XYLB
MEGA1
rec
GG_vs_GA + AA
0.003
1.48
1.14
1.92
G
A
A (0.0496
A A
5
(0.0037)
1
(0.0006)



(rs2234628)
LETS
rec
GG_vs_GA + AA
0.036
1.64
1.03
2.61
G
A
A (0.0569
A A
1
(0.0023)
0
(0)




LETS
Gen
GA_vs_AA
0.968
0
####
####
G
A
A (0.0569
A A
1
(0.0023)
0
(0)





Gen
GG_vs_AA
0.969
0
####
####
G
A
A (0.0569
A A
1
(0.0023)
0
(0)




MEGA1
Gen
GA_vs_AA
0.04
0.1
0.01
0.9
G
A
A (0.0496
A A
5
(0.0037)
1
(0.0006)





Gen
GG_vs_AA
0.095
0.16
0.02
1.38
G
A
A (0.0496
A A
5
(0.0037)
1
(0.0006)


hCV356522
ZBTB41
LETS
dom
TT + TC_vs_CC
0.055
1.41
0.99
2
T
C
T (0.0784
T T
6
(0.0135)
4
(0.0088)



(rs10732295)
MEGA1
dom
TT + TC_vs_CC
0.007
1.28
1.07
1.52
T
C
T (0.0931
T T
22
(0.0159)
19
(0.0108)




LETS
Gen
TC_vs_CC
0.07
1.39
0.97
2
T
C
T (0.0784
T T
6
(0.0135)
4
(0.0088)





Gen
TT_vs_CC
0.454
1.63
0.46
5.81
T
C
T (0.0784
T T
6
(0.0135)
4
(0.0088)




MEGA1
Gen
TC_vs_CC
0.014
1.26
1.05
1.51
T
C
T (0.0931
T T
22
(0.0159)
19
(0.0108)





Gen
TT_vs_CC
0.174
1.54
0.83
2.85
T
C
T (0.0931
T T
22
(0.0159)
19
(0.0108)


hCV25596789
ZNF544
LETS
add
G_vs_C
0.004
2.54
1.34
4.83
G
C
G (0.0144
G G
2
(0.0045)
0
(0)



(rs6510130)
MEGA1
add
G_vs_C
0.01
1.55
1.11
2.18
G
C
G (0.0182
G G
1
(0.0007)
0
(0)




LETS
Gen
GC_vs_CC
0.011
2.38
1.22
4.65
G
C
G (0.0144
G G
2
(0.0045)
0
(0)





Gen
GG_vs_CC
0.971
832450
51533
Inf
G
C
G (0.0144
G G
2
(0.0045)
0
(0)




MEGA1
Gen
GC_vs_CC
0.015
1.52
1.08
2.14
G
C
G (0.0182
G G
1
(0.0007)
0
(0)





Gen
GG_vs_CC
0.952
135256
0
####
G
C
G (0.0182
G G
1
(0.0007)
0
(0)


hCV25951992
ZWINT
MEGA1
dom
AA + AC_vs_CC
0.001
2.11
1.34
3.32
A
C
A (0.0091
A A
5
(0.0036)
1
(0.0006)



(rs11005328)
LETS
dom
AA + AC_vs_CC
0.03
2.32
1.09
4.96
A
C
A (0.0122
A A
0
(0)
1
(0.0022)




LETS
Gen
AA_vs_CC
0.969
0
####
####
A
C
A (0.0122
A A
0
(0)
1
(0.0022)





Gen
AC_vs_CC
0.018
2.58
1.17
5.66
A
C
A (0.0122
A A
0
(0)
1
(0.0022)




MEGA1
Gen
AA_vs_CC
0.09
6.41
0.75
55
A
C
A (0.0091
A A
5
(0.0036)
1
(0.0006)





Gen
AC_vs_CC
0.004
1.97
1.23
3.13
A
C
A (0.0091
A A
5
(0.0036)
1
(0.0006)



























CONTROL cnt


CONTROL cnt








CASE cnt
(CONTROL

CASE cnt
(CONTROL



marker
annot
Endpoint
Model
Genot2
(CASE frq2
frq)2
Genot3
(CASE frq3
frq)3


























hCV505733
(rs11126416)
LETS
Gen
A G
215
(0.4853
222
(0.4901)
G G
157
(0.3544
177
(0.3907)





MEGA1
Gen
A G
637
(0.4593
800
(0.4553)
G G
540
(0.3893
744
(0.4234)





LETS
Gen
A G
215
(0.4853
222
(0.4901)
G G
157
(0.3544
177
(0.3907)






Gen
A G
215
(0.4853
222
(0.4901)
G G
157
(0.3544
177
(0.3907)





MEGA1
Gen
A G
637
(0.4593
800
(0.4553)
G G
540
(0.3893
744
(0.4234)






Gen
A G
637
(0.4593
800
(0.4553)
G G
540
(0.3893
744
(0.4234)



hCV2879752
(rs1244565)
LETS
add
G A
227
(0.5147
214
(0.4724)
A A
99
(0.2245
135
(0.298)





MEGA1
add
G A
672
(0.4923
886
(0.5057)
A A
352
(0.2579
487
(0.278)





LETS
Gen
G A
227
(0.5147
214
(0.4724)
A A
99
(0.2245
135
(0.298)






Gen
G A
227
(0.5147
214
(0.4724)
A A
99
(0.2245
135
(0.298)





MEGA1
Gen
G A
672
(0.4923
886
(0.5057)
A A
352
(0.2579
487
(0.278)






Gen
G A
672
(0.4923
886
(0.5057)
A A
352
(0.2579
487
(0.278)



hCV11503470
(rs1800788)
MEGA1
add
T C
512
(0.3691
544
(0.3105)
C C
790
(0.5696
1101
(0.6284)





LETS
add
T C
156
(0.3521
144
(0.3186)
C C
256
(0.5779
291
(0.6438)





LETS
Gen
T C
156
(0.3521
144
(0.3186)
C C
256
(0.5779
291
(0.6438)






Gen
T C
156
(0.3521
144
(0.3186)
C C
256
(0.5779
291
(0.6438)





MEGA1
Gen
T C
512
(0.3691
544
(0.3105)
C C
790
(0.5696
1101
(0.6284)






Gen
T C
512
(0.3691
544
(0.3105)
C C
790
(0.5696
1101
(0.6284)



hCV15860433
(rs2070006)
MEGA1
add
T C
689
(0.4957
832
(0.4746)
C C
405
(0.2914
624
(0.356)





LETS
add
T C
211
(0.4785
217
(0.4822)
C C
135
(0.3061
161
(0.3578)





LETS
Gen
T C
211
(0.4785
217
(0.4822)
C C
135
(0.3061
161
(0.3578)






Gen
T C
211
(0.4785
217
(0.4822)
C C
135
(0.3061
161
(0.3578)





MEGA1
Gen
T C
689
(0.4957
832
(0.4746)
C C
405
(0.2914
624
(0.356)






Gen
T C
689
(0.4957
832
(0.4746)
C C
405
(0.2914
624
(0.356)



hCV2744023
(rs369328)
LETS
add
A G
229
(0.5169
232
(0.5133)
G G
98
(0.2212
133
(0.2942)





MEGA1
add
A G
680
(0.4871
872
(0.4966)
G G
346
(0.2479
480
(0.2733)





LETS
Gen
A G
229
(0.5169
232
(0.5133)
G G
98
(0.2212
133
(0.2942)






Gen
A G
229
(0.5169
232
(0.5133)
G G
98
(0.2212
133
(0.2942)





MEGA1
Gen
A G
680
(0.4871
872
(0.4966)
G G
346
(0.2479
480
(0.2733)






Gen
A G
680
(0.4871
872
(0.4966)
G G
346
(0.2479
480
(0.2733)



hCV27477533
(rs3756008)
MEGA1
add
T A
691
(0.4953
832
(0.4749)
A A
397
(0.2846
624
(0.3562)





LETS
add
T A
212
(0.4796
200
(0.4425)
A A
129
(0.2919
164
(0.3628)





LETS
Gen
T A
212
(0.4796
200
(0.4425)
A A
129
(0.2919
164
(0.3628)






Gen
T A
212
(0.4796
200
(0.4425)
A A
129
(0.2919
164
(0.3628)





MEGA1
Gen
T A
691
(0.4953
832
(0.4749)
A A
397
(0.2846
624
(0.3562)






Gen
T A
691
(0.4953
832
(0.4749)
A A
397
(0.2846
624
(0.3562)



hCV949676
(rs480802)
MEGA1
Gen
C T
440
(0.3262
559
(0.3213)
T T
826
(0.6123
1104
(0.6345)





LETS
Gen
C T
138
(0.3151
139
(0.3075)
T T
271
(0.6187
296
(0.6549)





LETS
Gen
C T
138
(0.3151
139
(0.3075)
T T
271
(0.6187
296
(0.6549)






Gen
C T
138
(0.3151
139
(0.3075)
T T
271
(0.6187
296
(0.6549)





MEGA1
Gen
C T
440
(0.3262
559
(0.3213)
T T
826
(0.6123
1104
(0.6345)






Gen
C T
440
(0.3262
559
(0.3213)
T T
826
(0.6123
1104
(0.6345)



hCV27904396
(rs4829996)
LETS
rec
A G
92
(0.2081
111
(0.245)
G G
286
(0.6471
263
(0.5806)





MEGA1
Gen
A G
300
(0.2158
346
(0.1977)
G G
859
(0.618
1069
(0.6109)





LETS
Gen
A G
92
(0.2081
111
(0.245)
G G
286
(0.6471
263
(0.5806)






Gen
A G
92
(0.2081
111
(0.245)
G G
286
(0.6471
263
(0.5806)





MEGA1
Gen
A G
300
(0.2158
346
(0.1977)
G G
859
(0.618
1069
(0.6109)






Gen
A G
300
(0.2158
346
(0.1977)
G G
859
(0.618
1069
(0.6109)



hCV837462
(rs528088)
LETS
Gen
C A
70
(0.1584
68
(0.1504)
A A
364
(0.8235
382
(0.8451)





MEGA1
dom
C A
193
(0.1385
237
(0.1354)
A A
1196
(0.858
1495
(0.8538)





LETS
Gen
C A
70
(0.1584
68
(0.1504)
A A
364
(0.8235
382
(0.8451)






Gen
C A
70
(0.1584
68
(0.1504)
A A
364
(0.8235
382
(0.8451)





MEGA1
Gen
C A
193
(0.1385
237
(0.1354)
A A
1196
(0.858
1495
(0.8538)






Gen
C A
193
(0.1385
237
(0.1354)
A A
1196
(0.858
1495
(0.8538)



hCV30440155
(rs6699146)
LETS
add
C G
204
(0.4647
207
(0.458)
G G
135
(0.3075
161
(0.3562)





MEGA1
add
C G
651
(0.4855
865
(0.4951)
G G
369
(0.2752
538
(0.308)





LETS
Gen
C G
204
(0.4647
207
(0.458)
G G
135
(0.3075
161
(0.3562)






Gen
C G
204
(0.4647
207
(0.458)
G G
135
(0.3075
161
(0.3562)





MEGA1
Gen
C G
651
(0.4855
865
(0.4951)
G G
369
(0.2752
538
(0.308)






Gen
C G
651
(0.4855
865
(0.4951)
G G
369
(0.2752
538
(0.308)



hCV28960679
(rs6844764)
LETS
rec
C G
210
(0.4751
234
(0.5177)
G G
158
(0.3575
136
(0.3009)





MEGA1
dom
C G
690
(0.4964
814
(0.467)
G G
467
(0.336
571
(0.3276)





LETS
Gen
C G
210
(0.4751
234
(0.5177)
G G
158
(0.3575
136
(0.3009)






Gen
C G
210
(0.4751
234
(0.5177)
G G
158
(0.3575
136
(0.3009)





MEGA1
Gen
C G
690
(0.4964
814
(0.467)
G G
467
(0.336
571
(0.3276)






Gen
C G
690
(0.4964
814
(0.467)
G G
467
(0.336
571
(0.3276)



hCV1952126
(rs7223784)
LETS
add
C A
164
(0.3702
188
(0.4159)
A A
248
(0.5598
221
(0.4889)





MEGA1
add
C A
527
(0.3808
688
(0.3925)
A A
766
(0.5535
918
(0.5237)





LETS
Gen
C A
164
(0.3702
188
(0.4159)
A A
248
(0.5598
221
(0.4889)






Gen
C A
164
(0.3702
188
(0.4159)
A A
248
(0.5598
221
(0.4889)





MEGA1
Gen
C A
527
(0.3808
688
(0.3925)
A A
766
(0.5535
918
(0.5237)






Gen
C A
527
(0.3808
688
(0.3925)
A A
766
(0.5535
918
(0.5237)



hCV31749285
(rs8178591)
LETS
rec
T C
160
(0.3612
200
(0.4415)
C C
243
(0.5485
221
(0.4879)





MEGA1
rec
T C
526
(0.3781
722
(0.4123)
C C
779
(0.56
903
(0.5157)





LETS
Gen
T C
160
(0.3612
200
(0.4415)
C C
243
(0.5485
221
(0.4879)






Gen
T C
160
(0.3612
200
(0.4415)
C C
243
(0.5485
221
(0.4879)





MEGA1
Gen
T C
526
(0.3781
722
(0.4123)
C C
779
(0.56
903
(0.5157)






Gen
T C
526
(0.3781
722
(0.4123)
C C
779
(0.56
903
(0.5157)



hCV3187716
AGTR1
LETS
dom
C A
199
(0.4543
184
(0.4116)
A A
195
(0.4452
224
(0.5011)




(rs5186)
MEGA1
add
C A
530
(0.3946
752
(0.4292)
A A
711
(0.5294
835
(0.4766)





LETS
Gen
C A
199
(0.4543
184
(0.4116)
A A
195
(0.4452
224
(0.5011)






Gen
C A
199
(0.4543
184
(0.4116)
A A
195
(0.4452
224
(0.5011)





MEGA1
Gen
C A
530
(0.3946
752
(0.4292)
A A
711
(0.5294
835
(0.4766)






Gen
C A
530
(0.3946
752
(0.4292)
A A
711
(0.5294
835
(0.4766)



hCV9493081
AKT3
LETS
add
T C
202
(0.457
174
(0.3858)
C C
190
(0.4299
245
(0.5432)




(rs1058304)
MEGA1
add
T C
553
(0.4096
748
(0.4262)
C C
645
(0.4778
879
(0.5009)





LETS
Gen
T C
202
(0.457
174
(0.3858)
C C
190
(0.4299
245
(0.5432)






Gen
T C
202
(0.457
174
(0.3858)
C C
190
(0.4299
245
(0.5432)





MEGA1
Gen
T C
553
(0.4096
748
(0.4262)
C C
645
(0.4778
879
(0.5009)






Gen
T C
553
(0.4096
748
(0.4262)
C C
645
(0.4778
879
(0.5009)



hCV30690780
AKT3
LETS
add
C A
177
(0.4032
142
(0.3149)
A A
223
(0.508
288
(0.6386)




(rs10737888)
MEGA1
add
C A
490
(0.3632
623
(0.3568)
A A
745
(0.5523
1034
(0.5922)





LETS
Gen
C A
177
(0.4032
142
(0.3149)
A A
223
(0.508
288
(0.6386)






Gen
C A
177
(0.4032
142
(0.3149)
A A
223
(0.508
288
(0.6386)





MEGA1
Gen
C A
490
(0.3632
623
(0.3568)
A A
745
(0.5523
1034
(0.5922)






Gen
C A
490
(0.3632
623
(0.3568)
A A
745
(0.5523
1034
(0.5922)



hCV31523557
AKT3
LETS
add
A G
163
(0.3696
120
(0.2667)
G G
254
(0.576
315
(0.7)




(rs10754807)
MEGA1
add
A G
461
(0.3415
532
(0.3028)
G G
815
(0.6037
1151
(0.6551)





LETS
Gen
A G
163
(0.3696
120
(0.2667)
G G
254
(0.576
315
(0.7)






Gen
A G
163
(0.3696
120
(0.2667)
G G
254
(0.576
315
(0.7)





MEGA1
Gen
A G
461
(0.3415
532
(0.3028)
G G
815
(0.6037
1151
(0.6551)






Gen
A G
461
(0.3415
532
(0.3028)
G G
815
(0.6037
1151
(0.6551)



hCV26719108
AKT3
LETS
add
C T
216
(0.4887
202
(0.4469)
T T
156
(0.3529
201
(0.4447)




(rs10927035)
MEGA1
add
C T
624
(0.4636
797
(0.4575)
T T
500
(0.3715
720
(0.4133)





LETS
Gen
C T
216
(0.4887
202
(0.4469)
T T
156
(0.3529
201
(0.4447)






Gen
C T
216
(0.4887
202
(0.4469)
T T
156
(0.3529
201
(0.4447)





MEGA1
Gen
C T
624
(0.4636
797
(0.4575)
T T
500
(0.3715
720
(0.4133)






Gen
C T
624
(0.4636
797
(0.4575)
T T
500
(0.3715
720
(0.4133)



hCV26719121
AKT3
LETS
add
C T
164
(0.371
121
(0.2677)
T T
253
(0.5724
316
(0.6991)




(rs10927041)
MEGA1
add
C T
453
(0.3358
531
(0.3026)
T T
824
(0.6108
1151
(0.6558)





LETS
Gen
C T
164
(0.371
121
(0.2677)
T T
253
(0.5724
316
(0.6991)






Gen
C T
164
(0.371
121
(0.2677)
T T
253
(0.5724
316
(0.6991)





MEGA1
Gen
C T
453
(0.3358
531
(0.3026)
T T
824
(0.6108
1151
(0.6558)






Gen
C T
453
(0.3358
531
(0.3026)
T T
824
(0.6108
1151
(0.6558)



hCV26719227
AKT3
LETS
add
A C
146
(0.3303
112
(0.2494)
C C
284
(0.6425
327
(0.7283)




(rs10927065)
MEGA1
add
A C
409
(0.303
478
(0.2727)
C C
889
(0.6585
1224
(0.6982)





LETS
Gen
A C
146
(0.3303
112
(0.2494)
C C
284
(0.6425
327
(0.7283)






Gen
A C
146
(0.3303
112
(0.2494)
C C
284
(0.6425
327
(0.7283)





MEGA1
Gen
A C
409
(0.303
478
(0.2727)
C C
889
(0.6585
1224
(0.6982)






Gen
A C
409
(0.303
478
(0.2727)
C C
889
(0.6585
1224
(0.6982)



hCV31523638
AKT3
LETS
add
A G
135
(0.3068
99
(0.219)
G G
293
(0.6659
344
(0.7611)




(rs12037013)
MEGA1
add
A G
384
(0.2844
455
(0.2594)
G G
926
(0.6859
1263
(0.7201)





LETS
Gen
A G
135
(0.3068
99
(0.219)
G G
293
(0.6659
344
(0.7611)






Gen
A G
135
(0.3068
99
(0.219)
G G
293
(0.6659
344
(0.7611)





MEGA1
Gen
A G
384
(0.2844
455
(0.2594)
G G
926
(0.6859
1263
(0.7201)






Gen
A G
384
(0.2844
455
(0.2594)
G G
926
(0.6859
1263
(0.7201)



hCV30690777
AKT3
MEGA1
add
A G
392
(0.291
451
(0.257)
G G
919
(0.6823
1277
(0.7276)




(rs12045585)
LETS
add
A G
131
(0.3011
108
(0.2432)
G G
293
(0.6736
328
(0.7387)





LETS
Gen
A G
131
(0.3011
108
(0.2432)
G G
293
(0.6736
328
(0.7387)






Gen
A G
131
(0.3011
108
(0.2432)
G G
293
(0.6736
328
(0.7387)





MEGA1
Gen
A G
392
(0.291
451
(0.257)
G G
919
(0.6823
1277
(0.7276)






Gen
A G
392
(0.291
451
(0.257)
G G
919
(0.6823
1277
(0.7276)



hCV31523650
AKT3
LETS
add
T C
163
(0.3721
130
(0.2889)
C C
250
(0.5708
304
(0.6756)




(rs12048930)
MEGA1
add
T C
472
(0.342
541
(0.3086)
C C
834
(0.6043
1130
(0.6446)





LETS
Gen
T C
163
(0.3721
130
(0.2889)
C C
250
(0.5708
304
(0.6756)






Gen
T C
163
(0.3721
130
(0.2889)
C C
250
(0.5708
304
(0.6756)





MEGA1
Gen
T C
472
(0.342
541
(0.3086)
C C
834
(0.6043
1130
(0.6446)






Gen
T C
472
(0.342
541
(0.3086)
C C
834
(0.6043
1130
(0.6446)



hCV30690778
AKT3
LETS
add
C T
163
(0.3713
125
(0.2772)
T T
257
(0.5854
311
(0.6896)




(rs12140414)
MEGA1
add
C T
443
(0.3284
553
(0.3151)
T T
847
(0.6279
1150
(0.6553)





LETS
Gen
C T
163
(0.3713
125
(0.2772)
T T
257
(0.5854
311
(0.6896)






Gen
C T
163
(0.3713
125
(0.2772)
T T
257
(0.5854
311
(0.6896)





MEGA1
Gen
C T
443
(0.3284
553
(0.3151)
T T
847
(0.6279
1150
(0.6553)






Gen
C T
443
(0.3284
553
(0.3151)
T T
847
(0.6279
1150
(0.6553)



hCV31523608
AKT3
MEGA1
add
G A
609
(0.4518
740
(0.4224)
A A
553
(0.4102
815
(0.4652)




(rs12744297)
LETS
add
G A
202
(0.458
181
(0.4013)
A A
182
(0.4127
227
(0.5033)





LETS
Gen
G A
202
(0.458
181
(0.4013)
A A
182
(0.4127
227
(0.5033)






Gen
G A
202
(0.458
181
(0.4013)
A A
182
(0.4127
227
(0.5033)





MEGA1
Gen
G A
609
(0.4518
740
(0.4224)
A A
553
(0.4102
815
(0.4652)






Gen
G A
609
(0.4518
740
(0.4224)
A A
553
(0.4102
815
(0.4652)



hCV233148
AKT3
LETS
add
C G
202
(0.456
174
(0.3841)
G G
191
(0.4312
247
(0.5453)




(rs1417121)
MEGA1
add
C G
573
(0.4128
745
(0.424)
G G
652
(0.4697
883
(0.5026)





LETS
Gen
C G
202
(0.456
174
(0.3841)
G G
191
(0.4312
247
(0.5453)






Gen
C G
202
(0.456
174
(0.3841)
G G
191
(0.4312
247
(0.5453)





MEGA1
Gen
C G
573
(0.4128
745
(0.424)
G G
652
(0.4697
883
(0.5026)






Gen
C G
573
(0.4128
745
(0.424)
G G
652
(0.4697
883
(0.5026)



hCV12073840
AKT3
LETS
Gen
T C
186
(0.4256
153
(0.3392)
C C
222
(0.508
274
(0.6075)




(rs14403)
MEGA1
Gen
T C
510
(0.3783
670
(0.3815)
C C
748
(0.5549
1001
(0.57)





LETS
Gen
T C
186
(0.4256
153
(0.3392)
C C
222
(0.508
274
(0.6075)






Gen
T C
186
(0.4256
153
(0.3392)
C C
222
(0.508
274
(0.6075)





MEGA1
Gen
T C
510
(0.3783
670
(0.3815)
C C
748
(0.5549
1001
(0.57)






Gen
T C
510
(0.3783
670
(0.3815)
C C
748
(0.5549
1001
(0.57)



hCV1678674
AKT3
LETS
add
C T
158
(0.3624
126
(0.2812)
T T
247
(0.5665
304
(0.6786)




(rs1458023)
MEGA1
add
C T
462
(0.3422
540
(0.308)
T T
808
(0.5985
1131
(0.6452)





LETS
Gen
C T
158
(0.3624
126
(0.2812)
T T
247
(0.5665
304
(0.6786)






Gen
C T
158
(0.3624
126
(0.2812)
T T
247
(0.5665
304
(0.6786)





MEGA1
Gen
C T
462
(0.3422
540
(0.308)
T T
808
(0.5985
1131
(0.6452)






Gen
C T
462
(0.3422
540
(0.308)
T T
808
(0.5985
1131
(0.6452)



hCV97631
AKT3
LETS
add
G T
182
(0.4127
143
(0.3171)
T T
224
(0.5079
287
(0.6364)




(rs1538773)
MEGA1
add
G T
493
(0.3655
621
(0.3542)
T T
754
(0.5589
1043
(0.595)





LETS
Gen
G T
182
(0.4127
143
(0.3171)
T T
224
(0.5079
287
(0.6364)






Gen
G T
182
(0.4127
143
(0.3171)
T T
224
(0.5079
287
(0.6364)





MEGA1
Gen
G T
493
(0.3655
621
(0.3542)
T T
754
(0.5589
1043
(0.595)






Gen
G T
493
(0.3655
621
(0.3542)
T T
754
(0.5589
1043
(0.595)



hCV8688111
AKT3
LETS
add
C G
159
(0.3647
125
(0.2803)
G G
257
(0.5894
309
(0.6928)




(rs1578275)
MEGA1
add
C G
434
(0.3229
541
(0.3097)
G G
852
(0.6339
1154
(0.6606)





LETS
Gen
C G
159
(0.3647
125
(0.2803)
G G
257
(0.5894
309
(0.6928)






Gen
C G
159
(0.3647
125
(0.2803)
G G
257
(0.5894
309
(0.6928)





MEGA1
Gen
C G
434
(0.3229
541
(0.3097)
G G
852
(0.6339
1154
(0.6606)






Gen
C G
434
(0.3229
541
(0.3097)
G G
852
(0.6339
1154
(0.6606)



hCV15885425
AKT3
LETS
add
C A
163
(0.3713
126
(0.2788)
A A
249
(0.5672
311
(0.6881)




(rs2290754)
MEGA1
add
C A
452
(0.3353
528
(0.301)
A A
820
(0.6083
1141
(0.6505)





LETS
Gen
C A
163
(0.3713
126
(0.2788)
A A
249
(0.5672
311
(0.6881)






Gen
C A
163
(0.3713
126
(0.2788)
A A
249
(0.5672
311
(0.6881)





MEGA1
Gen
C A
452
(0.3353
528
(0.301)
A A
820
(0.6083
1141
(0.6505)






Gen
C A
452
(0.3353
528
(0.301)
A A
820
(0.6083
1141
(0.6505)



hCV1678682
AKT3
LETS
add
T G
157
(0.3576
121
(0.2701)
G G
252
(0.574
309
(0.6897)




(rs320339)
MEGA1
add
T G
446
(0.3311
532
(0.3035)
G G
817
(0.6065
1146
(0.6537)





LETS
Gen
T G
157
(0.3576
121
(0.2701)
G G
252
(0.574
309
(0.6897)






Gen
T G
157
(0.3576
121
(0.2701)
G G
252
(0.574
309
(0.6897)





MEGA1
Gen
T G
446
(0.3311
532
(0.3035)
G G
817
(0.6065
1146
(0.6537)






Gen
T G
446
(0.3311
532
(0.3035)
G G
817
(0.6065
1146
(0.6537)



hCV29210363
AKT3
LETS
add
G A
179
(0.4087
142
(0.3149)
A A
221
(0.5046
287
(0.6364)




(rs6656918)
MEGA1
add
G A
490
(0.3632
626
(0.3569)
A A
748
(0.5545
1037
(0.5912)





LETS
Gen
G A
179
(0.4087
142
(0.3149)
A A
221
(0.5046
287
(0.6364)






Gen
G A
179
(0.4087
142
(0.3149)
A A
221
(0.5046
287
(0.6364)





MEGA1
Gen
G A
490
(0.3632
626
(0.3569)
A A
748
(0.5545
1037
(0.5912)






Gen
G A
490
(0.3632
626
(0.3569)
A A
748
(0.5545
1037
(0.5912)



hCV31523643
AKT3
LETS
add
G A
161
(0.3643
127
(0.281)
A A
254
(0.5747
310
(0.6858)




(rs6671475)
MEGA1
add
G A
453
(0.3356
533
(0.3046)
A A
821
(0.6081
1137
(0.6497)





LETS
Gen
G A
161
(0.3643
127
(0.281)
A A
254
(0.5747
310
(0.6858)






Gen
G A
161
(0.3643
127
(0.281)
A A
254
(0.5747
310
(0.6858)





MEGA1
Gen
G A
453
(0.3356
533
(0.3046)
A A
821
(0.6081
1137
(0.6497)






Gen
G A
453
(0.3356
533
(0.3046)
A A
821
(0.6081
1137
(0.6497)



hCV26719113
AKT3
LETS
add
T C
154
(0.3573
109
(0.2477)
C C
253
(0.587
315
(0.7159)




(rs7517340)
MEGA1
add
T C
431
(0.3207
519
(0.2974)
C C
835
(0.6213
1159
(0.6642)





LETS
Gen
T C
154
(0.3573
109
(0.2477)
C C
253
(0.587
315
(0.7159)






Gen
T C
154
(0.3573
109
(0.2477)
C C
253
(0.587
315
(0.7159)





MEGA1
Gen
T C
431
(0.3207
519
(0.2974)
C C
835
(0.6213
1159
(0.6642)






Gen
T C
431
(0.3207
519
(0.2974)
C C
835
(0.6213
1159
(0.6642)



hCV26034142
AKT3
LETS
add
C T
209
(0.4729
201
(0.4447)
T T
121
(0.2738
155
(0.3429)




(rs9428576)
MEGA1
rec
C T
634
(0.4703
887
(0.506)
T T
396
(0.2938
520
(0.2966)





LETS
Gen
C T
209
(0.4729
201
(0.4447)
T T
121
(0.2738
155
(0.3429)






Gen
C T
209
(0.4729
201
(0.4447)
T T
121
(0.2738
155
(0.3429)





MEGA1
Gen
C T
634
(0.4703
887
(0.506)
T T
396
(0.2938
520
(0.2966)






Gen
C T
634
(0.4703
887
(0.506)
T T
396
(0.2938
520
(0.2966)



hCV2303891
APOH
MEGA1
add
G C
106
(0.0758
189
(0.1076)
C C
1288
(0.9213
1565
(0.8907)




(rs1801690)
LETS
add
G C
29
(0.0662
44
(0.098)
C C
409
(0.9338
404
(0.8998)





LETS
Gen
G C
29
(0.0662
44
(0.098)
C C
409
(0.9338
404
(0.8998)






Gen
G C
29
(0.0662
44
(0.098)
C C
409
(0.9338
404
(0.8998)





MEGA1
Gen
G C
106
(0.0758
189
(0.1076)
C C
1288
(0.9213
1565
(0.8907)






Gen
G C
106
(0.0758
189
(0.1076)
C C
1288
(0.9213
1565
(0.8907)



hCV2456747
C1orf114
MEGA1
add
A G
641
(0.4595
739
(0.4225)
G G
542
(0.3885
795
(0.4545)




(rs3820059)
LETS
add
A G
210
(0.4751
181
(0.3996)
G G
177
(0.4005
228
(0.5033)





LETS
Gen
A G
210
(0.4751
181
(0.3996)
G G
177
(0.4005
228
(0.5033)






Gen
A G
210
(0.4751
181
(0.3996)
G G
177
(0.4005
228
(0.5033)





MEGA1
Gen
A G
641
(0.4595
739
(0.4225)
G G
542
(0.3885
795
(0.4545)






Gen
A G
641
(0.4595
739
(0.4225)
G G
542
(0.3885
795
(0.4545)



hCV2403368
C1QTNF6
LETS
rec
C G
145
(0.3281
183
(0.404)
G G
272
(0.6154
244
(0.5386)




(rs229526)
MEGA1
rec
C G
477
(0.3427
660
(0.3761)
G G
837
(0.6013
989
(0.5635)





LETS
Gen
C G
145
(0.3281
183
(0.404)
G G
272
(0.6154
244
(0.5386)






Gen
C G
145
(0.3281
183
(0.404)
G G
272
(0.6154
244
(0.5386)





MEGA1
Gen
C G
477
(0.3427
660
(0.3761)
G G
837
(0.6013
989
(0.5635)






Gen
C G
477
(0.3427
660
(0.3761)
G G
837
(0.6013
989
(0.5635)



hCV7574127
C6orf167
LETS
add
G A
225
(0.509
236
(0.521)
A A
137
(0.31
120
(0.2649)




(rs1737145)
MEGA1
add
G A
663
(0.4787
847
(0.4834)
A A
430
(0.3105
481
(0.2745)





LETS
Gen
G A
225
(0.509
236
(0.521)
A A
137
(0.31
120
(0.2649)






Gen
G A
225
(0.509
236
(0.521)
A A
137
(0.31
120
(0.2649)





MEGA1
Gen
G A
663
(0.4787
847
(0.4834)
A A
430
(0.3105
481
(0.2745)






Gen
G A
663
(0.4787
847
(0.4834)
A A
430
(0.3105
481
(0.2745)



hCV25959498
C7orf46
LETS
add
A G
48
(0.1086
63
(0.1394)
G G
393
(0.8891
383
(0.8473)




(rs34518648)
MEGA1
add
A G
183
(0.1315
262
(0.1493)
G G
1203
(0.8642
1476
(0.841)





LETS
Gen
A G
48
(0.1086
63
(0.1394)
G G
393
(0.8891
383
(0.8473)






Gen
A G
48
(0.1086
63
(0.1394)
G G
393
(0.8891
383
(0.8473)





MEGA1
Gen
A G
183
(0.1315
262
(0.1493)
G G
1203
(0.8642
1476
(0.841)






Gen
A G
183
(0.1315
262
(0.1493)
G G
1203
(0.8642
1476
(0.841)



hCV25959466
C7orf46
MEGA1
add
C T
182
(0.1307
263
(0.1503)
T T
1203
(0.8642
1469
(0.8394)




(rs35495590)
LETS
add
C T
48
(0.1086
63
(0.1394)
T T
393
(0.8891
384
(0.8496)





LETS
Gen
C T
48
(0.1086
63
(0.1394)
T T
393
(0.8891
384
(0.8496)






Gen
C T
48
(0.1086
63
(0.1394)
T T
393
(0.8891
384
(0.8496)





MEGA1
Gen
C T
182
(0.1307
263
(0.1503)
T T
1203
(0.8642
1469
(0.8394)






Gen
C T
182
(0.1307
263
(0.1503)
T T
1203
(0.8642
1469
(0.8394)



hCV25768636
CCDC36
MEGA1
rec
A G
639
(0.461
821
(0.4678)
G G
559
(0.4033
740
(0.4217)




(rs4279134)
LETS
rec
A G
197
(0.4457
199
(0.4412)
G G
177
(0.4005
204
(0.4523)





LETS
Gen
A G
197
(0.4457
199
(0.4412)
G G
177
(0.4005
204
(0.4523)






Gen
A G
197
(0.4457
199
(0.4412)
G G
177
(0.4005
204
(0.4523)





MEGA1
Gen
A G
639
(0.461
821
(0.4678)
G G
559
(0.4033
740
(0.4217)






Gen
A G
639
(0.461
821
(0.4678)
G G
559
(0.4033
740
(0.4217)



hCV25991132
CCDC41 ( )
MEGA1
rec
A G
195
(0.1403
311
(0.178)
G G
1182
(0.8504
1430
(0.8185)





LETS
rec
A G
58
(0.1309
78
(0.1722)
G G
384
(0.8668
370
(0.8168)





LETS
Gen
A G
58
(0.1309
78
(0.1722)
G G
384
(0.8668
370
(0.8168)






Gen
A G
58
(0.1309
78
(0.1722)
G G
384
(0.8668
370
(0.8168)





MEGA1
Gen
A G
195
(0.1403
311
(0.178)
G G
1182
(0.8504
1430
(0.8185)






Gen
A G
195
(0.1403
311
(0.178)
G G
1182
(0.8504
1430
(0.8185)



hCV3164397
CMYA5
LETS
rec
T C
93
(0.2109
136
(0.3002)
C C
339
(0.7687
309
(0.6821)




(rs10043986)
MEGA1
dom
T C
347
(0.2487
408
(0.233)
C C
1036
(0.7427
1309
(0.7476)





LETS
Gen
T C
93
(0.2109
136
(0.3002)
C C
339
(0.7687
309
(0.6821)






Gen
T C
93
(0.2109
136
(0.3002)
C C
339
(0.7687
309
(0.6821)





MEGA1
Gen
T C
347
(0.2487
408
(0.233)
C C
1036
(0.7427
1309
(0.7476)






Gen
T C
347
(0.2487
408
(0.233)
C C
1036
(0.7427
1309
(0.7476)



hCV3230083
CYP4V2
MEGA1
Gen
A C
702
(0.5223
842
(0.4803)
C C
360
(0.2679
582
(0.332)




(rs10013653)
LETS
Gen
A C
230
(0.5204
208
(0.4622)
C C
115
(0.2602
142
(0.3156)





LETS
Gen
A C
230
(0.5204
208
(0.4622)
C C
115
(0.2602
142
(0.3156)






Gen
A C
230
(0.5204
208
(0.4622)
C C
115
(0.2602
142
(0.3156)





MEGA1
Gen
A C
702
(0.5223
842
(0.4803)
C C
360
(0.2679
582
(0.332)






Gen
A C
702
(0.5223
842
(0.4803)
C C
360
(0.2679
582
(0.332)



hCV25990131
CYP4V2
MEGA1
add
C A
600
(0.4295
805
(0.459)
A A
648
(0.4639
720
(0.4105)




(rs13146272)
LETS
add
C A
208
(0.4717
189
(0.4191)
A A
201
(0.4558
199
(0.4412)





LETS
Gen
C A
208
(0.4717
189
(0.4191)
A A
201
(0.4558
199
(0.4412)






Gen
C A
208
(0.4717
189
(0.4191)
A A
201
(0.4558
199
(0.4412)





MEGA1
Gen
C A
600
(0.4295
805
(0.459)
A A
648
(0.4639
720
(0.4105)






Gen
C A
600
(0.4295
805
(0.459)
A A
648
(0.4639
720
(0.4105)



hCV15968043
CYP4V2
MEGA1
dom
A T
698
(0.504
839
(0.4811)
T T
395
(0.2852
605
(0.3469)




(rs2292423)
LETS
dom
A T
224
(0.5056
208
(0.4592)
T T
122
(0.2754
153
(0.3377)





LETS
Gen
A T
224
(0.5056
208
(0.4592)
T T
122
(0.2754
153
(0.3377)






Gen
A T
224
(0.5056
208
(0.4592)
T T
122
(0.2754
153
(0.3377)





MEGA1
Gen
A T
698
(0.504
839
(0.4811)
T T
395
(0.2852
605
(0.3469)






Gen
A T
698
(0.504
839
(0.4811)
T T
395
(0.2852
605
(0.3469)



hCV3230096
CYP4V2
LETS
dom
T C
227
(0.5136
211
(0.4668)
C C
120
(0.2715
149
(0.3296)




(rs3817184)
MEGA1
dom
T C
680
(0.4892
831
(0.4776)
C C
409
(0.2942
600
(0.3448)





LETS
Gen
T C
227
(0.5136
211
(0.4668)
C C
120
(0.2715
149
(0.3296)






Gen
T C
227
(0.5136
211
(0.4668)
C C
120
(0.2715
149
(0.3296)





MEGA1
Gen
T C
680
(0.4892
831
(0.4776)
C C
409
(0.2942
600
(0.3448)






Gen
T C
680
(0.4892
831
(0.4776)
C C
409
(0.2942
600
(0.3448)



hCV11786147
CYP4V2
LETS
dom
T G
223
(0.5103
208
(0.4643)
G G
120
(0.2746
150
(0.3348)




(rs4862662)
MEGA1
dom
T G
665
(0.4941
833
(0.476)
G G
403
(0.2994
614
(0.3509)





LETS
Gen
T G
223
(0.5103
208
(0.4643)
G G
120
(0.2746
150
(0.3348)






Gen
T G
223
(0.5103
208
(0.4643)
G G
120
(0.2746
150
(0.3348)





MEGA1
Gen
T G
665
(0.4941
833
(0.476)
G G
403
(0.2994
614
(0.3509)






Gen
T G
665
(0.4941
833
(0.476)
G G
403
(0.2994
614
(0.3509)



hCV3230084
CYP4V2
MEGA1
Gen
T C
670
(0.4989
803
(0.4594)
C C
426
(0.3172
657
(0.3759)




(rs7682918)
LETS
Gen
T C
239
(0.5432
210
(0.4656)
C C
126
(0.2864
154
(0.3415)





LETS
Gen
T C
239
(0.5432
210
(0.4656)
C C
126
(0.2864
154
(0.3415)






Gen
T C
239
(0.5432
210
(0.4656)
C C
126
(0.2864
154
(0.3415)





MEGA1
Gen
T C
670
(0.4989
803
(0.4594)
C C
426
(0.3172
657
(0.3759)






Gen
T C
670
(0.4989
803
(0.4594)
C C
426
(0.3172
657
(0.3759)



hCV26265231
CYP4V2
MEGA1
dom
A G
682
(0.5082
853
(0.4897)
G G
325
(0.2422
516
(0.2962)




(rs7684025)
LETS
dom
A G
228
(0.5147
204
(0.4503)
G G
99
(0.2235
133
(0.2936)





LETS
Gen
A G
228
(0.5147
204
(0.4503)
G G
99
(0.2235
133
(0.2936)






Gen
A G
228
(0.5147
204
(0.4503)
G G
99
(0.2235
133
(0.2936)





MEGA1
Gen
A G
682
(0.5082
853
(0.4897)
G G
325
(0.2422
516
(0.2962)






Gen
A G
682
(0.5082
853
(0.4897)
G G
325
(0.2422
516
(0.2962)



hCV9860072
DHX38
LETS
Gen
A C
224
(0.5056
195
(0.4305)
C C
157
(0.3544
196
(0.4327)




(rs1050362)
MEGA1
Gen
A C
632
(0.4586
797
(0.4562)
C C
541
(0.3926
730
(0.4179)





LETS
Gen
A C
224
(0.5056
195
(0.4305)
C C
157
(0.3544
196
(0.4327)






Gen
A C
224
(0.5056
195
(0.4305)
C C
157
(0.3544
196
(0.4327)





MEGA1
Gen
A C
632
(0.4586
797
(0.4562)
C C
541
(0.3926
730
(0.4179)






Gen
A C
632
(0.4586
797
(0.4562)
C C
541
(0.3926
730
(0.4179)



hCV2103346
DKFZP564J102
LETS
rec
C T
194
(0.4399
230
(0.51)
T T
143
(0.3243
144
(0.3193)




(rs11733307)
MEGA1
dom
C T
668
(0.4952
834
(0.4752)
T T
380
(0.2817
562
(0.3202)





LETS
Gen
C T
194
(0.4399
230
(0.51)
T T
143
(0.3243
144
(0.3193)






Gen
C T
194
(0.4399
230
(0.51)
T T
143
(0.3243
144
(0.3193)





MEGA1
Gen
C T
668
(0.4952
834
(0.4752)
T T
380
(0.2817
562
(0.3202)






Gen
C T
668
(0.4952
834
(0.4752)
T T
380
(0.2817
562
(0.3202)



hCV12086148
DKFZP564J102
LETS
rec
A G
138
(0.3129
168
(0.3725)
G G
279
(0.6327
258
(0.5721)




(rs1877321)
MEGA1
Gen
A G
491
(0.3543
625
(0.358)
G G
839
(0.6053
1021
(0.5848)





LETS
Gen
A G
138
(0.3129
168
(0.3725)
G G
279
(0.6327
258
(0.5721)






Gen
A G
138
(0.3129
168
(0.3725)
G G
279
(0.6327
258
(0.5721)





MEGA1
Gen
A G
491
(0.3543
625
(0.358)
G G
839
(0.6053
1021
(0.5848)






Gen
A G
491
(0.3543
625
(0.358)
G G
839
(0.6053
1021
(0.5848)



hCV25473516
DUSP11
LETS
Gen
T C
214
(0.4842
224
(0.4956)
C C
158
(0.3575
175
(0.3872)




(rs2272051)
MEGA1
Gen
T C
641
(0.4615
808
(0.4615)
C C
542
(0.3902
734
(0.4192)





LETS
Gen
T C
214
(0.4842
224
(0.4956)
C C
158
(0.3575
175
(0.3872)






Gen
T C
214
(0.4842
224
(0.4956)
C C
158
(0.3575
175
(0.3872)





MEGA1
Gen
T C
641
(0.4615
808
(0.4615)
C C
542
(0.3902
734
(0.4192)






Gen
T C
641
(0.4615
808
(0.4615)
C C
542
(0.3902
734
(0.4192)



hCV15871021
EBF1
LETS
rec
A G
191
(0.4321
238
(0.5254)
G G
181
(0.4095
149
(0.3289)




(rs2072495)
MEGA1
dom
A G
699
(0.5018
834
(0.4774)
G G
526
(0.3776
644
(0.3686)





LETS
Gen
A G
191
(0.4321
238
(0.5254)
G G
181
(0.4095
149
(0.3289)






Gen
A G
191
(0.4321
238
(0.5254)
G G
181
(0.4095
149
(0.3289)





MEGA1
Gen
A G
699
(0.5018
834
(0.4774)
G G
526
(0.3776
644
(0.3686)






Gen
A G
699
(0.5018
834
(0.4774)
G G
526
(0.3776
644
(0.3686)



hCV491830
EPS8L2
LETS
add
C T
206
(0.4703
227
(0.5033)
T T
158
(0.3607
130
(0.2882)




(rs3087546)
MEGA1
add
C T
667
(0.4805
822
(0.47)
T T
485
(0.3494
571
(0.3265)





LETS
Gen
C T
206
(0.4703
227
(0.5033)
T T
158
(0.3607
130
(0.2882)






Gen
C T
206
(0.4703
227
(0.5033)
T T
158
(0.3607
130
(0.2882)





MEGA1
Gen
C T
667
(0.4805
822
(0.47)
T T
485
(0.3494
571
(0.3265)






Gen
C T
667
(0.4805
822
(0.47)
T T
485
(0.3494
571
(0.3265)



hCV2017876
EPS8L3
LETS
add
A G
202
(0.456
216
(0.4779)
G G
145
(0.3273
123
(0.2721)




(rs3818562)
MEGA1
add
A G
677
(0.492
888
(0.508)
G G
417
(0.3031
466
(0.2666)





LETS
Gen
A G
202
(0.456
216
(0.4779)
G G
145
(0.3273
123
(0.2721)






Gen
A G
202
(0.456
216
(0.4779)
G G
145
(0.3273
123
(0.2721)





MEGA1
Gen
A G
677
(0.492
888
(0.508)
G G
417
(0.3031
466
(0.2666)






Gen
A G
677
(0.492
888
(0.508)
G G
417
(0.3031
466
(0.2666)



hCV12066124
F11
MEGA1
add
T C
682
(0.4903
865
(0.4932)
C C
476
(0.3422
482
(0.2748)




(rs2036914)
LETS
add
T C
215
(0.4853
216
(0.4768)
C C
159
(0.3589
138
(0.3046)





LETS
Gen
T C
215
(0.4853
216
(0.4768)
C C
159
(0.3589
138
(0.3046)






Gen
T C
215
(0.4853
216
(0.4768)
C C
159
(0.3589
138
(0.3046)





MEGA1
Gen
T C
682
(0.4903
865
(0.4932)
C C
476
(0.3422
482
(0.2748)






Gen
T C
682
(0.4903
865
(0.4932)
C C
476
(0.3422
482
(0.2748)



hCV16172935
F11
LETS
rec
G A
182
(0.4118
220
(0.4867)
A A
208
(0.4706
186
(0.4115)




(rs2241817)
MEGA1
rec
G A
625
(0.4516
808
(0.4644)
A A
620
(0.448
713
(0.4098)





LETS
Gen
G A
182
(0.4118
220
(0.4867)
A A
208
(0.4706
186
(0.4115)






Gen
G A
182
(0.4118
220
(0.4867)
A A
208
(0.4706
186
(0.4115)





MEGA1
Gen
G A
625
(0.4516
808
(0.4644)
A A
620
(0.448
713
(0.4098)






Gen
G A
625
(0.4516
808
(0.4644)
A A
620
(0.448
713
(0.4098)



hCV3230038
F11
LETS
add
T C
204
(0.4626
200
(0.4435)
C C
130
(0.2948
158
(0.3503)




(rs2289252)
MEGA1
add
T C
689
(0.5115
840
(0.48)
C C
344
(0.2554
601
(0.3434)





LETS
Gen
T C
204
(0.4626
200
(0.4435)
C C
130
(0.2948
158
(0.3503)






Gen
T C
204
(0.4626
200
(0.4435)
C C
130
(0.2948
158
(0.3503)





MEGA1
Gen
T C
689
(0.5115
840
(0.48)
C C
344
(0.2554
601
(0.3434)






Gen
T C
689
(0.5115
840
(0.48)
C C
344
(0.2554
601
(0.3434)



hCV27474895
F11
MEGA1
add
A C
692
(0.5018
838
(0.4794)
C C
361
(0.2618
598
(0.3421)




(rs3756011)
LETS
add
A C
208
(0.4695
200
(0.4425)
C C
128
(0.2889
160
(0.354)





LETS
Gen
A C
208
(0.4695
200
(0.4425)
C C
128
(0.2889
160
(0.354)






Gen
A C
208
(0.4695
200
(0.4425)
C C
128
(0.2889
160
(0.354)





MEGA1
Gen
A C
692
(0.5018
838
(0.4794)
C C
361
(0.2618
598
(0.3421)






Gen
A C
692
(0.5018
838
(0.4794)
C C
361
(0.2618
598
(0.3421)



hCV25474413
F11
LETS
Gen
A C
214
(0.4831
213
(0.4702)
C C
138
(0.3115
124
(0.2737)




(rs3822057)
MEGA1
Gen
A C
690
(0.5055
876
(0.4991)
C C
406
(0.2974
422
(0.2405)





LETS
Gen
A C
214
(0.4831
213
(0.4702)
C C
138
(0.3115
124
(0.2737)






Gen
A C
214
(0.4831
213
(0.4702)
C C
138
(0.3115
124
(0.2737)





MEGA1
Gen
A C
690
(0.5055
876
(0.4991)
C C
406
(0.2974
422
(0.2405)






Gen
A C
690
(0.5055
876
(0.4991)
C C
406
(0.2974
422
(0.2405)



hCV27490984
F11
LETS
rec
A G
181
(0.4095
221
(0.4889)
G G
207
(0.4683
185
(0.4093)




(rs3822058)
MEGA1
rec
A G
633
(0.4547
816
(0.4671)
G G
624
(0.4483
712
(0.4076)





LETS
Gen
A G
181
(0.4095
221
(0.4889)
G G
207
(0.4683
185
(0.4093)






Gen
A G
181
(0.4095
221
(0.4889)
G G
207
(0.4683
185
(0.4093)





MEGA1
Gen
A G
633
(0.4547
816
(0.4671)
G G
624
(0.4483
712
(0.4076)






Gen
A G
633
(0.4547
816
(0.4671)
G G
624
(0.4483
712
(0.4076)



hCV25474414
F11
MEGA1
add
G T
658
(0.4892
831
(0.4735)
T T
409
(0.3041
660
(0.3761)




(rs4253399)
LETS
add
G T
205
(0.4649
192
(0.4257)
T T
142
(0.322
179
(0.3969)





LETS
Gen
G T
205
(0.4649
192
(0.4257)
T T
142
(0.322
179
(0.3969)






Gen
G T
205
(0.4649
192
(0.4257)
T T
142
(0.322
179
(0.3969)





MEGA1
Gen
G T
658
(0.4892
831
(0.4735)
T T
409
(0.3041
660
(0.3761)






Gen
G T
658
(0.4892
831
(0.4735)
T T
409
(0.3041
660
(0.3761)



hCV26038139
F11
MEGA1
Gen
G A
643
(0.4619
814
(0.4646)
A A
607
(0.4361
689
(0.3933)




(rs4253405)
LETS
Gen
G A
179
(0.4059
225
(0.4978)
A A
199
(0.4512
175
(0.3872)





LETS
Gen
G A
179
(0.4059
225
(0.4978)
A A
199
(0.4512
175
(0.3872)






Gen
G A
179
(0.4059
225
(0.4978)
A A
199
(0.4512
175
(0.3872)





MEGA1
Gen
G A
643
(0.4619
814
(0.4646)
A A
607
(0.4361
689
(0.3933)






Gen
G A
643
(0.4619
814
(0.4646)
A A
607
(0.4361
689
(0.3933)



hCV3230119
F11
LETS
rec
C G
183
(0.415
222
(0.4912)
G G
206
(0.4671
182
(0.4027)




(rs4253430)
MEGA1
rec
C G
631
(0.454
812
(0.4635)
G G
624
(0.4489
722
(0.4121)





LETS
Gen
C G
183
(0.415
222
(0.4912)
G G
206
(0.4671
182
(0.4027)






Gen
C G
183
(0.415
222
(0.4912)
G G
206
(0.4671
182
(0.4027)





MEGA1
Gen
C G
631
(0.454
812
(0.4635)
G G
624
(0.4489
722
(0.4121)






Gen
C G
631
(0.454
812
(0.4635)
G G
624
(0.4489
722
(0.4121)



hCV8241630
F11
MEGA1
add
A G
666
(0.4904
816
(0.4663)
G G
403
(0.2968
662
(0.3783)




(rs925451)
LETS
add
A G
212
(0.4807
194
(0.4292)
G G
134
(0.3039
171
(0.3783)





LETS
Gen
A G
212
(0.4807
194
(0.4292)
G G
134
(0.3039
171
(0.3783)






Gen
A G
212
(0.4807
194
(0.4292)
G G
134
(0.3039
171
(0.3783)





MEGA1
Gen
A G
666
(0.4904
816
(0.4663)
G G
403
(0.2968
662
(0.3783)






Gen
A G
666
(0.4904
816
(0.4663)
G G
403
(0.2968
662
(0.3783)



hCV8726802
F2
MEGA1
add
A G
80
(0.0579
37
(0.0211)
G G
1301
(0.9421
1716
(0.9789)




(rs1799963)
LETS
add
A G
28
(0.0633
10
(0.0221)
G G
414
(0.9367
442
(0.9779)





LETS
Gen
G A
28
(0.0633
10
(0.0221)
A A
414
(0.9367
442
(0.9779)





MEGA1
Gen
A G
80
(0.0579
37
(0.0211)
G G
1301
(0.9421
1716
(0.9789)



hCV27480803
F5
MEGA1
add
C T
660
(0.4755
840
(0.4805)
T T
382
(0.2752
557
(0.3186)




(rs3766103)
LETS
add
C T
216
(0.4898
222
(0.4901)
T T
129
(0.2925
158
(0.3488)





LETS
Gen
C T
216
(0.4898
222
(0.4901)
T T
129
(0.2925
158
(0.3488)






Gen
C T
216
(0.4898
222
(0.4901)
T T
129
(0.2925
158
(0.3488)





MEGA1
Gen
C T
660
(0.4755
840
(0.4805)
T T
382
(0.2752
557
(0.3186)






Gen
C T
660
(0.4755
840
(0.4805)
T T
382
(0.2752
557
(0.3186)



hCV8919444
F5 (rs4524)
MEGA1
add
C T
440
(0.317
680
(0.3883)
T T
872
(0.6282
964
(0.5505)





LETS
add
C T
130
(0.2935
169
(0.3739)
T T
289
(0.6524
251
(0.5553)





LETS
Gen
C T
130
(0.2935
169
(0.3739)
T T
289
(0.6524
251
(0.5553)






Gen
C T
130
(0.2935
169
(0.3739)
T T
289
(0.6524
251
(0.5553)





MEGA1
Gen
C T
440
(0.317
680
(0.3883)
T T
872
(0.6282
964
(0.5505)






Gen
C T
440
(0.317
680
(0.3883)
T T
872
(0.6282
964
(0.5505)



hCV8919442
F5 (rs4525)
MEGA1
add
C T
431
(0.3148
685
(0.3899)
T T
864
(0.6311
965
(0.5492)





LETS
add
C T
128
(0.2909
168
(0.3733)
T T
287
(0.6523
251
(0.5578)





LETS
Gen
C T
128
(0.2909
168
(0.3733)
T T
287
(0.6523
251
(0.5578)






Gen
C T
128
(0.2909
168
(0.3733)
T T
287
(0.6523
251
(0.5578)





MEGA1
Gen
C T
431
(0.3148
685
(0.3899)
T T
864
(0.6311
965
(0.5492)






Gen
C T
431
(0.3148
685
(0.3899)
T T
864
(0.6311
965
(0.5492)



hCV8919451
F5 (rs6016)
MEGA1
add
A G
430
(0.31
679
(0.3869)
G G
879
(0.6337
968
(0.5516)





LETS
add
A G
130
(0.2948
170
(0.3778)
G G
287
(0.6508
249
(0.5533)





LETS
Gen
A G
130
(0.2948
170
(0.3778)
G G
287
(0.6508
249
(0.5533)






Gen
A G
130
(0.2948
170
(0.3778)
G G
287
(0.6508
249
(0.5533)





MEGA1
Gen
A G
430
(0.31
679
(0.3869)
G G
879
(0.6337
968
(0.5516)






Gen
A G
430
(0.31
679
(0.3869)
G G
879
(0.6337
968
(0.5516)



hCV2288095
F9 (rs378815)
LETS
Gen
T C
111
(0.2517
120
(0.2667)
C C
250
(0.5669
223
(0.4956)





MEGA1
Gen
T C
331
(0.2381
378
(0.2161)
C C
753
(0.5417
940
(0.5374)





LETS
Gen
T C
111
(0.2517
120
(0.2667)
C C
250
(0.5669
223
(0.4956)






Gen
T C
111
(0.2517
120
(0.2667)
C C
250
(0.5669
223
(0.4956)





MEGA1
Gen
T C
331
(0.2381
378
(0.2161)
C C
753
(0.5417
940
(0.5374)






Gen
T C
331
(0.2381
378
(0.2161)
C C
753
(0.5417
940
(0.5374)



hCV596326
F9 (rs398101)
LETS
rec
G A
91
(0.2068
120
(0.2655)
A A
274
(0.6227
240
(0.531)





MEGA1
Gen
G A
310
(0.224
350
(0.1998)
A A
817
(0.5903
1021
(0.5828)





LETS
Gen
G A
91
(0.2068
120
(0.2655)
A A
274
(0.6227
240
(0.531)






Gen
G A
91
(0.2068
120
(0.2655)
A A
274
(0.6227
240
(0.531)





MEGA1
Gen
G A
310
(0.224
350
(0.1998)
A A
817
(0.5903
1021
(0.5828)






Gen
G A
310
(0.224
350
(0.1998)
A A
817
(0.5903
1021
(0.5828)



hCV596330
F9 (rs422187)
LETS
add
C A
103
(0.2336
120
(0.2667)
A A
268
(0.6077
243
(0.54)





MEGA1
add
C A
314
(0.2274
361
(0.2062)
A A
824
(0.5967
1014
(0.5791)





LETS
Gen
C A
103
(0.2336
120
(0.2667)
A A
268
(0.6077
243
(0.54)






Gen
C A
103
(0.2336
120
(0.2667)
A A
268
(0.6077
243
(0.54)





MEGA1
Gen
C A
314
(0.2274
361
(0.2062)
A A
824
(0.5967
1014
(0.5791)






Gen
C A
314
(0.2274
361
(0.2062)
A A
824
(0.5967
1014
(0.5791)



hCV596331
F9 (rs6048)
LETS
rec
G A
99
(0.2235
122
(0.2693)
A A
274
(0.6185
244
(0.5386)





MEGA1
dom
G A
295
(0.215
347
(0.1994)
A A
844
(0.6152
1037
(0.596)





LETS
Gen
G A
99
(0.2235
122
(0.2693)
A A
274
(0.6185
244
(0.5386)






Gen
G A
99
(0.2235
122
(0.2693)
A A
274
(0.6185
244
(0.5386)





MEGA1
Gen
G A
295
(0.215
347
(0.1994)
A A
844
(0.6152
1037
(0.596)






Gen
G A
295
(0.215
347
(0.1994)
A A
844
(0.6152
1037
(0.596)



hCV2892877
FGA (rs6050)
LETS
add
C T
249
(0.5621
226
(0.4989)
T T
194
(0.4379
227
(0.5011)





MEGA1
add
C T
807
(0.5814
859
(0.4914)
T T
581
(0.4186
889
(0.5086)





LETS
Gen
C T
249
(0.5621
226
(0.4989)
T T
194
(0.4379
227
(0.5011)





MEGA1
Gen
C T
807
(0.5814
859
(0.4914)
T T
581
(0.4186
889
(0.5086)



hCV11503469
FGG
MEGA1
add
A T
624
(0.4486
687
(0.3917)
T T
593
(0.4263
928
(0.5291)




(rs2066854)
LETS
add
A T
183
(0.4207
187
(0.424)
T T
198
(0.4552
232
(0.5261)





LETS
Gen
A T
183
(0.4207
187
(0.424)
T T
198
(0.4552
232
(0.5261)






Gen
A T
183
(0.4207
187
(0.424)
T T
198
(0.4552
232
(0.5261)





MEGA1
Gen
A T
624
(0.4486
687
(0.3917)
T T
593
(0.4263
928
(0.5291)






Gen
A T
624
(0.4486
687
(0.3917)
T T
593
(0.4263
928
(0.5291)



hCV11503414
FGG
MEGA1
add
A G
608
(0.451
692
(0.3941)
G G
574
(0.4258
928
(0.5285)




(rs2066865)
LETS
add
A G
186
(0.4256
188
(0.4206)
G G
195
(0.4462
235
(0.5257)





LETS
Gen
A G
186
(0.4256
188
(0.4206)
G G
195
(0.4462
235
(0.5257)






Gen
A G
186
(0.4256
188
(0.4206)
G G
195
(0.4462
235
(0.5257)





MEGA1
Gen
A G
608
(0.451
692
(0.3941)
G G
574
(0.4258
928
(0.5285)






Gen
A G
608
(0.451
692
(0.3941)
G G
574
(0.4258
928
(0.5285)



hCV30505633
GNG12
LETS
add
T C
68
(0.1538
52
(0.1148)
C C
369
(0.8348
400
(0.883)




(rs7530537)
MEGA1
add
T C
206
(0.1486
229
(0.1304)
C C
1164
(0.8398
1515
(0.8628)





LETS
Gen
T C
68
(0.1538
52
(0.1148)
C C
369
(0.8348
400
(0.883)






Gen
T C
68
(0.1538
52
(0.1148)
C C
369
(0.8348
400
(0.883)





MEGA1
Gen
T C
206
(0.1486
229
(0.1304)
C C
1164
(0.8398
1515
(0.8628)






Gen
T C
206
(0.1486
229
(0.1304)
C C
1164
(0.8398
1515
(0.8628)



hCV8717873
GP6
MEGA1
add
G A
368
(0.2651
553
(0.3162)
A A
975
(0.7024
1135
(0.6489)




(rs1613662)
LETS
add
G A
117
(0.2641
143
(0.3157)
A A
316
(0.7133
291
(0.6424)





LETS
Gen
G A
117
(0.2641
143
(0.3157)
A A
316
(0.7133
291
(0.6424)






Gen
G A
117
(0.2641
143
(0.3157)
A A
316
(0.7133
291
(0.6424)





MEGA1
Gen
G A
368
(0.2651
553
(0.3162)
A A
975
(0.7024
1135
(0.6489)






Gen
G A
368
(0.2651
553
(0.3162)
A A
975
(0.7024
1135
(0.6489)



hCV1376342
GP6
LETS
Gen
C T
130
(0.2935
142
(0.3135)
T T
298
(0.6727
285
(0.6291)




(rs1654416)
MEGA1
rec
C T
393
(0.2875
580
(0.3307)
T T
925
(0.6767
1108
(0.6317)





LETS
Gen
C T
130
(0.2935
142
(0.3135)
T T
298
(0.6727
285
(0.6291)






Gen
C T
130
(0.2935
142
(0.3135)
T T
298
(0.6727
285
(0.6291)





MEGA1
Gen
C T
393
(0.2875
580
(0.3307)
T T
925
(0.6767
1108
(0.6317)






Gen
C T
393
(0.2875
580
(0.3307)
T T
925
(0.6767
1108
(0.6317)



hCV8717893
GP6
LETS
Gen
A G
130
(0.2941
142
(0.3135)
G G
297
(0.6719
285
(0.6291)




(rs1671192)
MEGA1
rec
A G
393
(0.2831
584
(0.3326)
G G
944
(0.6801
1108
(0.631)





LETS
Gen
A G
130
(0.2941
142
(0.3135)
G G
297
(0.6719
285
(0.6291)






Gen
A G
130
(0.2941
142
(0.3135)
G G
297
(0.6719
285
(0.6291)





MEGA1
Gen
A G
393
(0.2831
584
(0.3326)
G G
944
(0.6801
1108
(0.631)






Gen
A G
393
(0.2831
584
(0.3326)
G G
944
(0.6801
1108
(0.631)



hCV2575036
GRB10
LETS
add
G A
8
(0.0181
24
(0.053)
A A
433
(0.9819
429
(0.947)




(rs34432772)
MEGA1
add
G A
68
(0.0498
61
(0.0348)
A A
1297
(0.9495
1692
(0.9652)





LETS
Gen
G A
8
(0.0181
24
(0.053)
A A
433
(0.9819
429
(0.947)





MEGA1
Gen
G A
68
(0.0498
61
(0.0348)
A A
1297
(0.9495
1692
(0.9652)






Gen
G A
68
(0.0498
61
(0.0348)
A A
1297
(0.9495
1692
(0.9652)



hCV2699725
GUCY1B2
LETS
Gen
C G
33
(0.0755
19
(0.0424)
G G
401
(0.9176
428
(0.9554)




(rs11841997)
MEGA1
Gen
G C
102
(0.0731
98
(0.0558)
C C
1290
(0.9241
1654
(0.9414)





LETS
Gen
C G
33
(0.0755
19
(0.0424)
G G
401
(0.9176
428
(0.9554)






Gen
C G
33
(0.0755
19
(0.0424)
G G
401
(0.9176
428
(0.9554)





MEGA1
Gen
G C
102
(0.0731
98
(0.0558)
C C
1290
(0.9241
1654
(0.9414)






Gen
G C
102
(0.0731
98
(0.0558)
C C
1290
(0.9241
1654
(0.9414)



hCV25995678
hCV25995678
LETS
add
C T
61
(0.138
85
(0.1881)
T T
377
(0.8529
359
(0.7942)





MEGA1
dom
C T
222
(0.1594
277
(0.1586)
T T
1166
(0.837
1452
(0.8316)





LETS
Gen
C T
61
(0.138
85
(0.1881)
T T
377
(0.8529
359
(0.7942)






Gen
C T
61
(0.138
85
(0.1881)
T T
377
(0.8529
359
(0.7942)





MEGA1
Gen
C T
222
(0.1594
277
(0.1586)
T T
1166
(0.837
1452
(0.8316)






Gen
C T
222
(0.1594
277
(0.1586)
T T
1166
(0.837
1452
(0.8316)



hCV25996277
hCV25996277
LETS
add
T A
63
(0.1422
86
(0.1898)
A A
376
(0.8488
359
(0.7925)





MEGA1
Gen
T A
217
(0.157
277
(0.158)
A A
1160
(0.8394
1456
(0.8306)





LETS
Gen
T A
63
(0.1422
86
(0.1898)
A A
376
(0.8488
359
(0.7925)






Gen
T A
63
(0.1422
86
(0.1898)
A A
376
(0.8488
359
(0.7925)





MEGA1
Gen
T A
217
(0.157
277
(0.158)
A A
1160
(0.8394
1456
(0.8306)






Gen
T A
217
(0.157
277
(0.158)
A A
1160
(0.8394
1456
(0.8306)



hCV31199195
KCTD10
LETS
dom
C A
142
(0.3205
111
(0.245)
A A
289
(0.6524
328
(0.7241)




(rs10850234)
MEGA1
dom
C A
423
(0.3048
486
(0.2772)
A A
913
(0.6578
1215
(0.6931)





LETS
Gen
C A
142
(0.3205
111
(0.245)
A A
289
(0.6524
328
(0.7241)






Gen
C A
142
(0.3205
111
(0.245)
A A
289
(0.6524
328
(0.7241)





MEGA1
Gen
C A
423
(0.3048
486
(0.2772)
A A
913
(0.6578
1215
(0.6931)






Gen
C A
423
(0.3048
486
(0.2772)
A A
913
(0.6578
1215
(0.6931)



hCV27502514
KLF3
MEGA1
dom
A G
410
(0.2962
465
(0.2654)
G G
930
(0.672
1242
(0.7089)




(rs3796533)
LETS
dom
A G
146
(0.3296
122
(0.2693)
G G
280
(0.6321
316
(0.6976)





LETS
Gen
A G
146
(0.3296
122
(0.2693)
G G
280
(0.6321
316
(0.6976)






Gen
A G
146
(0.3296
122
(0.2693)
G G
280
(0.6321
316
(0.6976)





MEGA1
Gen
A G
410
(0.2962
465
(0.2654)
G G
930
(0.672
1242
(0.7089)






Gen
A G
410
(0.2962
465
(0.2654)
G G
930
(0.672
1242
(0.7089)



hCV11786258
KLKB1
LETS
Gen
A G
226
(0.5136
208
(0.4622)
G G
131
(0.2977
159
(0.3533)




(rs4253303)
MEGA1
Gen
A G
686
(0.4932
815
(0.4649)
G G
434
(0.312
656
(0.3742)





LETS
Gen
A G
226
(0.5136
208
(0.4622)
G G
131
(0.2977
159
(0.3533)






Gen
A G
226
(0.5136
208
(0.4622)
G G
131
(0.2977
159
(0.3533)





MEGA1
Gen
A G
686
(0.4932
815
(0.4649)
G G
434
(0.312
656
(0.3742)






Gen
A G
686
(0.4932
815
(0.4649)
G G
434
(0.312
656
(0.3742)



hCV540410
LASP1
LETS
Gen
A T
59
(0.1335
42
(0.0927)
T T
381
(0.862
407
(0.8985)




(rs609529)
MEGA1
Gen
A T
178
(0.1276
216
(0.123)
T T
1202
(0.8616
1535
(0.8741)





LETS
Gen
A T
59
(0.1335
42
(0.0927)
T T
381
(0.862
407
(0.8985)






Gen
A T
59
(0.1335
42
(0.0927)
T T
381
(0.862
407
(0.8985)





MEGA1
Gen
A T
178
(0.1276
216
(0.123)
T T
1202
(0.8616
1535
(0.8741)






Gen
A T
178
(0.1276
216
(0.123)
T T
1202
(0.8616
1535
(0.8741)



hDV70662128
LOC129656
LETS
add
A G
35
(0.0792
22
(0.0486)
G G
407
(0.9208
431
(0.9514)




(rs17043082)
MEGA1
add
A G
105
(0.0758
83
(0.0473)
G G
1275
(0.9206
1667
(0.9504)





LETS
Gen
A G
35
(0.0792
22
(0.0486)
G G
407
(0.9208
431
(0.9514)





MEGA1
Gen
A G
105
(0.0758
83
(0.0473)
G G
1275
(0.9206
1667
(0.9504)






Gen
A G
105
(0.0758
83
(0.0473)
G G
1275
(0.9206
1667
(0.9504)



hCV11541681
LOC200420
MEGA1
add
C G
662
(0.4756
815
(0.4644)
G G
502
(0.3606
697
(0.3972)




(rs2001490)
LETS
add
C G
220
(0.4966
228
(0.5033)
G G
142
(0.3205
165
(0.3642)





LETS
Gen
C G
220
(0.4966
228
(0.5033)
G G
142
(0.3205
165
(0.3642)






Gen
C G
220
(0.4966
228
(0.5033)
G G
142
(0.3205
165
(0.3642)





MEGA1
Gen
C G
662
(0.4756
815
(0.4644)
G G
502
(0.3606
697
(0.3972)






Gen
C G
662
(0.4756
815
(0.4644)
G G
502
(0.3606
697
(0.3972)



hCV2706410
LOC387646
LETS
Gen
C T
175
(0.3959
146
(0.323)
T T
234
(0.5294
276
(0.6106)




(rs7896532)
MEGA1
Gen
C T
535
(0.3914
622
(0.354)
T T
746
(0.5457
1014
(0.5771)





LETS
Gen
C T
175
(0.3959
146
(0.323)
T T
234
(0.5294
276
(0.6106)






Gen
C T
175
(0.3959
146
(0.323)
T T
234
(0.5294
276
(0.6106)





MEGA1
Gen
C T
535
(0.3914
622
(0.354)
T T
746
(0.5457
1014
(0.5771)






Gen
C T
535
(0.3914
622
(0.354)
T T
746
(0.5457
1014
(0.5771)



hCV1547677
LOC646030
LETS
add
G A
20
(0.0452
8
(0.0179)
A A
422
(0.9548
439
(0.9821)




(rs6505228)
MEGA1
add
G A
39
(0.0286
47
(0.0268)
A A
1312
(0.9605
1702
(0.9698)





LETS
Gen
G A
20
(0.0452
8
(0.0179)
A A
422
(0.9548
439
(0.9821)





MEGA1
Gen
G A
39
(0.0286
47
(0.0268)
A A
1312
(0.9605
1702
(0.9698)






Gen
G A
39
(0.0286
47
(0.0268)
A A
1312
(0.9605
1702
(0.9698)



hCV8827309
LOC728221
LETS
add
T C
107
(0.2437
83
(0.1836)
C C
321
(0.7312
364
(0.8053)




(rs1110796)
MEGA1
add
T C
339
(0.2453
368
(0.2131)
C C
1022
(0.7395
1335
(0.773)





LETS
Gen
T C
107
(0.2437
83
(0.1836)
C C
321
(0.7312
364
(0.8053)






Gen
T C
107
(0.2437
83
(0.1836)
C C
321
(0.7312
364
(0.8053)





MEGA1
Gen
T C
339
(0.2453
368
(0.2131)
C C
1022
(0.7395
1335
(0.773)






Gen
T C
339
(0.2453
368
(0.2131)
C C
1022
(0.7395
1335
(0.773)



hCV2103392
LOC728284
LETS
dom
T C
197
(0.4457
192
(0.4248)
C C
196
(0.4434
193
(0.427)




(rs12500826)
MEGA1
dom
T C
622
(0.4625
827
(0.4718)
C C
570
(0.4238
674
(0.3845)





LETS
Gen
T C
197
(0.4457
192
(0.4248)
C C
196
(0.4434
193
(0.427)






Gen
T C
197
(0.4457
192
(0.4248)
C C
196
(0.4434
193
(0.427)





MEGA1
Gen
T C
622
(0.4625
827
(0.4718)
C C
570
(0.4238
674
(0.3845)






Gen
T C
622
(0.4625
827
(0.4718)
C C
570
(0.4238
674
(0.3845)



hCV3230136
LOC728284
MEGA1
rec
A G
530
(0.3813
716
(0.4091)
G G
785
(0.5647
904
(0.5166)




(rs13116273)
LETS
rec
A G
146
(0.3311
183
(0.4049)
G G
264
(0.5986
238
(0.5265)





LETS
Gen
A G
146
(0.3311
183
(0.4049)
G G
264
(0.5986
238
(0.5265)






Gen
A G
146
(0.3311
183
(0.4049)
G G
264
(0.5986
238
(0.5265)





MEGA1
Gen
A G
530
(0.3813
716
(0.4091)
G G
785
(0.5647
904
(0.5166)






Gen
A G
530
(0.3813
716
(0.4091)
G G
785
(0.5647
904
(0.5166)



hCV3230131
LOC728284
LETS
rec
C T
149
(0.3371
182
(0.4035)
T T
262
(0.5928
238
(0.5277)




(rs13136269)
MEGA1
rec
C T
528
(0.3799
719
(0.4104)
T T
788
(0.5669
899
(0.5131)





LETS
Gen
C T
149
(0.3371
182
(0.4035)
T T
262
(0.5928
238
(0.5277)






Gen
C T
149
(0.3371
182
(0.4035)
T T
262
(0.5928
238
(0.5277)





MEGA1
Gen
C T
528
(0.3799
719
(0.4104)
T T
788
(0.5669
899
(0.5131)






Gen
C T
528
(0.3799
719
(0.4104)
T T
788
(0.5669
899
(0.5131)



hCV29821005
LOC728284
LETS
Gen
T C
170
(0.3864
147
(0.3267)
C C
250
(0.5682
284
(0.6311)




(rs6552970)
MEGA1
Gen
T C
463
(0.3442
528
(0.3009)
C C
820
(0.6097
1150
(0.6553)





LETS
Gen
T C
170
(0.3864
147
(0.3267)
C C
250
(0.5682
284
(0.6311)






Gen
T C
170
(0.3864
147
(0.3267)
C C
250
(0.5682
284
(0.6311)





MEGA1
Gen
T C
463
(0.3442
528
(0.3009)
C C
820
(0.6097
1150
(0.6553)






Gen
T C
463
(0.3442
528
(0.3009)
C C
820
(0.6097
1150
(0.6553)



hCV32209621
LOC728284
LETS
Gen
G A
226
(0.5125
202
(0.4499)
A A
124
(0.2812
134
(0.2984)




(rs6552971)





MEGA1
Gen
G A
669
(0.4959
854
(0.4866)
A A
375
(0.278
451
(0.257)





LETS
Gen
G A
226
(0.5125
202
(0.4499)
A A
124
(0.2812
134
(0.2984)






Gen
G A
226
(0.5125
202
(0.4499)
A A
124
(0.2812
134
(0.2984)





MEGA1
Gen
G A
669
(0.4959
854
(0.4866)
A A
375
(0.278
451
(0.257)






Gen
G A
669
(0.4959
854
(0.4866)
A A
375
(0.278
451
(0.257)



hCV32209620
LOC728284
LETS
dom
C T
166
(0.3773
145
(0.3215)
T T
251
(0.5705
285
(0.6319)




(rs6552972)
MEGA1
dom
C T
461
(0.344
527
(0.3022)
T T
817
(0.6097
1141
(0.6542)





LETS
Gen
C T
166
(0.3773
145
(0.3215)
T T
251
(0.5705
285
(0.6319)






Gen
C T
166
(0.3773
145
(0.3215)
T T
251
(0.5705
285
(0.6319)





MEGA1
Gen
C T
461
(0.344
527
(0.3022)
T T
817
(0.6097
1141
(0.6542)






Gen
C T
461
(0.344
527
(0.3022)
T T
817
(0.6097
1141
(0.6542)



hCV916107
LOC729138
LETS
add
T C
185
(0.4186
200
(0.4415)
C C
216
(0.4887
192
(0.4238)




(rs670659)
MEGA1
add
T C
620
(0.4457
773
(0.442)
C C
622
(0.4472
738
(0.422)





LETS
Gen
T C
185
(0.4186
200
(0.4415)
C C
216
(0.4887
192
(0.4238)






Gen
T C
185
(0.4186
200
(0.4415)
C C
216
(0.4887
192
(0.4238)





MEGA1
Gen
T C
620
(0.4457
773
(0.442)
C C
622
(0.4472
738
(0.422)






Gen
T C
620
(0.4457
773
(0.442)
C C
622
(0.4472
738
(0.422)



hCV30922162
LOC729672
LETS
add
T C
201
(0.4548
202
(0.4459)
C C
191
(0.4321
222
(0.4901)




(rs4334028)
MEGA1
add
T C
601
(0.433
748
(0.4262)
C C
655
(0.4719
874
(0.498)





LETS
Gen
T C
201
(0.4548
202
(0.4459)
C C
191
(0.4321
222
(0.4901)






Gen
T C
201
(0.4548
202
(0.4459)
C C
191
(0.4321
222
(0.4901)





MEGA1
Gen
T C
601
(0.433
748
(0.4262)
C C
655
(0.4719
874
(0.498)






Gen
T C
601
(0.433
748
(0.4262)
C C
655
(0.4719
874
(0.498)



hCV7504118
LOC729672
MEGA1
add
G A
595
(0.4293
734
(0.418)
A A
668
(0.482
902
(0.5137)




(rs967257)
LETS
add
G A
200
(0.4525
195
(0.4305)
A A
198
(0.448
229
(0.5055)





LETS
Gen
G A
200
(0.4525
195
(0.4305)
A A
198
(0.448
229
(0.5055)






Gen
G A
200
(0.4525
195
(0.4305)
A A
198
(0.448
229
(0.5055)





MEGA1
Gen
G A
595
(0.4293
734
(0.418)
A A
668
(0.482
902
(0.5137)






Gen
G A
595
(0.4293
734
(0.418)
A A
668
(0.482
902
(0.5137)



hCV11633415
LOC730144
MEGA1
add
C T
156
(0.1124
258
(0.147)
T T
1226
(0.8833
1486
(0.8467)




(rs4262503)
LETS
add
C T
51
(0.1151
67
(0.1482)
T T
392
(0.8849
381
(0.8429)





LETS
Gen
C T
51
(0.1151
67
(0.1482)
T T
392
(0.8849
381
(0.8429)






Gen
C T
51
(0.1151
67
(0.1482)
T T
392
(0.8849
381
(0.8429)





MEGA1
Gen
C T
156
(0.1124
258
(0.147)
T T
1226
(0.8833
1486
(0.8467)






Gen
C T
156
(0.1124
258
(0.147)
T T
1226
(0.8833
1486
(0.8467)



hCV2494846
LUZP1
MEGA1
rec
G T
386
(0.2775
491
(0.2801)
T T
950
(0.683
1217
(0.6942)




(rs3765407)
LETS
rec
G T
119
(0.2692
108
(0.2389)
T T
302
(0.6833
334
(0.7389)





LETS
Gen
G T
119
(0.2692
108
(0.2389)
T T
302
(0.6833
334
(0.7389)






Gen
G T
119
(0.2692
108
(0.2389)
T T
302
(0.6833
334
(0.7389)





MEGA1
Gen
G T
386
(0.2775
491
(0.2801)
T T
950
(0.683
1217
(0.6942)






Gen
G T
386
(0.2775
491
(0.2801)
T T
950
(0.683
1217
(0.6942)



hCV25752810
MDN1
MEGA1
add
C A
67
(0.049
59
(0.0336)
A A
1294
(0.9459
1693
(0.9641)




(rs4707557)
LETS
add
C A
22
(0.0498
11
(0.0244)
A A
417
(0.9434
439
(0.9734)





LETS
Gen
C A
22
(0.0498
11
(0.0244)
A A
417
(0.9434
439
(0.9734)






Gen
C A
22
(0.0498
11
(0.0244)
A A
417
(0.9434
439
(0.9734)





MEGA1
Gen
C A
67
(0.049
59
(0.0336)
A A
1294
(0.9459
1693
(0.9641)






Gen
C A
67
(0.049
59
(0.0336)
A A
1294
(0.9459
1693
(0.9641)



hCV16170613
MET
MEGA1
add
G A
113
(0.081
108
(0.0615)
A A
1279
(0.9168
1647
(0.9379)




(rs2237712)
LETS
add
G A
37
(0.0837
27
(0.0597)
A A
401
(0.9072
425
(0.9403)





LETS
Gen
G A
37
(0.0837
27
(0.0597)
A A
401
(0.9072
425
(0.9403)






Gen
G A
37
(0.0837
27
(0.0597)
A A
401
(0.9072
425
(0.9403)





MEGA1
Gen
G A
113
(0.081
108
(0.0615)
A A
1279
(0.9168
1647
(0.9379)






Gen
G A
113
(0.081
108
(0.0615)
A A
1279
(0.9168
1647
(0.9379)



hCV11726971
NFIA
LETS
Gen
G A
126
(0.2844
117
(0.2583)
A A
294
(0.6637
326
(0.7196)




(rs2065841)
MEGA1
Gen
G A
465
(0.3362
526
(0.2999)
A A
867
(0.6269
1153
(0.6574)





LETS
Gen
G A
126
(0.2844
117
(0.2583)
A A
294
(0.6637
326
(0.7196)






Gen
G A
126
(0.2844
117
(0.2583)
A A
294
(0.6637
326
(0.7196)





MEGA1
Gen
G A
465
(0.3362
526
(0.2999)
A A
867
(0.6269
1153
(0.6574)






Gen
G A
465
(0.3362
526
(0.2999)
A A
867
(0.6269
1153
(0.6574)



hCV30747430
NR1I2
MEGA1
add
T C
424
(0.3141
520
(0.2963)
C C
850
(0.6296
1170
(0.6667)




(rs11712211)
LETS
add
T C
122
(0.2773
115
(0.255)
C C
292
(0.6636
325
(0.7206)





LETS
Gen
T C
122
(0.2773
115
(0.255)
C C
292
(0.6636
325
(0.7206)






Gen
T C
122
(0.2773
115
(0.255)
C C
292
(0.6636
325
(0.7206)





MEGA1
Gen
T C
424
(0.3141
520
(0.2963)
C C
850
(0.6296
1170
(0.6667)






Gen
T C
424
(0.3141
520
(0.2963)
C C
850
(0.6296
1170
(0.6667)



hCV263841
NR1I2
LETS
add
C A
190
(0.4358
194
(0.4379)
A A
158
(0.3624
200
(0.4515)




(rs1523127)
MEGA1
add
C A
685
(0.49
851
(0.4843)
A A
463
(0.3312
645
(0.3671)





LETS
Gen
C A
190
(0.4358
194
(0.4379)
A A
158
(0.3624
200
(0.4515)






Gen
C A
190
(0.4358
194
(0.4379)
A A
158
(0.3624
200
(0.4515)





MEGA1
Gen
C A
685
(0.49
851
(0.4843)
A A
463
(0.3312
645
(0.3671)






Gen
C A
685
(0.49
851
(0.4843)
A A
463
(0.3312
645
(0.3671)



hCV4041
NR3C1
MEGA1
dom
T C
96
(0.0701
92
(0.0524)
C C
1269
(0.927
1662
(0.947)




(rs6190)
LETS
dom
T C
41
(0.0928
26
(0.0575)
C C
400
(0.905
425
(0.9403)





LETS
Gen
T C
41
(0.0928
26
(0.0575)
C C
400
(0.905
425
(0.9403)






Gen
T C
41
(0.0928
26
(0.0575)
C C
400
(0.905
425
(0.9403)





MEGA1
Gen
T C
96
(0.0701
92
(0.0524)
C C
1269
(0.927
1662
(0.947)






Gen
T C
96
(0.0701
92
(0.0524)
C C
1269
(0.927
1662
(0.947)



hCV2915511
OBSL1
LETS
Gen
C T
40
(0.0905
22
(0.0487)
T T
399
(0.9027
429
(0.9491)




(rs627530)
MEGA1
Gen
C T
92
(0.0661
126
(0.0718)
T T
1287
(0.9246
1624
(0.9254)





LETS
Gen
C T
40
(0.0905
22
(0.0487)
T T
399
(0.9027
429
(0.9491)






Gen
C T
40
(0.0905
22
(0.0487)
T T
399
(0.9027
429
(0.9491)





MEGA1
Gen
C T
92
(0.0661
126
(0.0718)
T T
1287
(0.9246
1624
(0.9254)






Gen
C T
92
(0.0661
126
(0.0718)
T T
1287
(0.9246
1624
(0.9254)



hCV16177220
ODZ1
MEGA1
add
T C
212
(0.1524
308
(0.1756)
C C
1054
(0.7577
1232
(0.7024)




(rs2266911)
LETS
add
T C
72
(0.1625
85
(0.1876)
C C
336
(0.7585
314
(0.6932)





LETS
Gen
T C
72
(0.1625
85
(0.1876)
C C
336
(0.7585
314
(0.6932)






Gen
T C
72
(0.1625
85
(0.1876)
C C
336
(0.7585
314
(0.6932)





MEGA1
Gen
T C
212
(0.1524
308
(0.1756)
C C
1054
(0.7577
1232
(0.7024)






Gen
T C
212
(0.1524
308
(0.1756)
C C
1054
(0.7577
1232
(0.7024)



hCV7584272
OR1B1
LETS
Gen
A G
187
(0.424
166
(0.3673)
G G
228
(0.517
262
(0.5796)




(rs1536929)
MEGA1
dom
A G
545
(0.3987
645
(0.3675)
G G
739
(0.5406
1012
(0.5766)





LETS
Gen
A G
187
(0.424
166
(0.3673)
G G
228
(0.517
262
(0.5796)






Gen
A G
187
(0.424
166
(0.3673)
G G
228
(0.517
262
(0.5796)





MEGA1
Gen
A G
545
(0.3987
645
(0.3675)
G G
739
(0.5406
1012
(0.5766)






Gen
A G
545
(0.3987
645
(0.3675)
G G
739
(0.5406
1012
(0.5766)



hCV9327878
OR7G1
MEGA1
add
G C
600
(0.4386
733
(0.4174)
C C
588
(0.4298
833
(0.4744)




(rs2217657)
LETS
add
G C
191
(0.4341
185
(0.4129)
C C
188
(0.4273
218
(0.4866)





LETS
Gen
G C
191
(0.4341
185
(0.4129)
C C
188
(0.4273
218
(0.4866)






Gen
G C
191
(0.4341
185
(0.4129)
C C
188
(0.4273
218
(0.4866)





MEGA1
Gen
G C
600
(0.4386
733
(0.4174)
C C
588
(0.4298
833
(0.4744)






Gen
G C
600
(0.4386
733
(0.4174)
C C
588
(0.4298
833
(0.4744)



hCV15990789
OTOG
MEGA1
rec
A G
600
(0.4402
857
(0.4889)
G G
543
(0.3984
617
(0.352)




(rs2355466)
LETS
rec
A G
205
(0.4638
241
(0.5344)
G G
162
(0.3665
130
(0.2882)





LETS
Gen
A G
205
(0.4638
241
(0.5344)
G G
162
(0.3665
130
(0.2882)






Gen
A G
205
(0.4638
241
(0.5344)
G G
162
(0.3665
130
(0.2882)





MEGA1
Gen
A G
600
(0.4402
857
(0.4889)
G G
543
(0.3984
617
(0.352)






Gen
A G
600
(0.4402
857
(0.4889)
G G
543
(0.3984
617
(0.352)



hCV8361354
PANX1
LETS
Gen
A C
203
(0.4582
223
(0.4923)
C C
192
(0.4334
160
(0.3532)




(rs1138800)
MEGA1
Gen
A C
636
(0.4582
875
(0.4994)
C C
545
(0.3927
650
(0.371)





LETS
Gen
A C
203
(0.4582
223
(0.4923)
C C
192
(0.4334
160
(0.3532)






Gen
A C
203
(0.4582
223
(0.4923)
C C
192
(0.4334
160
(0.3532)





MEGA1
Gen
A C
636
(0.4582
875
(0.4994)
C C
545
(0.3927
650
(0.371)






Gen
A C
636
(0.4582
875
(0.4994)
C C
545
(0.3927
650
(0.371)



hCV30500334
PHACTR3
LETS
add
A G
195
(0.4402
230
(0.5077)
G G
189
(0.4266
149
(0.3289)




(rs6128674)
MEGA1
add
A G
630
(0.4626
823
(0.4689)
G G
547
(0.4016
647
(0.3687)





LETS
Gen
A G
195
(0.4402
230
(0.5077)
G G
189
(0.4266
149
(0.3289)






Gen
A G
195
(0.4402
230
(0.5077)
G G
189
(0.4266
149
(0.3289)





MEGA1
Gen
A G
630
(0.4626
823
(0.4689)
G G
547
(0.4016
647
(0.3687)






Gen
A G
630
(0.4626
823
(0.4689)
G G
547
(0.4016
647
(0.3687)



hCV27474984
PIK3R1
MEGA1
add
A G
730
(0.5252
821
(0.4689)
G G
367
(0.264
568
(0.3244)




(rs3756668)
LETS
add
A G
223
(0.5045
231
(0.5122)
G G
109
(0.2466
133
(0.2949)





LETS
Gen
A G
223
(0.5045
231
(0.5122)
G G
109
(0.2466
133
(0.2949)






Gen
A G
223
(0.5045
231
(0.5122)
G G
109
(0.2466
133
(0.2949)





MEGA1
Gen
A G
730
(0.5252
821
(0.4689)
G G
367
(0.264
568
(0.3244)






Gen
A G
730
(0.5252
821
(0.4689)
G G
367
(0.264
568
(0.3244)



hCV7625318
PLEKHG4
LETS
Gen
A G
79
(0.1787
49
(0.1082)
G G
361
(0.8167
400
(0.883)




(rs3868142)
MEGA1
Gen
A G
224
(0.1614
236
(0.1346)
G G
1151
(0.8293
1501
(0.8562)





LETS
Gen
A G
79
(0.1787
49
(0.1082)
G G
361
(0.8167
400
(0.883)






Gen
A G
79
(0.1787
49
(0.1082)
G G
361
(0.8167
400
(0.883)





MEGA1
Gen
A G
224
(0.1614
236
(0.1346)
G G
1151
(0.8293
1501
(0.8562)






Gen
A G
224
(0.1614
236
(0.1346)
G G
1151
(0.8293
1501
(0.8562)



hCV8598986
POLR1A
LETS
rec
T C
176
(0.3982
198
(0.4381)
C C
238
(0.5385
209
(0.4624)




(rs4832233)
MEGA1
rec
T C
507
(0.3655
696
(0.3984)
C C
761
(0.5487
897
(0.5135)





LETS
Gen
T C
176
(0.3982
198
(0.4381)
C C
238
(0.5385
209
(0.4624)






Gen
T C
176
(0.3982
198
(0.4381)
C C
238
(0.5385
209
(0.4624)





MEGA1
Gen
T C
507
(0.3655
696
(0.3984)
C C
761
(0.5487
897
(0.5135)






Gen
T C
507
(0.3655
696
(0.3984)
C C
761
(0.5487
897
(0.5135)



hCV926518
PPP2R5C
LETS
Gen
G T
94
(0.2127
71
(0.1571)
T T
344
(0.7783
376
(0.8319)




(rs746781)
MEGA1
Gen
G T
269
(0.1971
297
(0.1692)
T T
1080
(0.7912
1432
(0.816)





LETS
Gen
G T
94
(0.2127
71
(0.1571)
T T
344
(0.7783
376
(0.8319)






Gen
G T
94
(0.2127
71
(0.1571)
T T
344
(0.7783
376
(0.8319)





MEGA1
Gen
G T
269
(0.1971
297
(0.1692)
T T
1080
(0.7912
1432
(0.816)






Gen
G T
269
(0.1971
297
(0.1692)
T T
1080
(0.7912
1432
(0.816)



hCV1841975
PROC
LETS
Gen
T A
215
(0.4864
224
(0.4956)
A A
127
(0.2873
147
(0.3252)




(rs1799810)
MEGA1
Gen
T A
655
(0.4719
864
(0.4946)
A A
410
(0.2954
554
(0.3171)





LETS
Gen
T A
215
(0.4864
224
(0.4956)
A A
127
(0.2873
147
(0.3252)






Gen
T A
215
(0.4864
224
(0.4956)
A A
127
(0.2873
147
(0.3252)





MEGA1
Gen
T A
655
(0.4719
864
(0.4946)
A A
410
(0.2954
554
(0.3171)






Gen
T A
655
(0.4719
864
(0.4946)
A A
410
(0.2954
554
(0.3171)



hCV8957432
RAC2 (rs6572)
MEGA1
rec
C G
676
(0.4867
862
(0.4917)
G G
405
(0.2916
557
(0.3177)





LETS
rec
C G
225
(0.5102
249
(0.5509)
G G
117
(0.2653
126
(0.2788)





LETS
Gen
C G
225
(0.5102
249
(0.5509)
G G
117
(0.2653
126
(0.2788)






Gen
C G
225
(0.5102
249
(0.5509)
G G
117
(0.2653
126
(0.2788)





MEGA1
Gen
C G
676
(0.4867
862
(0.4917)
G G
405
(0.2916
557
(0.3177)






Gen
C G
676
(0.4867
862
(0.4917)
G G
405
(0.2916
557
(0.3177)



hCV29271569
RDH13
LETS
add
C T
116
(0.2624
143
(0.3157)
T T
317
(0.7172
293
(0.6468)




(rs1626971)
MEGA1
add
C T
374
(0.2695
535
(0.305)
T T
971
(0.6996
1159
(0.6608)





LETS
Gen
C T
116
(0.2624
143
(0.3157)
T T
317
(0.7172
293
(0.6468)






Gen
C T
116
(0.2624
143
(0.3157)
T T
317
(0.7172
293
(0.6468)





MEGA1
Gen
C T
374
(0.2695
535
(0.305)
T T
971
(0.6996
1159
(0.6608)






Gen
C T
374
(0.2695
535
(0.305)
T T
971
(0.6996
1159
(0.6608)



hCV8703249
RDH13
LETS
add
T G
117
(0.2647
138
(0.3046)
G G
315
(0.7127
298
(0.6578)




(rs1654444)
MEGA1
add
T G
376
(0.2711
532
(0.303)
G G
970
(0.6994
1160
(0.6606)





LETS
Gen
T G
117
(0.2647
138
(0.3046)
G G
315
(0.7127
298
(0.6578)






Gen
T G
117
(0.2647
138
(0.3046)
G G
315
(0.7127
298
(0.6578)





MEGA1
Gen
T G
376
(0.2711
532
(0.303)
G G
970
(0.6994
1160
(0.6606)






Gen
T G
376
(0.2711
532
(0.303)
G G
970
(0.6994
1160
(0.6606)



hCV8717752
RDH13
LETS
add
A G
118
(0.267
137
(0.3031)
G G
317
(0.7172
298
(0.6593)




(rs1671217)
MEGA1
rec
A G
369
(0.2662
518
(0.2955)
G G
981
(0.7078
1183
(0.6748)





LETS
Gen
A G
118
(0.267
137
(0.3031)
G G
317
(0.7172
298
(0.6593)






Gen
A G
118
(0.267
137
(0.3031)
G G
317
(0.7172
298
(0.6593)





MEGA1
Gen
A G
369
(0.2662
518
(0.2955)
G G
981
(0.7078
1183
(0.6748)






Gen
A G
369
(0.2662
518
(0.2955)
G G
981
(0.7078
1183
(0.6748)



hCV11975296
SELP (rs6131)
MEGA1
add
T C
463
(0.3329
504
(0.2882)
C C
865
(0.6219
1179
(0.6741)





LETS
add
T C
142
(0.3213
121
(0.2671)
C C
273
(0.6176
312
(0.6887)





LETS
Gen
T C
142
(0.3213
121
(0.2671)
C C
273
(0.6176
312
(0.6887)






Gen
T C
142
(0.3213
121
(0.2671)
C C
273
(0.6176
312
(0.6887)





MEGA1
Gen
T C
463
(0.3329
504
(0.2882)
C C
865
(0.6219
1179
(0.6741)






Gen
T C
463
(0.3329
504
(0.2882)
C C
865
(0.6219
1179
(0.6741)



hCV9596963
SERPINA5
LETS
dom
G A
225
(0.5172
224
(0.4989)
A A
172
(0.3954
165
(0.3675)




(rs6115)
MEGA1
dom
G A
632
(0.456
775
(0.4434)
A A
617
(0.4452
759
(0.4342)





LETS
Gen
G A
225
(0.5172
224
(0.4989)
A A
172
(0.3954
165
(0.3675)






Gen
G A
225
(0.5172
224
(0.4989)
A A
172
(0.3954
165
(0.3675)





MEGA1
Gen
G A
632
(0.456
775
(0.4434)
A A
617
(0.4452
759
(0.4342)






Gen
G A
632
(0.456
775
(0.4434)
A A
617
(0.4452
759
(0.4342)



hCV16180170
SERPINC1
MEGA1
add
T C
259
(0.1863
283
(0.1613)
C C
1109
(0.7978
1457
(0.8302)




(rs2227589)
LETS
add
T C
93
(0.2099
70
(0.1549)
C C
344
(0.7765
378
(0.8363)





LETS
Gen
T C
93
(0.2099
70
(0.1549)
C C
344
(0.7765
378
(0.8363)






Gen
T C
93
(0.2099
70
(0.1549)
C C
344
(0.7765
378
(0.8363)





MEGA1
Gen
T C
259
(0.1863
283
(0.1613)
C C
1109
(0.7978
1457
(0.8302)






Gen
T C
259
(0.1863
283
(0.1613)
C C
1109
(0.7978
1457
(0.8302)



hCV1650632
SERPINC1
MEGA1
Gen
C T
615
(0.4593
792
(0.4528)
T T
533
(0.3981
760
(0.4345)




(rs5878)
LETS
Gen
C T
205
(0.468
174
(0.391)
T T
184
(0.4201
215
(0.4831)





LETS
Gen
C T
205
(0.468
174
(0.391)
T T
184
(0.4201
215
(0.4831)






Gen
C T
205
(0.468
174
(0.391)
T T
184
(0.4201
215
(0.4831)





MEGA1
Gen
C T
615
(0.4593
792
(0.4528)
T T
533
(0.3981
760
(0.4345)






Gen
C T
615
(0.4593
792
(0.4528)
T T
533
(0.3981
760
(0.4345)



hCV3216426
SFRS2IP
LETS
dom
T A
218
(0.4955
211
(0.472)
A A
135
(0.3068
117
(0.2617)




(rs7315731)
MEGA1
dom
T A
707
(0.5061
843
(0.4798)
A A
389
(0.2785
473
(0.2692)





LETS
Gen
T A
218
(0.4955
211
(0.472)
A A
135
(0.3068
117
(0.2617)






Gen
T A
218
(0.4955
211
(0.472)
A A
135
(0.3068
117
(0.2617)





MEGA1
Gen
T A
707
(0.5061
843
(0.4798)
A A
389
(0.2785
473
(0.2692)






Gen
T A
707
(0.5061
843
(0.4798)
A A
389
(0.2785
473
(0.2692)



hCV25602230
SIRT6
MEGA1
add
G T
46
(0.0332
36
(0.0205)
T T
1336
(0.9639
1716
(0.9789)




(rs7246235)
LETS
add
G T
15
(0.0339
5
(0.0111)
T T
425
(0.9615
447
(0.9889)





LETS
Gen
G T
15
(0.0339
5
(0.0111)
T T
425
(0.9615
447
(0.9889)






Gen
G T
15
(0.0339
5
(0.0111)
T T
425
(0.9615
447
(0.9889)





MEGA1
Gen
G T
46
(0.0332
36
(0.0205)
T T
1336
(0.9639
1716
(0.9789)






Gen
G T
46
(0.0332
36
(0.0205)
T T
1336
(0.9639
1716
(0.9789)



hCV2086329
SPARC
MEGA1
rec
G A
631
(0.4556
888
(0.5063)
A A
456
(0.3292
570
(0.325)




(rs4958487)
LETS
rec
G A
205
(0.4628
227
(0.5011)
A A
134
(0.3025
150
(0.3311)





LETS
Gen
G A
205
(0.4628
227
(0.5011)
A A
134
(0.3025
150
(0.3311)






Gen
G A
205
(0.4628
227
(0.5011)
A A
134
(0.3025
150
(0.3311)





MEGA1
Gen
G A
631
(0.4556
888
(0.5063)
A A
456
(0.3292
570
(0.325)






Gen
G A
631
(0.4556
888
(0.5063)
A A
456
(0.3292
570
(0.325)



hCV11466393
TACR1 (rs881)
LETS
add
G C
111
(0.2534
139
(0.3138)
C C
317
(0.7237
287
(0.6479)





MEGA1
add
G C
368
(0.264
508
(0.2898)
C C
994
(0.7131
1193
(0.6805)





LETS
Gen
G C
111
(0.2534
139
(0.3138)
C C
317
(0.7237
287
(0.6479)






Gen
G C
111
(0.2534
139
(0.3138)
C C
317
(0.7237
287
(0.6479)





MEGA1
Gen
G C
368
(0.264
508
(0.2898)
C C
994
(0.7131
1193
(0.6805)






Gen
G C
368
(0.264
508
(0.2898)
C C
994
(0.7131
1193
(0.6805)



hCV3216649
TAF1B
LETS
dom
A G
194
(0.4399
174
(0.3858)
G G
197
(0.4467
230
(0.51)




(rs1054565)
MEGA1
dom
A G
623
(0.4479
732
(0.4178)
G G
608
(0.4371
829
(0.4732)





LETS
Gen
A G
194
(0.4399
174
(0.3858)
G G
197
(0.4467
230
(0.51)






Gen
A G
194
(0.4399
174
(0.3858)
G G
197
(0.4467
230
(0.51)





MEGA1
Gen
A G
623
(0.4479
732
(0.4178)
G G
608
(0.4371
829
(0.4732)






Gen
A G
623
(0.4479
732
(0.4178)
G G
608
(0.4371
829
(0.4732)



hCV470708
THBS2
LETS
add
T G
193
(0.4367
180
(0.3991)
G G
199
(0.4502
233
(0.5166)




(rs10945408)
MEGA1
Gen
T G
588
(0.4215
747
(0.4264)
G G
655
(0.4695
852
(0.4863)





LETS
Gen
T G
193
(0.4367
180
(0.3991)
G G
199
(0.4502
233
(0.5166)






Gen
T G
193
(0.4367
180
(0.3991)
G G
199
(0.4502
233
(0.5166)





MEGA1
Gen
T G
588
(0.4215
747
(0.4264)
G G
655
(0.4695
852
(0.4863)






Gen
T G
588
(0.4215
747
(0.4264)
G G
655
(0.4695
852
(0.4863)



hCV3272537
TIAM1
LETS
dom
A T
214
(0.4853
207
(0.458)
T T
127
(0.288
155
(0.3429)




(rs497689)
MEGA1
dom
A T
702
(0.5076
802
(0.4596)
T T
404
(0.2921
596
(0.3415)





LETS
Gen
A T
214
(0.4853
207
(0.458)
T T
127
(0.288
155
(0.3429)






Gen
A T
214
(0.4853
207
(0.458)
T T
127
(0.288
155
(0.3429)





MEGA1
Gen
A T
702
(0.5076
802
(0.4596)
T T
404
(0.2921
596
(0.3415)






Gen
A T
702
(0.5076
802
(0.4596)
T T
404
(0.2921
596
(0.3415)



hCV27833944
TNFSF4
LETS
add
C T
89
(0.2014
71
(0.1578)
T T
348
(0.7873
376
(0.8356)




(rs6702339)
MEGA1
add
C T
256
(0.1847
284
(0.1619)
T T
1105
(0.7973
1454
(0.829)





LETS
Gen
C T
89
(0.2014
71
(0.1578)
T T
348
(0.7873
376
(0.8356)






Gen
C T
89
(0.2014
71
(0.1578)
T T
348
(0.7873
376
(0.8356)





MEGA1
Gen
C T
256
(0.1847
284
(0.1619)
T T
1105
(0.7973
1454
(0.829)






Gen
C T
256
(0.1847
284
(0.1619)
T T
1105
(0.7973
1454
(0.829)



hCV1723643
UMODL1
LETS
rec
C A
144
(0.3265
173
(0.3836)
A A
278
(0.6304
256
(0.5676)




(rs220130)
MEGA1
rec
C A
431
(0.3114
597
(0.3408)
A A
894
(0.646
1060
(0.605)





LETS
Gen
C A
144
(0.3265
173
(0.3836)
A A
278
(0.6304
256
(0.5676)






Gen
C A
144
(0.3265
173
(0.3836)
A A
278
(0.6304
256
(0.5676)





MEGA1
Gen
C A
431
(0.3114
597
(0.3408)
A A
894
(0.646
1060
(0.605)






Gen
C A
431
(0.3114
597
(0.3408)
A A
894
(0.646
1060
(0.605)



hCV7581501
USP45
LETS
Gen
C G
99
(0.2235
73
(0.1611)
G G
335
(0.7562
373
(0.8234)




(rs1323717)
MEGA1
Gen
C G
287
(0.2062
367
(0.209)
G G
1079
(0.7751
1372
(0.7813)





LETS
Gen
C G
99
(0.2235
73
(0.1611)
G G
335
(0.7562
373
(0.8234)






Gen
C G
99
(0.2235
73
(0.1611)
G G
335
(0.7562
373
(0.8234)





MEGA1
Gen
C G
287
(0.2062
367
(0.209)
G G
1079
(0.7751
1372
(0.7813)






Gen
C G
287
(0.2062
367
(0.209)
G G
1079
(0.7751
1372
(0.7813)



hCV15949414
XYLB
MEGA1
rec
A G
89
(0.0653
172
(0.0981)
G G
1269
(0.931
1581
(0.9014)




(rs2234628)
LETS
rec
A G
31
(0.0703
51
(0.1138)
G G
409
(0.9274
397
(0.8862)





LETS
Gen
A G
31
(0.0703
51
(0.1138)
G G
409
(0.9274
397
(0.8862)






Gen
A G
31
(0.0703
51
(0.1138)
G G
409
(0.9274
397
(0.8862)





MEGA1
Gen
A G
89
(0.0653
172
(0.0981)
G G
1269
(0.931
1581
(0.9014)






Gen
A G
89
(0.0653
172
(0.0981)
G G
1269
(0.931
1581
(0.9014)



hCV356522
ZBTB41
LETS
dom
T C
81
(0.1828
63
(0.1391)
C C
356
(0.8036
386
(0.8521)




(rs10732295)
MEGA1
dom
T C
274
(0.1975
289
(0.1646)
C C
1091
(0.7866
1448
(0.8246)





LETS
Gen
T C
81
(0.1828
63
(0.1391)
C C
356
(0.8036
386
(0.8521)






Gen
T C
81
(0.1828
63
(0.1391)
C C
356
(0.8036
386
(0.8521)





MEGA1
Gen
T C
274
(0.1975
289
(0.1646)
C C
1091
(0.7866
1448
(0.8246)






Gen
T C
274
(0.1975
289
(0.1646)
C C
1091
(0.7866
1448
(0.8246)



hCV25596789
ZNF544
LETS
add
G C
29
(0.0658
13
(0.0288)
C C
410
(0.9297
438
(0.9712)




(rs6510130)
MEGA1
add
G C
76
(0.0544
64
(0.0364)
C C
1320
(0.9449
1693
(0.9636)





LETS
Gen
G C
29
(0.0658
13
(0.0288)
C C
410
(0.9297
438
(0.9712)






Gen
G C
29
(0.0658
13
(0.0288)
C C
410
(0.9297
438
(0.9712)





MEGA1
Gen
G C
76
(0.0544
64
(0.0364)
C C
1320
(0.9449
1693
(0.9636)






Gen
G C
76
(0.0544
64
(0.0364)
C C
1320
(0.9449
1693
(0.9636)



hCV25951992
ZWINT
MEGA1
dom
A C
46
(0.033
30
(0.0171)
C C
1345
(0.9635
1725
(0.9823)




(rs11005328)
LETS
dom
A C
22
(0.0499
9
(0.0199)
C C
419
(0.9501
442
(0.9779)





LETS
Gen
A C
22
(0.0499
9
(0.0199)
C C
419
(0.9501
442
(0.9779)






Gen
A C
22
(0.0499
9
(0.0199)
C C
419
(0.9501
442
(0.9779)





MEGA1
Gen
A C
46
(0.033
30
(0.0171)
C C
1345
(0.9635
1725
(0.9823)






Gen
A C
46
(0.033
30
(0.0171)
C C
1345
(0.9635
1725
(0.9823)

















TABLE 21





Unadjusted association of 92 SNPs with DVT in LETS (p <= 0.05) that have not been tested in MEGA-1





































CONTROL cnt










Allele

CASE cnt
(CONTROL


marker
annotation
P-value
parameter
Model
OR (95% CI)
RiskAllele
NonRiskAllele
(CONTROL frq
Genot
(CASE frq
frq)























hCV10008773
ANK1
0.04327
CC_vs_CT + TT
rec
1.31
C
T
T (0.2732
T T
32
(0.0722)
33
(0.073)



(rs750625)



(1.00828819022294-1.71)


hCV11342584
(rs6696864)
0.03793
AT_vs_TT
Gen
1.36 (1.02-1.81)
A
T
A (0.3825
A A
66
(0.15)
73
(0.1619)


hCV11503431
FGG
4.6E−05
TT_vs_CC
Gen
3.01 (1.77-5.11)
T
C
T (0.2622
T T
55
(0.1244)
22
(0.0487)



(rs2066861)
9.5E−05
TT_vs_TC + CC
rec
2.78
T
C
T (0.2622
T T
55
(0.1244)
22
(0.0487)







(1.66280836758397-4.64)




0.00035
T_vs_C
add
1.46
T
C
T (0.2622
T T
55
(0.1244)
22
(0.0487)







(1.18656074071138-1.8)




0.01879
TT + TC_vs_CC
dom
1.37
T
C
T (0.2622
T T
55
(0.1244)
22
(0.0487)







(1.05370601437504-1.78)


hCV11559107
UNC5C
0.00338
AG_vs_GG
Gen
1.54 (1.15-2.06)
A
G
A (0.1837
A A
19
(0.0431)
24
(0.0535)



(rs2626053)
0.00999
AA + AG_vs_GG
dom
1.44 (1.09-1.89)
A
G
A (0.1837
A A
19
(0.0431)
24
(0.0535)


hCV11853483
FGG
5.5E−05
AA_vs_GG
Gen
2.98
A
G
A (0.2605
A A
54
(0.1224)
22
(0.0488)



(rs12644950)



(1.753373778484-5.07)




0.00014
AA_vs_AG + GG
rec
2.72
A
G
A (0.2605
A A
54
(0.1224)
22
(0.0488)







(1.62669691396322-4.55)




0.00028
A_vs_G
add
1.47
A
G
A (0.2605
A A
54
(0.1224)
22
(0.0488)







(1.19493352233274-1.81)




0.01296
AA + AG_vs_GG
dom
1.4
A
G
A (0.2605
A A
54
(0.1224)
22
(0.0488)







(1.07313147656834-1.82)


hCV11853496
FGG
6.8E−05
TT_vs_AA
Gen
2.89
T
A
T (0.2622
T T
55
(0.1244)
23
(0.0509)



(rs7654093)



(1.71409632424687-4.87)




0.00016
TT_vs_TA + AA
rec
2.65
T
A
T (0.2622
T T
55
(0.1244)
23
(0.0509)







(1.59864873064354-4.4)




0.00036
T_vs_A
add
1.46
T
A
T (0.2622
T T
55
(0.1244)
23
(0.0509)







(1.18479576515509-1.79)




0.01572
TT + TA_vs_AA
dom
1.38
T
A
T (0.2622
T T
55
(0.1244)
23
(0.0509)







(1.06306565580364-1.8)


hCV11942562
ACE (rs4343)
0.04168
AA + AG_vs_GG
dom
1.39
A
G
G (0.5088
G G
89
(0.2014)
117
(0.2588)







(1.01235519054438-1.9)


hCV11962159
(rs2000745)
0.03396
TT_vs_CC
Gen
9.4
T
C
T (0.082
T T
9
(0.0204)
1
(0.0022)







(1.1848774278982-74.54)




0.03409
TT_vs_TC + CC
rec
9.37
T
C
T (0.082
T T
9
(0.0204)
1
(0.0022)







(1.1829594063581-74.3)


hCV11975250
F5 (rs6025)
6.6E−12
TT + TC_vs_CC
dom
7.67 (4.29-13.71)
T
C
T (0.0155
T T
8
(0.0181)
0
(0)




8.6E−12
AA + AG_vs_GG
dom
7.17 (4.07-12.62)
A
G
T (0.0155
T T
8
(0.0181)
0
(0)




1.6E−11
T_vs_C
add
7.19 (4.05-12.77)
T
C
T (0.0155
T T
8
(0.0181)
0
(0)




1.9E−11
A_vs_G
add
6.74 (3.86-11.77)
A
G
T (0.0155
T T
8
(0.0181)
0
(0)




8.2E−11
TC_vs_CC
Gen
6.96 (3.88-12.5)
T
C
T (0.0155
T T
8
(0.0181)
0
(0)




1.1E−10
AG_vs_GG
Gen
6.51 (3.68-11.5)
A
G
T (0.0155
T T
8
(0.0181)
0
(0)


hCV11975651
SERPINC1
0.04802
GG_vs_GC + CC
rec
0.27
G
C
G (0.1098
G G
3
(0.0068)
11
(0.0244)



(rs677)



(0.0759132784778174-0.99)


hCV11975658
(rs1951626)
0.03516
AG_vs_GG
Gen
1.35 (1.02-1.78)
A
G
A (0.3
A A
43
(0.0973)
41
(0.0911)




0.03523
AA + AG_vs_GG
dom
1.33 (1.02-1.73)
A
G
A (0.3
A A
43
(0.0973)
41
(0.0911)


hCV1198623
KRT8
0.00813
GG_vs_CC
Gen
1.76 (1.16-2.68)
G
C
C (0.3595
C C
45
(0.1016)
72
(0.1593)



(rs2638504)
0.01655
G_vs_C
add
1.26 (1.04-1.52)
G
C
C (0.3595
C C
45
(0.1016)
72
(0.1593)




0.03471
GC_vs_CC
Gen
1.58 (1.03-2.42)
G
C
C (0.3595
C C
45
(0.1016)
72
(0.1593)


hCV12098639
RIC8A (rs3216)
0.01529
CG_vs_GG
Gen
2.72
C
G
G (0.1887
G G
9
(0.0204)
23
(0.0508)







(1.21159130646804-6.1)




0.01785
CC + CG_vs_GG
dom
2.57
C
G
G (0.1887
G G
9
(0.0204)
23
(0.0508)







(1.17720092620202-5.63)




0.02169
CC_vs_GG
Gen
2.51
C
G
G (0.1887
G G
9
(0.0204)
23
(0.0508)







(1.14432781614601-5.52)


hCV1376206
NLRP2
0.04509
CT_vs_TT
Gen
1.33
C
T
C (0.2777
C C
38
(0.086)
38
(0.0841)



(rs10412915)



(1.00618961419825-1.75)


hCV1376246
NLRP2
0.04168
AA_vs_AC + CC
rec
1.37
A
C
C (0.5121
C C
107
(0.2415)
112
(0.2472)



(rs12768)



(1.01192726345419-1.85)


hCV1420741
(rs444124)
0.01513
CC_vs_GG
Gen
1.8
C
G
C (0.2739
C C
53
(0.1196)
33
(0.0735)







(1.11978427423371-2.88)




0.02069
CC_vs_CG + GG
rec
1.71
C
G
C (0.2739
C C
53
(0.1196)
33
(0.0735)







(1.0857630416532-2.7)




0.03078
C_vs_G
add
1.25
C
G
C (0.2739
C C
53
(0.1196)
33
(0.0735)







(1.02065803823507-1.52)


hCV1455329
(rs16018)
0.0104
GA_vs_AA
Gen
1.44
G
A
G (0.2942
G G
35
(0.0792)
46
(0.1018)







(1.08866000283568-1.89)




0.03679
GG + GA_vs_AA
dom
1.32
G
A
G (0.2942
G G
35
(0.0792)
46
(0.1018)







(1.01735211455419-1.72)


hCV15864094
DARS2
0.02341
GG + GA_vs_AA
dom
1.54
G
A
G (0.0668
G G
6
(0.0136)
4
(0.0089)



(rs2068871)



(1.05976036974367-2.23)




0.02708
G_vs_A
add
1.46
G
A
G (0.0668
G G
6
(0.0136)
4
(0.0089)







(1.04392416525319-2.05)




0.03009
GA_vs_AA
Gen
1.53
G
A
G (0.0668
G G
6
(0.0136)
4
(0.0089)







(1.04171464630086-2.24)


hCV15947925
TNFRSF14
0.0278
TT + TC_vs_CC
dom
4.17
T
C
T (0.0033
T T
1
(0.0023)
0
(0)



(rs2234163)



(1.16858968730866-14.86)




0.02805
T_vs_C
add
4.02
T
C
T (0.0033
T T
1
(0.0023)
0
(0)







(1.16184582447559-13.94)




0.04069
TC_vs_CC
Gen
3.82
T
C
T (0.0033
T T
1
(0.0023)
0
(0)







(1.05841588676064-13.79)


hCV15953063
(rs2953331)
0.01795
AA + AG_vs_GG
dom
1.38
A
G
A (0.3308
A A
60
(0.1364)
55
(0.1217)







(1.05693553923995-1.8)




0.02267
AG_vs_GG
Gen
1.39
A
G
A (0.3308
A A
60
(0.1364)
55
(0.1217)







(1.0470340893344-1.84)




0.04192
A_vs_G
add
1.22
A
G
A (0.3308
A A
60
(0.1364)
55
(0.1217)







(1.00735955225147-1.48)


hCV15956054
SERPINC1
0.04188
TC_vs_CC
Gen
1.42
T
C
T (0.1087
T T
4
(0.0092)
11
(0.0247)



(rs2227594)



(1.01288299286844-1.98)


hCV15956055
SERPINC1
0.04439
TG_vs_GG
Gen
1.41 (1.01-1.98)
T
G
T (0.1084
T T
4
(0.0092)
11
(0.0248)



(rs2227593)


hCV15956059
SERPINC1
0.02277
T_vs_C
add
1.44
T
C
T (0.0865
T T
6
(0.0136)
3
(0.0067)



(rs2227592)



(1.05163705309124-1.96)




0.02759
TT + TC_vs_CC
dom
1.46
T
C
T (0.0865
T T
6
(0.0136)
3
(0.0067)







(1.04229099896258-2.03)




0.04197
TC_vs_CC
Gen
1.42
T
C
T (0.0865
T T
6
(0.0136)
3
(0.0067)







(1.01292745754821-2)


hCV15977624
RDH13
0.04128
AA_vs_AG + GG
rec
1.73 (1.02-2.93)
A
G
A (0.2461
A A
39
(0.0882)
24
(0.053)



(rs2305543)


hCV16000557
LOC390988
0.00253
TT_vs_CC
Gen
1.81
T
C
T (0.4302
T T
108
(0.246)
78
(0.1729)



(rs2377041)



(1.23100609226457-2.65)




0.00283
T_vs_C
add
1.34
T
C
T (0.4302
T T
108
(0.246)
78
(0.1729)







(1.10500557605069-1.62)




0.0076
TT_vs_TC + CC
rec
1.56 (1.13-2.16)
T
C
T (0.4302
T T
108
(0.246)
78
(0.1729)




0.02713
TT + TC_vs_CC
dom
1.39
T
C
T (0.4302
T T
108
(0.246)
78
(0.1729)







(1.03825477779782-1.87)


hCV1605386
PKNOX1
0.00313
GA_vs_AA
Gen
2.14
G
A
A (0.311
A A
28
(0.0638)
50
(0.1119)



(rs234736)



(1.29136514770623-3.54)




0.0126
GG + GA_vs_AA
dom
1.85
G
A
A (0.311
A A
28
(0.0638)
50
(0.1119)







(1.14079578150342-3)


hCV16135173
(rs2146372)
0.02501
CC + CG_vs_GG
dom
1.47
C
G
C (0.0878
C C
6
(0.0136)
5
(0.0111)







(1.04923410893692-2.05)




0.02618
CG_vs_GG
Gen
1.48
C
G
C (0.0878
C C
6
(0.0136)
5
(0.0111)







(1.04735910608363-2.08)




0.03375
C_vs_G
add
1.39
C
G
C (0.0878
C C
6
(0.0136)
5
(0.0111)







(1.02581539781861-1.89)


hCV18996
ANKS1B
0.04369
TT_vs_CC
Gen
1.99
T
C
C (0.2434
C C
14
(0.0317)
27
(0.0597)



(rs638177)



(1.01964405681199-3.88)




0.04845
TT + TC_vs_CC
dom
1.94
T
C
C (0.2434
C C
14
(0.0317)
27
(0.0597)







(1.00452097379001-3.76)


hCV1900162
PTPN22
0.01558
TC_vs_CC
Gen
0.07 (0.01-0.61)
T
C
C (0.1221
C C
8
(0.0278)
1
(0.0029)



(rs11102685)
0.03279
TT + TC_vs_CC
dom
0.1 (0.01-0.83)
T
C
C (0.1221
C C
8
(0.0278)
1
(0.0029)




0.04005
TT_vs_CC
Gen
0.11 (0.01-0.91)
T
C
C (0.1221
C C
8
(0.0278)
1
(0.0029)


hCV1937195
CCDC8
0.01441
G_vs_A
add
1.43
G
A
A (0.1358
A A
7
(0.0158)
12
(0.0265)



(rs34186470)



(1.07317264786011-1.89)




0.01494
GG_vs_GA + AA
rec
1.5
G
A
A (0.1358
A A
7
(0.0158)
12
(0.0265)







(1.0815208090679-2.07)


hCV1974936
(rs4648648)
0.01009
CC_vs_CT + TT
rec
1.48
C
T
T (0.5088
T T
93
(0.2104)
109
(0.2406)







(1.09857002225632-2)




0.0232
C_vs_T
add
1.25
C
T
T (0.5088
T T
93
(0.2104)
109
(0.2406)







(1.03042165019262-1.5)




0.02746
CC_vs_TT
Gen
1.53
C
T
T (0.5088
T T
93
(0.2104)
109
(0.2406)







(1.04851513911575-2.24)


hCV1974951
TNFRSF14
0.01935
GG_vs_GA + AA
rec
1.42
G
A
A (0.4945
A A
93
(0.2099)
102
(0.2262)



(rs2234161)



(1.05893671316625-1.92)


hCV1974967
(rs2147905)
0.01956
AA_vs_AG + GG
rec
1.43
A
G
G (0.5066
G G
97
(0.2195)
111
(0.245)







(1.0586829787411-1.92)




0.0449
A_vs_G
add
1.21
A
G
G (0.5066
G G
97
(0.2195)
111
(0.245)







(1.0043557390248-1.46)


hCV22272816
GLOD4
0.0413
GG_vs_GA + AA
rec
1.32
G
A
A (0.2969
A A
35
(0.0794)
44
(0.0971)



(rs2249542)



(1.01088520538692-1.71)




0.04909
G_vs_A
add
1.23
G
A
A (0.2969
A A
35
(0.0794)
44
(0.0971)







(1.00081269894164-1.5)


hCV25611352
RAF1
0.00089
TC_vs_CC
Gen
3.3
T
C
C (0.2113
C C
12
(0.0271)
32
(0.0708)



(rs3729926)



(1.63135248280203-6.66)




0.00364
TT + TC_vs_CC
dom
2.73
T
C
C (0.2113
C C
12
(0.0271)
32
(0.0708)







(1.38738506813726-5.37)




0.00907
TT_vs_CC
Gen
2.48
T
C
C (0.2113
C C
12
(0.0271)
32
(0.0708)







(1.25420196929067-4.92)


hCV25649928
DEGS1 ( )
0.00685
G_vs_A
add
2.58 (1.3-5.12)
G
A
G (0.0135
G G
0
(0)
0
(0)





GA_vs_AA
Gen
2.58 (1.3-5.12)
G
A
G (0.0135
G G
0
(0)
0
(0)





GG + GA_vs_AA
dom
2.58 (1.3-5.12)
G
A
G (0.0135
G G
0
(0)
0
(0)


hCV25767872
KIAA1546
0.04821
A_vs_G
add
2.1
A
G
A (0.0121
A A
0
(0)
0
(0)



(rs6843141)



(1.00587211662689-4.38)





AA + AG_vs_GG
dom
2.1
A
G
A (0.0121
A A
0
(0)
0
(0)







(1.00587211662689-4.38)





AG_vs_GG
Gen
2.1
A
G
A (0.0121
A A
0
(0)
0
(0)







(1.00587211662689-4.38)


hCV2605707
CDK6
0.04581
CC_vs_GG
Gen
1.8
C
G
G (0.2655
G G
20
(0.0456)
35
(0.0774)



(rs42041)



(1.01098902434728-3.2)


hCV26338456
SDCCAG8
0.04489
GG + GA_vs_AA
dom
1.38
G
A
A (0.5
A A
86
(0.1946)
113
(0.2506)



(rs10927011)



(1.00743666566744-1.9)


hCV26338482
SDCCAG8
0.02994
TT_vs_CC
Gen
1.74
T
C
T (0.2711
T T
45
(0.1025)
29
(0.0644)



(rs10803143)



(1.05555612599845-2.88)




0.04165
TT_vs_TC + CC
rec
1.66
T
C
T (0.2711
T T
45
(0.1025)
29
(0.0644)







(1.0193099474508-2.7)


hCV26887434
RGS7
0.04698
CC_vs_AA
Gen
1.47
C
A
C (0.4248
C C
99
(0.224)
78
(0.1726)



(rs12723522)



(1.0051583138784-2.15)


hCV26895255
GP6
0.04243
CC_vs_CT + TT
rec
2.03
C
T
C (0.2174
C C
25
(0.0566)
13
(0.0287)



(rs11669150)



(1.0244638955455-4.02)


hCV27020269
(rs7659613)
0.02343
CC_vs_GG
Gen
1.56
C
G
C (0.4047
C C
95
(0.2154)
73
(0.1619)







(1.06156384252267-2.28)




0.02703
C_vs_G
add
1.24
C
G
C (0.4047
C C
95
(0.2154)
73
(0.1619)







(1.02429403887418-1.49)




0.04138
CC_vs_CG + GG
rec
1.42
C
G
C (0.4047
C C
95
(0.2154)
73
(0.1619)







(1.01385341422313-1.99)


hCV27102953
LOC647718
0.00713
TT_vs_CC
Gen
1.7
T
C
T (0.4519
T T
112
(0.2551)
83
(0.1857)



(rs4648360)



(1.15505198766522-2.5)




0.00775
T_vs_C
add
1.3
T
C
T (0.4519
T T
112
(0.2551)
83
(0.1857)







(1.07164121464812-1.58)




0.01291
TT_vs_TC + CC
rec
1.5
T
C
T (0.4519
T T
112
(0.2551)
83
(0.1857)







(1.08992095886976-2.07)


hCV27102978
LOC647718
0.00037
C_vs_A
add
1.43
C
A
A (0.5344
A A
85
(0.1923)
118
(0.2616)



(rs7537581)



(1.17286039578863-1.73)




0.00039
CC_vs_AA
Gen
2.03
C
A
A (0.5344
A A
85
(0.1923)
118
(0.2616)







(1.37196942703233-2.99)




0.00101
CC_vs_CA + AA
rec
1.69
C
A
A (0.5344
A A
85
(0.1923)
118
(0.2616)







(1.23512192592463-2.3)




0.01374
CC + CA_vs_AA
dom
1.49
C
A
A (0.5344
A A
85
(0.1923)
118
(0.2616)







(1.08473599302907-2.04)


hCV27103080
(rs4648459)
0.00385
TT_vs_GG
Gen
1.76
T
G
T (0.4305
T T
108
(0.2443)
78
(0.1722)







(1.19923635734498-2.58)




0.00458
T_vs_G
add
1.32
T
G
T (0.4305
T T
108
(0.2443)
78
(0.1722)







(1.08862166155631-1.59)




0.00807
TT_vs_TG + GG
rec
1.55
T
G
T (0.4305
T T
108
(0.2443)
78
(0.1722)







(1.12162097064999-2.15)




0.04586
TT + TG_vs_GG
dom
1.35
T
G
T (0.4305
T T
108
(0.2443)
78
(0.1722)







(1.00549674456945-1.81)


hCV27103182
(rs4609377)
0.00077
C_vs_T
add
1.39
C
T
T (0.5133
T T
78
(0.1761)
112
(0.2478)







(1.14837160766132-1.69)




0.00082
CC_vs_TT
Gen
1.94
C
T
T (0.5133
T T
78
(0.1761)
112
(0.2478)







(1.31528974268535-2.86)




0.00467
CC_vs_CT + TT
rec
1.54
C
T
T (0.5133
T T
78
(0.1761)
112
(0.2478)







(1.14249698884992-2.08)




0.00898
CC + CT_vs_TT
dom
1.54
C
T
T (0.5133
T T
78
(0.1761)
112
(0.2478)







(1.11419540235736-2.13)


hCV27103188
(rs7511879)
0.00386
GG_vs_GA + AA
rec
1.59
G
A
G (0.4636
G G
120
(0.2715)
86
(0.1898)







(1.16090265496612-2.18)




0.00463
GG_vs_AA
Gen
1.75
G
A
G (0.4636
G G
120
(0.2715)
86
(0.1898)







(1.18753475086407-2.57)




0.00485
G_vs_A
add
1.32
G
A
G (0.4636
G G
120
(0.2715)
86
(0.1898)







(1.08809986054585-1.6)


hCV27103189
(rs12031493)
0.00933
G_vs_A
add
1.29
G
A
A (0.5133
A A
86
(0.1959)
110
(0.2434)







(1.06498516575119-1.57)




0.0103
GG_vs_AA
Gen
1.66
G
A
A (0.5133
A A
86
(0.1959)
110
(0.2434)







(1.12671323564467-2.44)




0.01303
GG_vs_GA + AA
rec
1.47
G
A
A (0.5133
A A
86
(0.1959)
110
(0.2434)







(1.08458487392409-1.99)


hCV27103207
(rs6424062)
0.00385
AA_vs_GG
Gen
1.76
A
G
A (0.4305
A A
108
(0.2438)
78
(0.1722)







(1.19923635734499-2.58)




0.00453
A_vs_G
add
1.32
A
G
A (0.4305
A A
108
(0.2438)
78
(0.1722)







(1.08899212231946-1.59)




0.0085
AA_vs_AG + GG
rec
1.55
A
G
A (0.4305
A A
108
(0.2438)
78
(0.1722)







(1.11833165727631-2.15)




0.04367
AA + AG_vs_GG
dom
1.35
A
G
A (0.4305
A A
108
(0.2438)
78
(0.1722)







(1.00859469798602-1.81)


hCV2716314
CTSB (rs8005)
0.04236
A_vs_C
add
1.24
A
C
A (0.2522
A A
36
(0.0816)
28
(0.0619)







(1.00756185015975-1.54)


hCV2734332
39783
0.00283
GA_vs_AA
Gen
2.07 (1.28-3.33)
G
A
A (0.323
A A
32
(0.0722)
59
(0.1305)



(rs10759757)
0.01256
GG_vs_AA
Gen
1.82 (1.14-2.91)
G
A
A (0.323
A A
32
(0.0722)
59
(0.1305)


hCV27476043
RDH13
0.03332
AA_vs_AG + GG
rec
2.8
A
G
A (0.1512
A A
16
(0.0362)
6
(0.0132)



(rs3745912)



(1.08474967907152-7.22)




0.04
AA_vs_GG
Gen
2.71
A
G
A (0.1512
A A
16
(0.0362)
6
(0.0132)







(1.04653998737852-7.01)


hCV27937396
(rs4634201)
0.04871
CC_vs_TT
Gen
1.97
C
T
C (0.1858
C C
25
(0.0567)
14
(0.031)







(1.00383697586705-3.87)


hCV2811695
FTO
0.00707
C_vs_A
add
1.46 (1.11-1.93)
C
A
C (0.1056
C C
13
(0.0294)
6
(0.0133)



(rs940214)
0.01189
CC + CA_vs_AA
dom
1.49 (1.09-2.04)
C
A
C (0.1056
C C
13
(0.0294)
6
(0.0133)




0.03143
CA_vs_AA
Gen
1.43 (1.03-1.97)
C
A
C (0.1056
C C
13
(0.0294)
6
(0.0133)


hCV2852784
CYP17A1
0.01777
A_vs_G
add
1.27 (1.04-1.54)
A
G
G (0.412
G G
54
(0.1244)
73
(0.1648)



(rs743572)
0.0271
AA_vs_GG
Gen
1.59 (1.05-2.41)
A
G
G (0.412
G G
54
(0.1244)
73
(0.1648)




0.03431
AA_vs_AG + GG
rec
1.34 (1.02-1.77)
A
G
G (0.412
G G
54
(0.1244)
73
(0.1648)


hCV2892855
FGG
0.00076
CC_vs_CT + TT
rec
1.62
C
T
T (0.4546
T T
64
(0.1451)
87
(0.1925)



(rs6536024)



(1.22305766829666-2.14)




0.0009
C_vs_T
add
1.39
C
T
T (0.4546
T T
64
(0.1451)
87
(0.1925)







(1.14291480827487-1.68)




0.00284
CC_vs_TT
Gen
1.83
C
T
T (0.4546
T T
64
(0.1451)
87
(0.1925)







(1.22982199650641-2.71)


hCV2892869
(rs13109457)
0.00029
AA_vs_GG
Gen
2.5
A
G
A (0.2772
A A
58
(0.1315)
27
(0.0599)







(1.52334238718455-4.1)




0.00037
AA_vs_AG + GG
rec
2.38
A
G
A (0.2772
A A
58
(0.1315)
27
(0.0599)







(1.47584712337765-3.83)




0.00249
A_vs_G
add
1.37
A
G
A (0.2772
A A
58
(0.1315)
27
(0.0599)







(1.11676316556903-1.68)


hCV2892893
(rs12648258)
0.01399
A_vs_T
add
1.32
A
T
A (0.1947
A A
31
(0.0703)
17
(0.0376)







(1.05814542701223-1.65)




0.01963
AA_vs_TT
Gen
2.08
A
T
A (0.1947
A A
31
(0.0703)
17
(0.0376)







(1.12423038179963-3.84)




0.033
AA_vs_AT + TT
rec
1.93
A
T
A (0.1947
A A
31
(0.0703)
17
(0.0376)







(1.05470532431105-3.55)




0.04454
AA + AT_vs_TT
dom
1.32
A
T
A (0.1947
A A
31
(0.0703)
17
(0.0376)







(1.00678919794171-1.73)


hCV2892905
PLRG1
0.03327
C_vs_T
add
1.27
C
T
C (0.2103
C C
33
(0.0755)
21
(0.047)



(rs12642770)



(1.01895685789595-1.58)




0.04994
CC_vs_TT
Gen
1.77
C
T
C (0.2103
C C
33
(0.0755)
21
(0.047)







(1.00015868058748-3.15)


hCV2892918
(rs12511469)
0.02229
A_vs_T
add
1.3
A
T
A (0.1973
A A
31
(0.0705)
18
(0.0399)







(1.03749332929128-1.62)




0.03037
AA_vs_TT
Gen
1.95
A
T
A (0.1973
A A
31
(0.0705)
18
(0.0399)







(1.06535995989442-3.57)




0.04836
AA_vs_AT + TT
rec
1.82
A
T
A (0.1973
A A
31
(0.0705)
18
(0.0399)







(1.00432829446122-3.31)


hCV2892926
(rs7662567)
0.00586
C_vs_T
add
1.36
C
T
C (0.1984
C C
34
(0.078)
18
(0.0399)







(1.09357836651693-1.7)




0.00915
CC_vs_TT
Gen
2.21
C
T
C (0.1984
C C
34
(0.078)
18
(0.0399)







(1.21714661169315-4.01)




0.01776
CC_vs_CT + TT
rec
2.03
C
T
C (0.1984
C C
34
(0.078)
18
(0.0399)







(1.13094724249255-3.66)




0.02387
CC + CT_vs_TT
dom
1.37
C
T
C (0.1984
C C
34
(0.078)
18
(0.0399)







(1.04211330687034-1.79)


hCV2892927
(rs13123551)
0.01436
AA_vs_AT + TT
rec
1.42
A
T
T (0.4524
T T
71
(0.1617)
85
(0.1881)







(1.07291037992945-1.89)




0.02592
A_vs_T
add
1.24
A
T
T (0.4524
T T
71
(0.1617)
85
(0.1881)







(1.02650891219607-1.51)


hCV29521317
LIMD1
0.02272
G_vs_A
add
1.62 (1.07-2.45)
G
A
G (0.0454
G G
1
(0.0023)
0
(0)



(rs7648441)
0.02712
GG + GA_vs_AA
dom
1.6 (1.05-2.44)
G
A
G (0.0454
G G
1
(0.0023)
0
(0)




0.03349
GA_vs_AA
Gen
1.58 (1.04-2.4)
G
A
G (0.0454
G G
1
(0.0023)
0
(0)


hCV29983641
(rs10008078)
0.00588
AA_vs_GG
Gen
2.34
A
G
A (0.1993
A A
35
(0.0795)
17
(0.0379)







(1.27718823993844-4.27)




0.00921
A_vs_G
add
1.34 (1.08-1.67)
A
G
A (0.1993
A A
35
(0.0795)
17
(0.0379)




0.00957
AA_vs_AG + GG
rec
2.2 (1.21-3.98)
A
G
A (0.1993
A A
35
(0.0795)
17
(0.0379)


hCV30002208
(rs9402927)
0.04695
AA + AG_vs_GG
dom
1.46 (1.01-2.12)
A
G
G (0.4069
G G
55
(0.1253)
78
(0.1729)


hCV30040828
TNFSF4
0.03454
TT + TC_vs_CC
dom
1.45 (1.03-2.04)
T
C
T (0.0824
T T
5
(0.0113)
4
(0.0089)



(rs6700269)




0.03713
TC_vs_CC
Gen
1.45
T
C
T (0.0824
T T
5
(0.0113)
4
(0.0089)







(1.02251331249644-2.06)




0.04223
T_vs_C
add
1.39 (1.01-1.91)
T
C
T (0.0824
T T
5
(0.0113)
4
(0.0089)


hCV30548253
(rs9425773)
0.02996
AC_vs_CC
Gen
2.77
A
C
C (0.1478
C C
7
(0.0159)
17
(0.0378)







(1.10401013563533-6.96)


hCV305844
LOC728077
0.0275
CC_vs_CG + GG
rec
1.49 (1.05-2.13)
C
G
C (0.383
C C
86
(0.1941)
63
(0.1391)



(rs4823562)


hCV30711231
(rs12642469)
0.02106
A_vs_G
add
1.3 (1.04-1.62)
A
G
A (0.198
A A
32
(0.0724)
18
(0.0398)




0.02334
AA_vs_GG
Gen
2.01
A
G
A (0.198
A A
32
(0.0724)
18
(0.0398)







(1.09904034857764-3.66)




0.03665
AA_vs_AG + GG
rec
1.88
A
G
A (0.198
A A
32
(0.0724)
18
(0.0398)







(1.04000430618758-3.41)


hCV31475431
MMEL1
0.0372
GG_vs_GT + TT
rec
1.42
G
T
T (0.117
T T
6
(0.0135)
3
(0.0066)



(rs12133956)



(1.02106867570514-1.98)


hCV31863982
(rs7659024)
2.2E−05
AA_vs_GG
Gen
3.13
A
G
A (0.2622
A A
57
(0.129)
22
(0.0487)







(1.84942397608161-5.31)




4.6E−05
AA_vs_AG + GG
rec
2.89
A
G
A (0.2622
A A
57
(0.129)
22
(0.0487)







(1.73628966491938-4.82)




0.0002
A_vs_G
add
1.48 (1.2-1.82)
A
G
A (0.2622
A A
57
(0.129)
22
(0.0487)




0.01564
AA + AG_vs_GG
dom
1.38 (1.06-1.8)
A
G
A (0.2622
A A
57
(0.129)
22
(0.0487)


hCV31965333
(rs10797390)
0.00973
CC_vs_TT
Gen
1.67
C
T
T (0.4934
T T
76
(0.1723)
105
(0.2323)







(1.13170137567537-2.46)




0.01032
C_vs_T
add
1.29 (1.06-1.56)
C
T
T (0.4934
T T
76
(0.1723)
105
(0.2323)




0.02629
CC + CT_vs_TT
dom
1.45 (1.05-2.02)
C
T
T (0.4934
T T
76
(0.1723)
105
(0.2323)


hCV31997958
CHMP7
0.00266
GG_vs_GA + AA
rec
1.79
G
A
G (0.3516
G G
81
(0.1837)
50
(0.1116)



(rs12544038)



(1.22451031007049-2.62)




0.00301
GG_vs_AA
Gen
1.86
G
A
G (0.3516
G G
81
(0.1837)
50
(0.1116)







(1.23542884303164-2.81)




0.00969
G_vs_A
add
1.29 (1.06-1.56)
G
A
G (0.3516
G G
81
(0.1837)
50
(0.1116)


hCV3205858
PXDNL
0.04375
CC_vs_CT + TT
rec
1.47
C
T
C (0.3565
C C
76
(0.1716)
56
(0.1236)



(rs2979122)



(1.01081147987946-2.13)


hCV3210786
C1orf164
0.00202
CC_vs_CT + TT
rec
2.02
C
T
C (0.2962
C C
61
(0.138)
33
(0.0735)



(rs11582970)



(1.29239242014763-3.15)




0.00463
CC_vs_TT
Gen
1.96
C
T
C (0.2962
C C
61
(0.138)
33
(0.0735)







(1.22969863581067-3.12)


hCV32212664
(rs12642646)
0.00716
AA_vs_AG + GG
rec
1.5
A
G
G (0.4878
G G
90
(0.2041)
96
(0.2124)







(1.11615682413902-2.01)


hCV7429782
FGG
0.01428
T_vs_A
add
1.3 (1.05-1.6)
T
A
A (0.3131
A A
28
(0.0633)
40
(0.0885)



(rs1118823)
0.0193
TT_vs_TA + AA
rec
1.37
T
A
A (0.3131
A A
28
(0.0633)
40
(0.0885)







(1.05227516552433-1.78)


hCV7429793
(rs1025154)
0.01309
C_vs_T
add
1.32 (1.06-1.65)
C
T
C (0.198
C C
31
(0.0701)
18
(0.0398)




0.02761
CC_vs_TT
Gen
1.97
C
T
C (0.198
C C
31
(0.0701)
18
(0.0398)







(1.07778558946615-3.61)




0.03429
CC + CT_vs_TT
dom
1.34 (1.02-1.75)
C
T
C (0.198
C C
31
(0.0701)
18
(0.0398)




0.04931
CC_vs_CT + TT
rec
1.82
C
T
C (0.198
C C
31
(0.0701)
18
(0.0398)







(1.00180479357554-3.3)


hCV788647
(rs729045)
0.01217
AA_vs_GG
Gen
1.69 (1.12-2.54)
A
G
G (0.4393
G G
56
(0.127)
82
(0.181)




0.01497
A_vs_G
add
1.28 (1.05-1.55)
A
G
G (0.4393
G G
56
(0.127)
82
(0.181)


hCV813581
OR4C11
0.01556
T_vs_G
add
1.47 (1.08-2)
T
G
T (0.0583
T T
21
(0.0513)
10
(0.0233)



(rs491160)
0.02979
TT + TG_vs_GG
dom
1.61 (1.05-2.47)
T
G
T (0.0583
T T
21
(0.0513)
10
(0.0233)




0.03083
TT_vs_GG
Gen
2.33 (1.08-5.01)
T
G
T (0.0583
T T
21
(0.0513)
10
(0.0233)




0.03607
TT_vs_TG + GG
rec
2.27 (1.05-4.88)
T
G
T (0.0583
T T
21
(0.0513)
10
(0.0233)


hCV8727391
C17orf81
0.01705
AG_vs_GG
Gen
1.71 (1.1-2.66)
A
G
G (0.3595
G G
40
(0.0903)
63
(0.1394)



(rs414206)


hCV8857351
RGS7
0.03561
TT_vs_TC + CC
rec
1.42 (1.02-1.98)
T
C
T (0.4248
T T
101
(0.229)
78
(0.1726)



(rs2341021)


hCV8911768
SERPINC1
0.01702
T_vs_C
add
1.46 (1.07-1.98)
T
C
T (0.0856
T T
7
(0.0159)
4
(0.0089)



(rs941988)
0.02739
TC_vs_CC
Gen
1.47 (1.04-2.08)
T
C
T (0.0856
T T
7
(0.0159)
4
(0.0089)


hCV8919450
F5 (rs6017)
0.00317
AA_vs_AG + GG
rec
1.5 (1.15-1.97)
A
G
G (0.2567
G G
26
(0.0594)
31
(0.0692)




0.00978
A_vs_G
add
1.33 (1.07-1.65)
A
G
G (0.2567
G G
26
(0.0594)
31
(0.0692)


hCV8941510
CDSN
0.04988
CC_vs_AA
Gen
2.46 (1-6.07)
C
A
C (0.1411
C C
16
(0.0364)
7
(0.0156)



(rs1042127)


hCV9114656
CFHR5
0.04258
C_vs_T
add
1.42 (1.01-1.99)
C
T
C (0.0706
C C
5
(0.0113)
2
(0.0044)



(rs9427662)


hCV9680592
MIPEP
0.03902
GA_vs_AA
Gen
0.55 (0.31-0.97)
G
A
A (0.2539
A A
34
(0.0769)
23
(0.0508)



(rs17079372)


hDV70683187
(rs16846561)
0.02204
G_vs_C
add
1.43 (1.05-1.93)
G
C
G (0.09
G G
7
(0.0159)
4
(0.0089)




0.03622
GC_vs_CC
Gen
1.44 (1.02-2.02)
G
C
G (0.09
G G
7
(0.0159)
4
(0.0089)


hDV70683212
RC3H1
0.04442
G_vs_C
add
1.45 (1.01-2.07)
G
C
G (0.0633
G G
3
(0.0068)
1
(0.0022)



(rs16846593)


hDV70683382
RABGAP1L
0.04002
C_vs_G
add
1.49 (1.02-2.18)
C
G
C (0.0515
C C
4
(0.0091)
2
(0.0045)



(rs16846815)


hDV70965621
(rs17534243)
0.0283
GA_vs_AA
Gen
1.37 (1.03-1.81)
G
A
G (0.2157
G G
26
(0.059)
24
(0.0531)



























CONTROL cnt


CONTROL cnt








CASE cnt
(CONTROL

CASE cnt
(CONTROL



marker
annotation
P-value
parameter
Genot2
(CASE frq2
frq)2
Genot3
(CASE frq3
frq)3


























hCV10008773
ANK1
0.04327
CC_vs_CT + TT
T C
148
(0.3341
181
(0.4004)
C C
263
(0.5937
238
(0.5265)




(rs750625)



hCV11342584
(rs6696864)
0.03793
AT_vs_TT
A T
225
(0.5114
199
(0.4412)
T T
149
(0.3386
179
(0.3969)



hCV11503431
FGG
4.6E−05
TT_vs_CC
T C
190
(0.4299
193
(0.427)
C C
197
(0.4457
237
(0.5243)




(rs2066861)
9.5E−05
TT_vs_TC + CC
T C
190
(0.4299
193
(0.427)
C C
197
(0.4457
237
(0.5243)





0.00035
T_vs_C
T C
190
(0.4299
193
(0.427)
C C
197
(0.4457
237
(0.5243)





0.01879
TT + TC_vs_CC
T C
190
(0.4299
193
(0.427)
C C
197
(0.4457
237
(0.5243)



hCV11559107
UNC5C
0.00338
AG_vs_GG
A G
156
(0.3537
117
(0.2606)
G G
266
(0.6032
308
(0.686)




(rs2626053)
0.00999
AA + AG_vs_GG
A G
156
(0.3537
117
(0.2606)
G G
266
(0.6032
308
(0.686)



hCV11853483
FGG
5.5E−05
AA_vs_GG
A G
191
(0.4331
191
(0.4235)
G G
196
(0.4444
238
(0.5277)




(rs12644950)
0.00014
AA_vs_AG + GG
A G
191
(0.4331
191
(0.4235)
G G
196
(0.4444
238
(0.5277)





0.00028
A_vs_G
A G
191
(0.4331
191
(0.4235)
G G
196
(0.4444
238
(0.5277)





0.01296
AA + AG_vs_GG
A G
191
(0.4331
191
(0.4235)
G G
196
(0.4444
238
(0.5277)



hCV11853496
FGG
6.8E−05
TT_vs_AA
T A
190
(0.4299
191
(0.4226)
A A
197
(0.4457
238
(0.5265)




(rs7654093)
0.00016
TT_vs_TA + AA
T A
190
(0.4299
191
(0.4226)
A A
197
(0.4457
238
(0.5265)





0.00036
T_vs_A
T A
190
(0.4299
191
(0.4226)
A A
197
(0.4457
238
(0.5265)





0.01572
TT + TA_vs_AA
T A
190
(0.4299
191
(0.4226)
A A
197
(0.4457
238
(0.5265)



hCV11942562
ACE (rs4343)
0.04168
AA + AG_vs_GG
G A
232
(0.5249
226
(0.5)
A A
121
(0.2738
109
(0.2412)



hCV11962159
(rs2000745)
0.03396
TT_vs_CC
T C
70
(0.1587
72
(0.1596)
C C
362
(0.8209
378
(0.8381)





0.03409
TT_vs_TC + CC
T C
70
(0.1587
72
(0.1596)
C C
362
(0.8209
378
(0.8381)



hCV11975250
F5 (rs6025)
6.6E−12
TT + TC_vs_CC
T C
79
(0.1787
14
(0.031)
C C
355
(0.8032
438
(0.969)





8.6E−12
AA + AG_vs_GG
T C
79
(0.1787
14
(0.031)
C C
355
(0.8032
438
(0.969)





1.6E−11
T_vs_C
T C
79
(0.1787
14
(0.031)
C C
355
(0.8032
438
(0.969)





1.9E−11
A_vs_G
T C
79
(0.1787
14
(0.031)
C C
355
(0.8032
438
(0.969)





8.2E−11
TC_vs_CC
T C
79
(0.1787
14
(0.031)
C C
355
(0.8032
438
(0.969)





1.1E−10
AG_vs_GG
T C
79
(0.1787
14
(0.031)
C C
355
(0.8032
438
(0.969)



hCV11975651
SERPINC1
0.04802
GG_vs_GC + CC
G C
96
(0.2177
77
(0.1707)
C C
342
(0.7755
363
(0.8049)




(rs677)



hCV11975658
(rs1951626)
0.03516
AG_vs_GG
A G
213
(0.4819
188
(0.4178)
G G
186
(0.4208
221
(0.4911)





0.03523
AA + AG_vs_GG
A G
213
(0.4819
188
(0.4178)
G G
186
(0.4208
221
(0.4911)



hCV1198623
KRT8
0.00813
GG_vs_CC
C G
179
(0.4041
181
(0.4004)
G G
219
(0.4944
199
(0.4403)




(rs2638504)
0.01655
G_vs_C
C G
179
(0.4041
181
(0.4004)
G G
219
(0.4944
199
(0.4403)





0.03471
GC_vs_CC
C G
179
(0.4041
181
(0.4004)
G G
219
(0.4944
199
(0.4403)



hCV12098639
RIC8A (rs3216)
0.01529
CG_vs_GG
G C
133
(0.3009
125
(0.2759)
C C
300
(0.6787
305
(0.6733)





0.01785
CC + CG_vs_GG
G C
133
(0.3009
125
(0.2759)
C C
300
(0.6787
305
(0.6733)





0.02169
CC_vs_GG
G C
133
(0.3009
125
(0.2759)
C C
300
(0.6787
305
(0.6733)



hCV1376206
NLRP2
0.04509
CT_vs_TT
C T
199
(0.4502
175
(0.3872)
T T
205
(0.4638
239
(0.5288)




(rs10412915)



hCV1376246
NLRP2
0.04168
AA_vs_AC + CC
C A
211
(0.4763
240
(0.5298)
A A
125
(0.2822
101
(0.223)




(rs12768)



hCV1420741
(rs444124)
0.01513
CC_vs_GG
C G
179
(0.4041
180
(0.4009)
G G
211
(0.4763
236
(0.5256)





0.02069
CC_vs_CG + GG
C G
179
(0.4041
180
(0.4009)
G G
211
(0.4763
236
(0.5256)





0.03078
C_vs_G
C G
179
(0.4041
180
(0.4009)
G G
211
(0.4763
236
(0.5256)



hCV1455329
(rs16018)
0.0104
GA_vs_AA
G A
211
(0.4774
174
(0.385)
A A
196
(0.4434
232
(0.5133)





0.03679
GG + GA_vs_AA
G A
211
(0.4774
174
(0.385)
A A
196
(0.4434
232
(0.5133)



hCV15864094
DARS2
0.02341
GG + GA_vs_AA
G A
73
(0.1659
52
(0.1158)
A A
361
(0.8205
393
(0.8753)




(rs2068871)
0.02708
G_vs_A
G A
73
(0.1659
52
(0.1158)
A A
361
(0.8205
393
(0.8753)





0.03009
GA_vs_AA
G A
73
(0.1659
52
(0.1158)
A A
361
(0.8205
393
(0.8753)



hCV15947925
TNFRSF14
0.0278
TT + TC_vs_CC
T C
11
(0.0248
3
(0.0066)
C C
431
(0.9729
449
(0.9934)




(rs2234163)
0.02805
T_vs_C
T C
11
(0.0248
3
(0.0066)
C C
431
(0.9729
449
(0.9934)





0.04069
TC_vs_CC
T C
11
(0.0248
3
(0.0066)
C C
431
(0.9729
449
(0.9934)



hCV15953063
(rs2953331)
0.01795
AA + AG_vs_GG
A G
212
(0.4818
189
(0.4181)
G G
168
(0.3818
208
(0.4602)





0.02267
AG_vs_GG
A G
212
(0.4818
189
(0.4181)
G G
168
(0.3818
208
(0.4602)





0.04192
A_vs_G
A G
212
(0.4818
189
(0.4181)
G G
168
(0.3818
208
(0.4602)



hCV15956054
SERPINC1
0.04188
TC_vs_CC
T C
98
(0.2258
75
(0.1682)
C C
332
(0.765
360
(0.8072)




(rs2227594)



hCV15956055
SERPINC1
0.04439
TG_vs_GG
T G
97
(0.224
74
(0.167)
G G
332
(0.7667
358
(0.8081)




(rs2227593)



hCV15956059
SERPINC1
0.02277
T_vs_C
T C
93
(0.2114
72
(0.1596)
C C
341
(0.775
376
(0.8337)




(rs2227592)
0.02759
TT + TC_vs_CC
T C
93
(0.2114
72
(0.1596)
C C
341
(0.775
376
(0.8337)





0.04197
TC_vs_CC
T C
93
(0.2114
72
(0.1596)
C C
341
(0.775
376
(0.8337)



hCV15977624
RDH13
0.04128
AA_vs_AG + GG
A G
147
(0.3326
175
(0.3863)
G G
256
(0.5792
254
(0.5607)




(rs2305543)



hCV16000557
LOC390988
0.00253
TT_vs_CC
T C
223
(0.508
232
(0.5144)
C C
108
(0.246
141
(0.3126)




(rs2377041)
0.00283
T_vs_C
T C
223
(0.508
232
(0.5144)
C C
108
(0.246
141
(0.3126)





0.0076
TT_vs_TC + CC
T C
223
(0.508
232
(0.5144)
C C
108
(0.246
141
(0.3126)





0.02713
TT + TC_vs_CC
T C
223
(0.508
232
(0.5144)
C C
108
(0.246
141
(0.3126)



hCV1605386
PKNOX1
0.00313
GA_vs_AA
A G
213
(0.4852
178
(0.3982)
G G
198
(0.451
219
(0.4899)




(rs234736)
0.0126
GG + GA_vs_AA
A G
213
(0.4852
178
(0.3982)
G G
198
(0.451
219
(0.4899)



hCV16135173
(rs2146372)
0.02501
CC + CG_vs_GG
C G
93
(0.2104
69
(0.1533)
G G
343
(0.776
376
(0.8356)





0.02618
CG_vs_GG
C G
93
(0.2104
69
(0.1533)
G G
343
(0.776
376
(0.8356)





0.03375
C_vs_G
C G
93
(0.2104
69
(0.1533)
G G
343
(0.776
376
(0.8356)



hCV18996
ANKS1B
0.04369
TT_vs_CC
C T
161
(0.3643
166
(0.3673)
T T
267
(0.6041
259
(0.573)




(rs638177)
0.04845
TT + TC_vs_CC
C T
161
(0.3643
166
(0.3673)
T T
267
(0.6041
259
(0.573)



hCV1900162
PTPN22
0.01558
TC_vs_CC
C T
48
(0.1667
81
(0.2382)
T T
232
(0.8056
258
(0.7588)




(rs11102685)
0.03279
TT + TC_vs_CC
C T
48
(0.1667
81
(0.2382)
T T
232
(0.8056
258
(0.7588)





0.04005
TT_vs_CC
C T
48
(0.1667
81
(0.2382)
T T
232
(0.8056
258
(0.7588)



hCV1937195
CCDC8
0.01441
G_vs_A
A G
72
(0.1625
99
(0.2185)
G G
364
(0.8217
342
(0.755)




(rs34186470)
0.01494
GG_vs_GA + AA
A G
72
(0.1625
99
(0.2185)
G G
364
(0.8217
342
(0.755)



hCV1974936
(rs4648648)
0.01009
CC_vs_CT + TT
T C
217
(0.491
243
(0.5364)
C C
132
(0.2986
101
(0.223)





0.0232
C_vs_T
T C
217
(0.491
243
(0.5364)
C C
132
(0.2986
101
(0.223)





0.02746
CC_vs_TT
T C
217
(0.491
243
(0.5364)
C C
132
(0.2986
101
(0.223)



hCV1974951
TNFRSF14
0.01935
GG_vs_GA + AA
A G
214
(0.4831
242
(0.5366)
G G
136
(0.307
107
(0.2373)




(rs2234161)



hCV1974967
(rs2147905)
0.01956
AA_vs_AG + GG
G A
212
(0.4796
237
(0.5232)
A A
133
(0.3009
105
(0.2318)





0.0449
A_vs_G
G A
212
(0.4796
237
(0.5232)
A A
133
(0.3009
105
(0.2318)



hCV22272816
GLOD4
0.0413
GG_vs_GA + AA
A G
154
(0.3492
181
(0.3996)
G G
252
(0.5714
228
(0.5033)




(rs2249542)
0.04909
G_vs_A
A G
154
(0.3492
181
(0.3996)
G G
252
(0.5714
228
(0.5033)



hCV25611352
RAF1
0.00089
TC_vs_CC
C T
157
(0.3552
127
(0.281)
T T
273
(0.6176
293
(0.6482)




(rs3729926)
0.00364
TT + TC_vs_CC
C T
157
(0.3552
127
(0.281)
T T
273
(0.6176
293
(0.6482)





0.00907
TT_vs_CC
C T
157
(0.3552
127
(0.281)
T T
273
(0.6176
293
(0.6482)



hCV25649928
DEGS1 ( )
0.00685
G_vs_A
G A
29
(0.0667
12
(0.027)
A A
406
(0.9333
433
(0.973)






GA_vs_AA
G A
29
(0.0667
12
(0.027)
A A
406
(0.9333
433
(0.973)






GG + GA_vs_AA
G A
29
(0.0667
12
(0.027)
A A
406
(0.9333
433
(0.973)



hCV25767872
KIAA1546
0.04821
A_vs_G
A G
22
(0.0497
11
(0.0243)
G G
421
(0.9503
442
(0.9757)




(rs6843141)

AA + AG_vs_GG
A G
22
(0.0497
11
(0.0243)
G G
421
(0.9503
442
(0.9757)






AG_vs_GG
A G
22
(0.0497
11
(0.0243)
G G
421
(0.9503
442
(0.9757)



hCV2605707
CDK6
0.04581
CC_vs_GG
G C
165
(0.3759
170
(0.3761)
C C
254
(0.5786
247
(0.5465)




(rs42041)



hCV26338456
SDCCAG8
0.04489
GG + GA_vs_AA
A G
238
(0.5385
225
(0.4989)
G G
118
(0.267
113
(0.2506)




(rs10927011)



hCV26338482
SDCCAG8
0.02994
TT_vs_CC
T C
185
(0.4214
186
(0.4133)
C C
209
(0.4761
235
(0.5222)




(rs10803143)





0.04165
TT_vs_TC + CC
T C
185
(0.4214
186
(0.4133)
C C
209
(0.4761
235
(0.5222)



hCV26887434
RGS7
0.04698
CC_vs_AA
C A
217
(0.491
228
(0.5044)
A A
126
(0.2851
146
(0.323)




(rs12723522)



hCV26895255
GP6
0.04243
CC_vs_CT + TT
C T
148
(0.3348
171
(0.3775)
T T
269
(0.6086
269
(0.5938)




(rs11669150)



hCV27020269
(rs7659613)
0.02343
CC_vs_GG
C G
213
(0.483
219
(0.4856)
G G
133
(0.3016
159
(0.3525)





0.02703
C_vs_G
C G
213
(0.483
219
(0.4856)
G G
133
(0.3016
159
(0.3525)





0.04138
CC_vs_CG + GG
C G
213
(0.483
219
(0.4856)
G G
133
(0.3016
159
(0.3525)



hCV27102953
LOC647718
0.00713
TT_vs_CC
T C
227
(0.5171
238
(0.5324)
C C
100
(0.2278
126
(0.2819)




(rs4648360)
0.00775
T_vs_C
T C
227
(0.5171
238
(0.5324)
C C
100
(0.2278
126
(0.2819)





0.01291
TT_vs_TC + CC
T C
227
(0.5171
238
(0.5324)
C C
100
(0.2278
126
(0.2819)



hCV27102978
LOC647718
0.00037
C_vs_A
A C
230
(0.5204
246
(0.5455)
C C
127
(0.2873
87
(0.1929)




(rs7537581)
0.00039
CC_vs_AA
A C
230
(0.5204
246
(0.5455)
C C
127
(0.2873
87
(0.1929)





0.00101
CC_vs_CA + AA
A C
230
(0.5204
246
(0.5455)
C C
127
(0.2873
87
(0.1929)





0.01374
CC + CA_vs_AA
A C
230
(0.5204
246
(0.5455)
C C
127
(0.2873
87
(0.1929)



hCV27103080
(rs4648459)
0.00385
TT_vs_GG
T G
223
(0.5045
234
(0.5166)
G G
111
(0.2511
141
(0.3113)





0.00458
T_vs_G
T G
223
(0.5045
234
(0.5166)
G G
111
(0.2511
141
(0.3113)





0.00807
TT_vs_TG + GG
T G
223
(0.5045
234
(0.5166)
G G
111
(0.2511
141
(0.3113)





0.04586
TT + TG_vs_GG
T G
223
(0.5045
234
(0.5166)
G G
111
(0.2511
141
(0.3113)



hCV27103182
(rs4609377)
0.00077
C_vs_T
T C
230
(0.5192
240
(0.531)
C C
135
(0.3047
100
(0.2212)





0.00082
CC_vs_TT
T C
230
(0.5192
240
(0.531)
C C
135
(0.3047
100
(0.2212)





0.00467
CC_vs_CT + TT
T C
230
(0.5192
240
(0.531)
C C
135
(0.3047
100
(0.2212)





0.00898
CC + CT_vs_TT
T C
230
(0.5192
240
(0.531)
C C
135
(0.3047
100
(0.2212)



hCV27103188
(rs7511879)
0.00386
GG_vs_GA + AA
G A
227
(0.5136
248
(0.5475)
A A
95
(0.2149
119
(0.2627)





0.00463
GG_vs_AA
G A
227
(0.5136
248
(0.5475)
A A
95
(0.2149
119
(0.2627)





0.00485
G_vs_A
G A
227
(0.5136
248
(0.5475)
A A
95
(0.2149
119
(0.2627)



hCV27103189
(rs12031493)
0.00933
G_vs_A
A G
226
(0.5148
244
(0.5398)
G G
127
(0.2893
98
(0.2168)





0.0103
GG_vs_AA
A G
226
(0.5148
244
(0.5398)
G G
127
(0.2893
98
(0.2168)





0.01303
GG_vs_GA + AA
A G
226
(0.5148
244
(0.5398)
G G
127
(0.2893
98
(0.2168)



hCV27103207
(rs6424062)
0.00385
AA_vs_GG
A G
224
(0.5056
234
(0.5166)
G G
111
(0.2506
141
(0.3113)





0.00453
A_vs_G
A G
224
(0.5056
234
(0.5166)
G G
111
(0.2506
141
(0.3113)





0.0085
AA_vs_AG + GG
A G
224
(0.5056
234
(0.5166)
G G
111
(0.2506
141
(0.3113)





0.04367
AA + AG_vs_GG
A G
224
(0.5056
234
(0.5166)
G G
111
(0.2506
141
(0.3113)



hCV2716314
CTSB (rs8005)
0.04236
A_vs_C
A C
188
(0.4263
172
(0.3805)
C C
217
(0.4921
252
(0.5575)



hCV2734332
39783
0.00283
GA_vs_AA
A G
195
(0.4402
174
(0.385)
G G
216
(0.4876
219
(0.4845)




(rs10759757)
0.01256
GG_vs_AA
A G
195
(0.4402
174
(0.385)
G G
216
(0.4876
219
(0.4845)



hCV27476043
RDH13
0.03332
AA_vs_AG + GG
A G
109
(0.2466
125
(0.2759)
G G
317
(0.7172
322
(0.7108)




(rs3745912)
0.04
AA_vs_GG
A G
109
(0.2466
125
(0.2759)
G G
317
(0.7172
322
(0.7108)



hCV27937396
(rs4634201)
0.04871
CC_vs_TT
C T
146
(0.3311
140
(0.3097)
T T
270
(0.6122
298
(0.6593)



hCV2811695
FTO
0.00707
C_vs_A
C A
106
(0.2398
83
(0.1844)
A A
323
(0.7308
361
(0.8022)




(rs940214)
0.01189
CC + CA_vs_AA
C A
106
(0.2398
83
(0.1844)
A A
323
(0.7308
361
(0.8022)





0.03143
CA_vs_AA
C A
106
(0.2398
83
(0.1844)
A A
323
(0.7308
361
(0.8022)



hCV2852784
CYP17A1
0.01777
A_vs_G
G A
202
(0.4654
219
(0.4944)
A A
178
(0.4101
151
(0.3409)




(rs743572)
0.0271
AA_vs_GG
G A
202
(0.4654
219
(0.4944)
A A
178
(0.4101
151
(0.3409)





0.03431
AA_vs_AG + GG
G A
202
(0.4654
219
(0.4944)
A A
178
(0.4101
151
(0.3409)



hCV2892855
FGG
0.00076
CC_vs_CT + TT
T C
205
(0.4649
237
(0.5243)
C C
172
(0.39
128
(0.2832)




(rs6536024)
0.0009
C_vs_T
T C
205
(0.4649
237
(0.5243)
C C
172
(0.39
128
(0.2832)





0.00284
CC_vs_TT
T C
205
(0.4649
237
(0.5243)
C C
172
(0.39
128
(0.2832)



hCV2892869
(rs13109457)
0.00029
AA_vs_GG
A G
187
(0.424
196
(0.4346)
G G
196
(0.4444
228
(0.5055)





0.00037
AA_vs_AG + GG
A G
187
(0.424
196
(0.4346)
G G
196
(0.4444
228
(0.5055)





0.00249
A_vs_G
A G
187
(0.424
196
(0.4346)
G G
196
(0.4444
228
(0.5055)



hCV2892893
(rs12648258)
0.01399
A_vs_T
A T
153
(0.3469
142
(0.3142)
T T
257
(0.5828
293
(0.6482)





0.01963
AA_vs_TT
A T
153
(0.3469
142
(0.3142)
T T
257
(0.5828
293
(0.6482)





0.033
AA_vs_AT + TT
A T
153
(0.3469
142
(0.3142)
T T
257
(0.5828
293
(0.6482)





0.04454
AA + AT_vs_TT
A T
153
(0.3469
142
(0.3142)
T T
257
(0.5828
293
(0.6482)



hCV2892905
PLRG1
0.03327
C_vs_T
C T
156
(0.357
146
(0.3266)
T T
248
(0.5675
280
(0.6264)




(rs12642770)
0.04994
CC_vs_TT
C T
156
(0.357
146
(0.3266)
T T
248
(0.5675
280
(0.6264)



hCV2892918
(rs12511469)
0.02229
A_vs_T
A T
152
(0.3455
142
(0.3149)
T T
257
(0.5841
291
(0.6452)





0.03037
AA_vs_TT
A T
152
(0.3455
142
(0.3149)
T T
257
(0.5841
291
(0.6452)





0.04836
AA_vs_AT + TT
A T
152
(0.3455
142
(0.3149)
T T
257
(0.5841
291
(0.6452)



hCV2892926
(rs7662567)
0.00586
C_vs_T
C T
154
(0.3532
143
(0.3171)
T T
248
(0.5688
290
(0.643)





0.00915
CC_vs_TT
C T
154
(0.3532
143
(0.3171)
T T
248
(0.5688
290
(0.643)





0.01776
CC_vs_CT + TT
C T
154
(0.3532
143
(0.3171)
T T
248
(0.5688
290
(0.643)





0.02387
CC + CT_vs_TT
C T
154
(0.3532
143
(0.3171)
T T
248
(0.5688
290
(0.643)



hCV2892927
(rs13123551)
0.01436
AA_vs_AT + TT
T A
210
(0.4784
239
(0.5288)
A A
158
(0.3599
128
(0.2832)





0.02592
A_vs_T
T A
210
(0.4784
239
(0.5288)
A A
158
(0.3599
128
(0.2832)



hCV29521317
LIMD1
0.02272
G_vs_A
G A
60
(0.1357
41
(0.0907)
A A
381
(0.862
411
(0.9093)




(rs7648441)
0.02712
GG + GA_vs_AA
G A
60
(0.1357
41
(0.0907)
A A
381
(0.862
411
(0.9093)





0.03349
GA_vs_AA
G A
60
(0.1357
41
(0.0907)
A A
381
(0.862
411
(0.9093)



hCV29983641
(rs10008078)
0.00588
AA_vs_GG
A G
152
(0.3455
145
(0.3229)
G G
253
(0.575
287
(0.6392)





0.00921
A_vs_G
A G
152
(0.3455
145
(0.3229)
G G
253
(0.575
287
(0.6392)





0.00957
AA_vs_AG + GG
A G
152
(0.3455
145
(0.3229)
G G
253
(0.575
287
(0.6392)



hCV30002208
(rs9402927)
0.04695
AA + AG_vs_GG
G A
219
(0.4989
211
(0.4678)
A A
165
(0.3759
162
(0.3592)



hCV30040828
TNFSF4
0.03454
TT + TC_vs_CC
T C
88
(0.1995
66
(0.147)
C C
348
(0.7891
379
(0.8441)




(rs6700269)
0.03713
TC_vs_CC
T C
88
(0.1995
66
(0.147)
C C
348
(0.7891
379
(0.8441)





0.04223
T_vs_C
T C
88
(0.1995
66
(0.147)
C C
348
(0.7891
379
(0.8441)



hCV30548253
(rs9425773)
0.02996
AC_vs_CC
C A
113
(0.2568
99
(0.22)
A A
320
(0.7273
334
(0.7422)



hCV305844
LOC728077
0.0275
CC_vs_CG + GG
C G
186
(0.4199
221
(0.4879)
G G
171
(0.386
169
(0.3731)




(rs4823562)



hCV30711231
(rs12642469)
0.02106
A_vs_G
A G
152
(0.3439
143
(0.3164)
G G
258
(0.5837
291
(0.6438)





0.02334
AA_vs_GG
A G
152
(0.3439
143
(0.3164)
G G
258
(0.5837
291
(0.6438)





0.03665
AA_vs_AG + GG
A G
152
(0.3439
143
(0.3164)
G G
258
(0.5837
291
(0.6438)



hCV31475431
MMEL1
0.0372
GG_vs_GT + TT
T G
70
(0.158
100
(0.2208)
G G
367
(0.8284
350
(0.7726)




(rs12133956)



hCV31863982
(rs7659024)
2.2E−05
AA_vs_GG
A G
189
(0.4276
193
(0.427)
G G
196
(0.4434
237
(0.5243)





4.6E−05
AA_vs_AG + GG
A G
189
(0.4276
193
(0.427)
G G
196
(0.4434
237
(0.5243)





0.0002
A_vs_G
A G
189
(0.4276
193
(0.427)
G G
196
(0.4434
237
(0.5243)





0.01564
AA + AG_vs_GG
A G
189
(0.4276
193
(0.427)
G G
196
(0.4434
237
(0.5243)



hCV31965333
(rs10797390)
0.00973
CC_vs_TT
T C
231
(0.5238
236
(0.5221)
C C
134
(0.3039
111
(0.2456)





0.01032
C_vs_T
T C
231
(0.5238
236
(0.5221)
C C
134
(0.3039
111
(0.2456)





0.02629
CC + CT_vs_TT
T C
231
(0.5238
236
(0.5221)
C C
134
(0.3039
111
(0.2456)



hCV31997958
CHMP7
0.00266
GG_vs_GA + AA
G A
201
(0.4558
215
(0.4799)
A A
159
(0.3605
183
(0.4085)




(rs12544038)
0.00301
GG_vs_AA
G A
201
(0.4558
215
(0.4799)
A A
159
(0.3605
183
(0.4085)





0.00969
G_vs_A
G A
201
(0.4558
215
(0.4799)
A A
159
(0.3605
183
(0.4085)



hCV3205858
PXDNL
0.04375
CC_vs_CT + TT
C T
196
(0.4424
211
(0.4658)
T T
171
(0.386
186
(0.4106)




(rs2979122)



hCV3210786
C1orf164
0.00202
CC_vs_CT + TT
C T
177
(0.4005
200
(0.4454)
T T
204
(0.4615
216
(0.4811)




(rs11582970)
0.00463
CC_vs_TT
C T
177
(0.4005
200
(0.4454)
T T
204
(0.4615
216
(0.4811)



hCV32212664
(rs12642646)
0.00716
AA_vs_AG + GG
G A
211
(0.4785
249
(0.5509)
A A
140
(0.3175
107
(0.2367)



hCV7429782
FGG
0.01428
T_vs_A
A T
175
(0.3959
203
(0.4491)
T T
239
(0.5407
209
(0.4624)




(rs1118823)
0.0193
TT_vs_TA + AA
A T
175
(0.3959
203
(0.4491)
T T
239
(0.5407
209
(0.4624)



hCV7429793
(rs1025154)
0.01309
C_vs_T
C T
157
(0.3552
143
(0.3164)
T T
254
(0.5747
291
(0.6438)





0.02761
CC_vs_TT
C T
157
(0.3552
143
(0.3164)
T T
254
(0.5747
291
(0.6438)





0.03429
CC + CT_vs_TT
C T
157
(0.3552
143
(0.3164)
T T
254
(0.5747
291
(0.6438)





0.04931
CC_vs_CT + TT
C T
157
(0.3552
143
(0.3164)
T T
254
(0.5747
291
(0.6438)



hCV788647
(rs729045)
0.01217
AA_vs_GG
G A
227
(0.5147
234
(0.5166)
A A
158
(0.3583
137
(0.3024)





0.01497
A_vs_G
G A
227
(0.5147
234
(0.5166)
A A
158
(0.3583
137
(0.3024)



hCV813581
OR4C11
0.01556
T_vs_G
T G
37
(0.0905
30
(0.0699)
G G
351
(0.8582
389
(0.9068)




(rs491160)
0.02979
TT + TG_vs_GG
T G
37
(0.0905
30
(0.0699)
G G
351
(0.8582
389
(0.9068)





0.03083
TT_vs_GG
T G
37
(0.0905
30
(0.0699)
G G
351
(0.8582
389
(0.9068)





0.03607
TT_vs_TG + GG
T G
37
(0.0905
30
(0.0699)
G G
351
(0.8582
389
(0.9068)



hCV8727391
C17orf81
0.01705
AG_vs_GG
G A
216
(0.4876
199
(0.4403)
A A
187
(0.4221
190
(0.4204)




(rs414206)



hCV8857351
RGS7
0.03561
TT_vs_TC + CC
T C
210
(0.4762
228
(0.5044)
C C
130
(0.2948
146
(0.323)




(rs2341021)



hCV8911768
SERPINC1
0.01702
T_vs_C
T C
92
(0.2091
69
(0.1533)
C C
341
(0.775
377
(0.8378)




(rs941988)
0.02739
TC_vs_CC
T C
92
(0.2091
69
(0.1533)
C C
341
(0.775
377
(0.8378)



hCV8919450
F5 (rs6017)
0.00317
AA_vs_AG + GG
G A
126
(0.2877
168
(0.375)
A A
286
(0.653
249
(0.5558)





0.00978
A_vs_G
G A
126
(0.2877
168
(0.375)
A A
286
(0.653
249
(0.5558)



hCV8941510
CDSN
0.04988
CC_vs_AA
C A
118
(0.2682
113
(0.2511)
A A
306
(0.6955
330
(0.7333)




(rs1042127)



hCV9114656
CFHR5
0.04258
C_vs_T
C T
76
(0.1723
60
(0.1325)
T T
360
(0.8163
391
(0.8631)




(rs9427662)



hCV9680592
MIPEP
0.03902
GA_vs_AA
A G
149
(0.3371
184
(0.4062)
G G
259
(0.586
246
(0.543)




(rs17079372)



hDV70683187
(rs16846561)
0.02204
G_vs_C
G C
95
(0.2159
73
(0.1622)
C C
338
(0.7682
373
(0.8289)





0.03622
GC_vs_CC
G C
95
(0.2159
73
(0.1622)
C C
338
(0.7682
373
(0.8289)



hDV70683212
RC3H1
0.04442
G_vs_C
G C
72
(0.1633
55
(0.1222)
C C
366
(0.8299
394
(0.8756)




(rs16846593)



hDV70683382
RABGAP1L
0.04002
C_vs_G
C G
59
(0.1338
42
(0.094)
G G
378
(0.8571
403
(0.9016)




(rs16846815)



hDV70965621
(rs17534243)
0.0283
GA_vs_AA
G A
173
(0.3923
147
(0.3252)
A A
242
(0.5488
281
(0.6217)

















TABLE 22





Unadjusted association of 9 SNPs with DVT in MEGA-1 (p <= 0.05) that have not been tested in LETS
































Allele








OR (95%
Risk
NonRisk
(CONTROL



marker
annot
P-value
parameter
Model
Cl)
Allele
Allele
frq)
Genot





hCV11629656
(rs17284)
0.000279
GG + GT vs TT
dom
4.05 (1.9-
G
T
G (0.0037
G G







8.61)








0.000997
GT vs TT
Gen
5.21 (1.95-
G
T
G (0.0037
G G







13.91)








0.001553
G vs T
add
2.44 (1.4-
G
T
G (0.0037
G G







4.23)






hCV11629657
(rs17286)
0.000274
AA + AG vs GG
dom
4.06 (1.91-
A
G
A (0.0037
A A







8.63)








0.000984
AG vs GG
Gen
5.22 (1.95-
A
G
A (0.0037
A A







13.94)








0.001529
A vs G
add
2.44 (1.41-
A
G
A (0.0037
A A







4.24)






hCV11922386
MDM2
0.006966
CT vs TT
Gen
3.34 (1.39-
C
T
C (0.0037
C C



(rs1846401)



8.02)








0.009319
CC + CT vs TT
dom
2.73 (1.28-
C
T
C (0.0037
C C







5.81)








0.03014
C vs T
add
1.96 (1.07-
C
T
C (0.0037
C C







3.59)






hCV1825046
PROCR
0.000399
T vs C
add
1.21 (1.09-
T
C
C (0.4011
C C



(rs2069952)



1.34)








0.000746
TT vs CC
Gen
1.46 (1.17-
T
C
C (0.4011
C C







1.82)








0.00224
TT vs TC + CC
rec
1.26 (1.08-
T
C
C (0.4011
C C







1.45)








0.006881
TT + TC vs CC
dom
1.32 (1.08-
T
C
C (0.4011
C C







1.62)






hCV1841974
(rs1799809)
0.001032
GG vs GA + AA
rec
1.34 (1.12-
G
A
G (0.4338
G G







1.59)








0.001263
GG vs AA
Gen
1.39 (1.14-
G
A
G (0.4338
G G







1.7)








0.002126
G vs A
add
1.17 (1.06-
G
A
G (0.4338
G G







1.29)






hCV2532034
F13B
0.010904
CT vs TT
Gen
1.28 (1.06-
C
T
C (0.0896
C C



(rs6003)



1.55)








0.01363
CC + CT vs TT
dom
1.26 (1.05-
C
T
C (0.0896
C C







1.52)








0.025493
C vs T
add
1.21 (1.02-
C
T
C (0.0896
C C







1.44)






hCV25597241
AQP2
0.046904
A vs G
add
1.19 (1-
A
G
A (0.083
A A



(rs3782320)



1.42)






hCV3170967
PLEKHA4
0.038558
CC vs CG + GG
rec
1.27 (1.01-
C
G
C (0.3233
C C



(rs556052)



1.59)






hDV71075942
(rs8176719)
3.47E−31
G vs T
add
1.9 (1.71-
G
T
G (0.3313
G G







2.12)








3.29E−30
GG + GT vs TT
dom
2.48 (2.12-
G
T
G (0.3313
G G







2.89)








1.26E−25
GG vs TT
Gen
3.32 (2.65-
G
T
G (0.3313
G G







4.15)








8.35E−23
GT vs TT
Gen
2.27 (1.93-
G
T
G (0.3313
G G







2.67)








3.19E−12
GG vs GT + TT
rec
2.04 (1.67-
G
T
G (0.3313
G G







2.49)




















CONTROL


CONTROL


CONTROL




cnt


cnt


cnt



CASE cnt
(CONTROL
Genot
CASE cnt
(CONTROL
Geno
CASE cnt
(CONTROL


marker
(CASE frq
frq)
2
(CASE frq2
frq)2
t3
(CASE frq3
frq)3





hCV11629656
 8 (0.0059)
 4 (0.0023)
G T
 20 (0.0146
 5 (0.0029)
T T
1339 (0.9795
1743 (0.9949)



 8 (0.0059)
 4 (0.0023)
G T
 20 (0.0146
 5 (0.0029)
T T
1339 (0.9795
1743 (0.9949)



 8 (0.0059)
 4 (0.0023)
G T
 20 (0.0146
 5 (0.0029)
T T
1339 (0.9795
1743 (0.9949)


hCV11629657
 8 (0.0059)
 4 (0.0023)
A G
 20 (0.0146
 5 (0.0029)
G G
1338 (0.9795
1745 (0.9949)



 8 (0.0059)
 4 (0.0023)
A G
 20 (0.0146
 5 (0.0029)
G G
1338 (0.9795
1745 (0.9949)



 8 (0.0059)
 4 (0.0023)
A G
 20 (0.0146
 5 (0.0029)
G G
1338 (0.9795
1745 (0.9949)


hCV11922386
 3 (0.0022)
 3 (0.0017)
C T
 18 (0.0132
 7 (0.004)
T T
1345 (0.9846
1747 (0.9943)



 3 (0.0022)
 3 (0.0017)
C T
 18 (0.0132
 7 (0.004)
T T
1345 (0.9846
1747 (0.9943)



 3 (0.0022)
 3 (0.0017)
C T
 18 (0.0132
 7 (0.004)
T T
1345 (0.9846
1747 (0.9943)


hCV1825046
174 (0.1292)
288 (0.1641)
C T
613 (0.4551
832 (0.4741)
T T
 560 (0.4157
 635 (0.3618)



174 (0.1292)
288 (0.1641)
C T
613 (0.4551
832 (0.4741)
T T
 560 (0.4157
 635 (0.3618)



174 (0.1292)
288 (0.1641)
C T
613 (0.4551
832 (0.4741)
T T
 560 (0.4157
 635 (0.3618)



174 (0.1292)
288 (0.1641)
C T
613 (0.4551
832 (0.4741)
T T
 560 (0.4157
 635 (0.3618)


hCV1841974
317 (0.2348)
327 (0.1865)
G A
644 (0.477
867 (0.4946)
A A
 389 (0.2881
 559 (0.3189)



317 (0.2348)
327 (0.1865)
G A
644 (0.477
867 (0.4946)
A A
 389 (0.2881
 559 (0.3189)



317 (0.2348)
327 (0.1865)
G A
644 (0.477
867 (0.4946)
A A
 389 (0.2881
 559 (0.3189)


hCV2532034
 15 (0.0116)
 20 (0.0118)
C T
248 (0.1911
265 (0.1557)
T T
1035 (0.7974
1417 (0.8325)



 15 (0.0116)
 20 (0.0118)
C T
248 (0.1911
265 (0.1557)
T T
1035 (0.7974
1417 (0.8325)



 15 (0.0116)
 20 (0.0118)
C T
248 (0.1911
265 (0.1557)
T T
1035 (0.7974
1417 (0.8325)


hCV25597241
 14 (0.0104)
 13 (0.0074)
A G
235 (0.1743
265 (0.1511)
G G
1099 (0.8153
1476 (0.8415)


hCV3170967
169 (0.1224)
173 (0.0991)
C G
579 (0.4193
783 (0.4485)
G G
 633 (0.4584
 790 (0.4525)


hDV71075942
272 (0.2022)
194 (0.1107)
G T
741 (0.5509
773 (0.4412)
T T
 332 (0.2468
 785 (0.4481)



272 (0.2022)
194 (0.1107)
G T
741 (0.5509
773 (0.4412)
T T
 332 (0.2468
 785 (0.4481)



272 (0.2022)
194 (0.1107)
G T
741 (0.5509
773 (0.4412)
T T
 332 (0.2468
 785 (0.4481)



272 (0.2022)
194 (0.1107)
G T
741 (0.5509
773 (0.4412)
T T
 332 (0.2468
 785 (0.4481)



272 (0.2022)
194 (0.1107)
G T
741 (0.5509
773 (0.4412)
T T
 332 (0.2468
 785 (0.4481)
















TABLE 23





Age- and sex-adjusted association of 41 SNPs with DVT in LETS, MEGA-1, and MEGA-2
































Gene


NonRef
Risk

Control


P-




Case
Case


Marker
Symbol
RS number
RefAllele
Allele
Allele
Stratum
RAF
Model
Parameter
value
OddsRatio
OR95l
OR95u
Genot
Count3
Freq3





hCV11503414
FGG
rs2066865
G
A
A
LETS
0.263982
additive
hCV11503414.AA.AG.adtv
5E−04
1.448
1.17734
1.780951
GG
195
0.45








MEGA-1
0.274644
additive
hCV11503414.AA.AG.adtv
9E−10
1.4046
1.25977
1.566181
GG
574
0.43








MEGA-2
0.260379
additive
hCV11503414.AA.AG.adtv
1E−08
1.352
1.21875
1.499831
GG
577
0.46


hCV11503469
FGG
rs2066854
T
A
A
LETS
0.259382
additive
hCV11503469.AA.AT.adtv
2E−04
1.4852
1.20554
1.829853
TT
196
0.44








MEGA-1
0.275242
additive
hCV11503469.AA.AT.adtv
7E−10
1.402
1.25909
1.561084
TT
593
0.43








MEGA-2
0.261723
additive
hCV11503469.AA.AT.adtv
2E−08
1.3459
1.21349
1.492657
TT
577
0.46


hCV11503470

rs1800788
C
T
T
LETS
0.196903
additive
hCV11503470.TT.TC.adtv
0.014
1.3226
1.0586
1.652468
CC
256
0.58








MEGA-1
0.216448
additive
hCV11503470.TT.TC.adtv
0.008
1.1694
1.04176
1.312675
CC
790
0.57








MEGA-2
0.202849
additive
hCV11503470.TT.TC.adtv
2E−04
1.236
1.10482
1.382765
CC
731
0.58


hCV11975250
F5
rs6025
C
T
T
LETS
0.015487
additive
hCV11975250.TT.TC.adtv
2E−11
7.1787
4.04207
12.7492
CC
354
0.8








MEGA-1
0.027335
additive
hCV11975250.TT.TC.adtv
1E−30
4.0963
3.22255
5.207016
CC
1120
0.8








MEGA-2
0.025825
additive
hCV11975250.TT.TC.adtv
1E−39
4.273
3.44263
5.30362
CC
1029
0.81


hCV12066124
F11
rs2036914
C
T
C
LETS
0.543046
additive
hCV12066124.TT.TC.adtv
0.013
0.7892
0.65464
0.951525
CC
159
0.36








MEGA-1
0.521677
additive
hCV12066124.TT.TC.adtv
2E−07
0.7657
0.69212
0.846995
CC
476
0.34








MEGA-2
0.51645
additive
hCV12066124.TT.TC.adtv
7E−12
0.7138
0.64823
0.786089
CC
445
0.36


hCV15860433

rs2070006
C
T
T
LETS
0.401111
additive
hCV15860433.TT.TC.adtv
0.024
1.241
1.02908
1.496544
CC
135
0.31








MEGA-1
0.406963
additive
hCV15860433.TT.TC.adtv
4E−05
1.2352
1.11709
1.365809
CC
405
0.29








MEGA-2
0.388687
additive
hCV15860433.TT.TC.adtv
2E−06
1.2603
1.14598
1.386016
CC
390
0.31


hCV16180170
SERPINC1
rs2227589
C
T
T
LETS
0.086283
additive
hCV16180170.TT.TC.adtv
0.026
1.421
1.04306
1.935767
CC
344
0.78








MEGA-1
0.089174
additive
hCV16180170.TT.TC.adtv
0.009
1.2448
1.05553
1.4679
CC
1109
0.8








MEGA-2
0.095028
additive
hCV16180170.TT.TC.adtv
9E−04
1.2863
1.10835
1.49275
CC
1001
0.77


hCV233148
KT3/SDCCAG
rs1417121
G
C
C
LETS
0.262693
additive
hCV233148.CC.CG.adtv
3E−04
1.4537
1.18416
1.78458
GG
191
0.43








MEGA-1
0.285592
additive
hCV233148.CC.CG.adtv
0.001
1.1955
1.07302
1.332
GG
652
0.47








MEGA-2
0.273489
additive
hCV233148.CC.CG.adtv
0.018
1.1326
1.02189
1.255409
GG
626
0.5


hCV25990131
CYP4V2
rs13146272
A
C
A
LETS
0.649007
additive
hCV25990131.CC.CA.adtv
0.048
0.8182
0.67063
0.998308
AA
202
0.46








MEGA-1
0.640046
additive
hCV25990131.CC.CA.adtv
0.001
0.8434
0.75935
0.936754
AA
648
0.46








MEGA-2
0.641387
additive
hCV25990131.CC.CA.adtv
6E−05
0.8101
0.73057
0.898278
AA
561
0.48


hCV27474895
F11
rs3756011
C
A
A
LETS
0.424779
additive
hCV27474895.AA.AC.adtv
0.035
1.2135
1.01344
1.452968
CC
128
0.29








MEGA-1
0.418432
additive
hCV27474895.AA.AC.adtv
4E−08
1.3273
1.19988
1.468181
CC
361
0.26








MEGA-2
0.396894
additive
hCV27474895.AA.AC.adtv
2E−12
1.4043
1.27743
1.543811
CC
342
0.27


hCV27477533
F11
rs3756008
A
T
T
LETS
0.415929
additive
hCV27477533.TT.TA.adtv
0.031
1.2211
1.01816
1.464466
AA
129
0.29








MEGA-1
0.406625
additive
hCV27477533.TT.TA.adtv
9E−07
1.286
1.16309
1.42186
AA
397
0.28








MEGA-2
0.388969
additive
hCV27477533.TT.TA.adtv
2E−12
1.4088
1.28095
1.549479
AA
346
0.28


hCV8241630
F11
rs925451
G
A
A
LETS
0.40708
additive
hCV8241630.AA.AG.adtv
0.046
1.2036
1.00372
1.443218
GG
134
0.3








MEGA-1
0.388794
additive
hCV8241630.AA.AG.adtv
4E−08
1.3296
1.20124
1.471753
GG
403
0.3








MEGA-2
0.373285
additive
hCV8241630.AA.AG.adtv
1E−11
1.3879
1.26191
1.526573
GG
374
0.3


hCV8717873
GP6/RDH13
rs1613662
A
G
A
LETS
0.800221
additive
hCV8717873.GG.GA.adtv
0.013
0.7329
0.57372
0.936291
AA
316
0.71








MEGA-1
0.807033
additive
hCV8717873.GG.GA.adtv
0.004
0.8249
0.72386
0.940033
AA
975
0.7








MEGA-2
0.822156
additive
hCV8717873.GG.GA.adtv
0.031
0.8709
0.76791
0.987716
AA
915
0.7


hCV8726802
F2
rs1799963
G
A
A
LETS
0.011111
additive
hCV8726802.AA.AG.adtv
0.004
2.99
1.43284
6.239603
GG
414
0.94








MEGA-1
0.010559
additive
hCV8726802.AA.AG.adtv
2E−07
2.8476
1.91526
4.233889
GG
1301
0.94








MEGA-2
0.009653
additive
hCV8726802.AA.AG.adtv
1E−10
3.2096
2.25263
4.57324
GG
1219
0.94


hCV8919444
F5
rs4524
T
C
T
LETS
0.742257
additive
hCV8919444.CC.CT.adtv
0.006
0.7351
0.5915
0.913666
TT
289
0.65








MEGA-1
0.744717
additive
hCV8919444.CC.CT.adtv
1E−04
0.793
0.70449
0.892524
TT
872
0.63








MEGA-2
0.7332
additive
hCV8919444.CC.CT.adtv
6E−07
0.7525
0.67308
0.841315
TT
773
0.62


hCV15949414
XYLB
rs2234628
G
A
G
LETS
0.94308
dominant
hCV15949414.GG.dom
0.036
0.6085
0.38271
0.967377
GG
409
0.93








MEGA-1
0.950371
dominant
hCV15949414.GG.dom
0.003
0.6754
0.51964
0.87772
GG
1269
0.93








MEGA-2
0.946416
dominant
hCV15949414.GG.dom
0.025
0.7617
0.6
0.966871
GG
1152
0.92


hCV15968043
CYP4V2
rs2292423
T
A
A
LETS
0.432671
dominant
hCV15968043.TT.dom
0.043
1.3422
1.00887
1.7856
TT
122
0.28








MEGA-1
0.412794
dominant
hCV15968043.TT.dom
2E−04
1.3378
1.14802
1.559058
TT
395
0.29








MEGA-2
0.406888
dominant
hCV15968043.TT.dom
7E−07
1.4572
1.25589
1.690689
TT
330
0.27


hCV263841
NR1I2
rs1523127
A
C
C
LETS
0.331126
recessive
hCV263841.CC.rec
2E−04
1.9998
1.38179
2.894094
AA
160
0.36








MEGA-1
0.391106
recessive
hCV263841.CC.rec
0.018
1.2569
1.03941
1.52002
AA
462
0.33








MEGA-2
0.379129
recessive
hCV263841.CC.rec
0.027
1.2241
1.02327
1.464342
AA
480
0.37


hCV916107
RGS7
rs670659
C
T
C
LETS
0.644592
recessive
hCV916107.TT.rec
0.048
0.6546
0.43
0.99638
CC
216
0.49








MEGA-1
0.643021
recessive
hCV916107.TT.rec
0.012
0.755
0.60684
0.939319
CC
622
0.45








MEGA-2
0.64079
recessive
hCV916107.TT.rec
0.021
0.778
0.62855
0.963064
CC
548
0.42


hCV1841975
PROC
rs1799810
A
T
T
LETS
0.426991
additive
hCV1841975.TT.TA.adtv
0.074
1.1855
0.98365
1.428736
AA
127
0.29








MEGA-1
0.435604
additive
hCV1841975.TT.TA.adtv
0.01 
1.1388
1.03113
1.257773
AA
410
0.3








MEGA-2
0.428546
additive
hCV1841975.TT.TA.adtv
7E−04
1.1795
1.07246
1.297319
AA
336
0.27


hCV25474413
F11
rs3822057
C
A
C
LETS
0.50883
additive
hCV25474413.AA.AC.adtv
0.066
0.8427
0.70217
1.011372
CC
138
0.31








MEGA-1
0.490023
additive
hCV25474413.AA.AC.adtv
2E−06
0.7817
0.70639
0.865066
CC
406
0.3








MEGA-2
0.479993
additive
hCV25474413.AA.AC.adtv
2E−10
0.7357
0.66925
0.808801
CC
391
0.31


hCV2892877
FGA
rs6050
T
C
C
LETS
0.249448
additive
hCV2892877.CC.CT.adtv
0.058
1.2897
0.9909
1.678671
TT
194
0.44








MEGA-1
0.245709
additive
hCV2892877.CC.CT.adtv
7E−07
1.4325
1.24272
1.651308
TT
581
0.42








MEGA-2
0.230097
additive
hCV2892877.CC.CT.adtv
2E−04
1.3033
1.13392
1.498055
TT
510
0.48


hCV3230038
F11
rs2289252
C
T
T
LETS
0.427938
additive
hCV3230038.TT.TC.adtv
0.062
1.187
0.99174
1.420769
CC
130
0.29








MEGA-1
0.41681
additive
hCV3230038.TT.TC.adtv
9E−09
1.3489
1.21786
1.493929
CC
344
0.26








MEGA-2
0.395638
additive
hCV3230038.TT.TC.adtv
2E−12
1.4074
1.28018
1.547352
CC
343
0.27


hCV596331
F9
rs6048
A
G
A
LETS
0.673289
additive
hCV596331.GG.GA.adtv
0.026
0.8222
0.69227
0.976638
AA
274
0.62








MEGA-1
0.69609
additive
hCV596331.GG.GA.adtv
0.065
0.9185
0.83911
1.005393
AA
844
0.62








MEGA-2
0.699614
additive
hCV596331.GG.GA.adtv
0.094
0.9302
0.85473
1.012392
AA
797
0.61


hCV11786258
KLKB1
rs4253303
G
A
A
LETS
0.415929
dominant
hCV11786258.GG.dom
0.09 
1.2752
0.96283
1.688914
GG
132
0.3








MEGA-1
0.39355
dominant
hCV11786258.GG.dom
2E−04
1.3243
1.14055
1.537568
GG
434
0.31








MEGA-2
0.392883
dominant
hCV11786258.GG.dom
7E−06
1.3922
1.20483
1.608816
GG
364
0.29


hCV3230096
CYP4V2
rs3817184
C
T
T
LETS
0.436947
dominant
hCV3230096.CC.dom
0.056
1.3236
0.99247
1.765259
CC
120
0.27








MEGA-1
0.416379
dominant
hCV3230096.CC.dom
0.002
1.2697
1.09046
1.478413
CC
409
0.29








MEGA-2
0.414836
dominant
hCV3230096.CC.dom
6E−06
1.4043
1.21187
1.627272
CC
338
0.27


hCV11541681
NAT8B
rs2001490
G
C
C
LETS
0.384106
recessive
hCV11541681.CC.rec
0.038
1.4687
1.02118
2.112445
GG
142
0.32








MEGA-1
0.370296
recessive
hCV11541681.CC.rec
0.046
1.2211
1.00323
1.486365
GG
502
0.36








MEGA-2
0.372281
recessive
hCV11541681.CC.rec
0.093
1.17
0.97407
1.405291
GG
490
0.38


hCV1859855

text missing or illegible when filed OLGA3/POLtext missing or illegible when filed

rs2291260
T
C
C
LETS
0.193157
recessive
hCV1859855.CC.rec
0.234
1.4721
0.7791
2.78168
TT
269
0.61








MEGA-1
0.219714
recessive
hCV1859855.CC.rec
2E−04
1.8088
1.32175
2.475445
TT
797
0.58








MEGA-2
0.217825
recessive
hCV1859855.CC.rec
0.035
1.3716
1.0217
1.841426
TT
743
0.58


hCV1874482
ZDHHC6
rs2306158
G
A
G
LETS
0.603563
recessive
hCV1874482.AA.rec
0.029
0.6576
0.45097
0.958845
GG
197
0.45








MEGA-1
0.637435
recessive
hCV1874482.AA.rec
0.901
0.9863
0.79453
1.224375
GG
570
0.41








MEGA-2
0.640047
recessive
482.AA.re
0.044
0.8014
0.64583
0.994348
GG
462
0.43


hCV15793897
KLKB1
rs3087505
G
A
G
LETS
0.899113
additive
hCV15793897.AA.AG.adtv
0.172
0.7939
0.56997
1.105919
GG
370
0.84








MEGA-1
0.88683
additive
hCV15793897.AA.AG.adtv
0.006
0.7891
0.66696
0.933557
GG
1139
0.82








MEGA-2
0.889009
additive
hCV15793897.AA.AG.adtv
9E−04
0.7628
0.65053
0.894335
GG
1050
0.84


hCV15871021
EBF1
rs2072495
G
A
G
LETS
0.591611
additive
hCV15871021.AA.AG.adtv
0.142
0.8667
0.71601
1.049207
GG
181
0.41








MEGA-1
0.607102
additive
hCV15871021.AA.AG.adtv
0.074
0.9092
0.81901
1.009384
GG
526
0.38








MEGA-2
0.605159
additive
hCV15871021.AA.AG.adtv
0.073
0.9144
0.82917
1.008452
GG
490
0.39


hCV22272267
KLKB1
rs3733402
A
G
A
LETS
0.548673
additive
hCV22272267.GG.GA.adtv
0.669
0.9604
0.79793
1.155992
AA
142
0.32








MEGA-1
0.509703
additive
hCV22272267.GG.GA.adtv
2E−06
0.7815
0.70564
0.865522
AA
444
0.32








MEGA-2
0.515971
additive
hCV22272267.GG.GA.adtv
4E−06
0.7975
0.72433
0.877967
AA
389
0.31


hCV2303891
APOH
rs1801690
C
G
C
LETS
0.948775
additive
hCV2303891.GG.GC.adtv
0.043
0.6069
0.37388
0.984984
CC
411
0.94








MEGA-1
0.94302
dominant
hCV2303891.CC.dom
0.002
0.6822
0.53384
0.871787
CC
1285
0.92








MEGA-2
0.946824
dominant
hCV2303891.CC.dom
0.131
0.8388
0.66754
1.053943
CC
1140
0.91


hCV25620145
PROCR
rs867186
A
G
G
LETS
0.124169
additive
hCV25620145.GG.GA.adtv
0.112
1.2446
0.9505
1.62976
AA
320
0.72








MEGA-1
0.122222
additive
hCV25620145.GG.GA.adtv
0.012
1.2067
1.04274
1.396475
AA
1018
0.73








MEGA-2
0.12575
additive
hCV25620145.GG.GA.adtv
0.068
1.1355
0.99044
1.301869
AA
960
0.74


hCV8827309
SUMF1
rs1110796
C
T
T
LETS
0.102876
additive
hCV8827309.TT.TC.adtv
0.005
1.4964
1.12625
1.988271
CC
321
0.73








MEGA-1
0.12044
additive
hCV8827309.TT.TC.adtv
0.04 
1.1711
1.00737
1.361357
CC
1022
0.74








MEGA-2
0.124954
recessive
hCV8827309.TT.rec
0.075
1.5107
0.95904
2.37983
CC
947
0.76


hCV8957432
RAC2
rs6572
G
C
C
LETS
0.445796
recessive
hCV8957432.CC.rec
0.043
1.409
1.01101
1.963723
GG
117
0.27








MEGA-1
0.436395
recessive
hCV8957432.CC.rec
0.034
1.207
1.01423
1.436506
GG
405
0.29








MEGA-2
0.448227
dominant
hCV8957432.GG.dom
0.093
1.1318
0.97954
1.307629
GG
369
0.28


hCV2086329
SPARC
rs4958487
A
G
A
MEGA-2
0.555135
recessive
hCV2086329.GG.rec
0.045
0.8386
0.70592
0.996203
AA
394
0.31







G
LETS
0.418322
recessive
hCV2086329.GG.rec
0.013
1.5201
1.09176
2.116484
AA
134
0.3








MEGA-1
0.421848
recessive
hCV2086329.GG.rec
0.001
1.3419
1.12173
1.605263
AA
456
0.33


hCV25768636

text missing or illegible when filed CDC36/USP1

rs4279134
G
A
A
LETS
0.327051
recessive
hCV25768636.AA.rec
0.035
1.5294
1.02978
2.271413
GG
177
0.4








MEGA-1
0.344641
recessive
hCV25768636.AA.rec
0.037
1.256
1.01355
1.556464
GG
559
0.4







G
MEGA-2
0.644432
recessive
hCV25768636.AA.rec
0.042
0.8065
0.65574
0.991971
GG
581
0.46


hCV29821005
LOC728284
rs6552970
C
T
C
MEGA-2
0.845877
additive
hCV29821005.TT.TC.adtv
0.003
0.8107
0.70689
0.929688
CC
912
0.78







T
LETS
0.205556
additive
hCV29821005.TT.TC.adtv
0.089
1.2192
0.97054
1.531643
CC
250
0.57








MEGA-1
0.194413
additive
hCV29821005.TT.TC.adtv
0.025
1.1511
1.01771
1.302014
CC
820
0.61


hCV31199195
KCTD10
rs10850234
A
C
A
MEGA-2
0.829957
dominant
hCV31199195.AA.dom
0.08
0.8767
0.75671
1.015687
AA
896
0.72







C
LETS
0.153422
dominant
hCV31199195.AA.dom
0.019
1.4068
1.05768
1.871125
AA
289
0.65








MEGA-1
0.168379
dominant
hCV31199195.AA.dom
0.045
1.1666
1.00343
1.356282
AA
913
0.66


hCV11975651
SERPINC1
rs677
C
G
C
LETS
0.890244
recessive
hCV11975651.GG.rec
0.048
0.274
0.07591
0.98926
CC
342
0.78







C
MEGA-2
0.873245
additive
hCV11975651.GG.GC.adtv
0.041
0.8568
0.7386
0.99401
CC
990
0.79







G
LETS
0.109756
general
hCV11975651.GC
0.1 
1.324
0.94755
1.850018
CC
342
0.78





























Gene


NonRef
Risk

Control-
Control


Case
Control-
Control-


Case
Control-
Control-


Marker
Symbol
RS number
RefAllele
Allele
Allele
Stratum
Count3
Freq3
Genot2
CaseCount4
Freq4
Count4
Freq4
Genot3
CaseCount5
Freq5
Count5
Freq5





hCV11503414
FGG
rs2066865
G
A
A
LETS
235
0.5
AG
186
0.426
188
0.42
AA
56
0.13
24
0.054








MEGA-1
927
0.5
AG
608
0.451
692
0.39
AA
166
0.12
136
0.077








MEGA-2
1499
0.5
AG
536
0.43
1064
0.39
AA
134
0.11
183
0.067


hCV11503469
FGG
rs2066854
T
A
A
LETS
240
0.5
AT
192
0.434
191
0.42
AA
54
0.12
22
0.049








MEGA-1
927
0.5
AT
624
0.449
687
0.39
AA
174
0.13
139
0.079








MEGA-2
1496
0.5
AT
530
0.426
1070
0.39
AA
137
0.11
185
0.067


hCV11503470

rs1800788
C
T
T
LETS
291
0.6
TC
156
0.352
144
0.32
TT
31
0.07
17
0.038








MEGA-1
1100
0.6
TC
512
0.369
544
0.31
TT
85
0.06
107
0.061








MEGA-2
1764
0.6
TC
445
0.355
893
0.32
TT
78
0.06
116
0.042


hCV11975250
F5
rs6025
C
T
T
LETS
438
1
TC
78
0.177
14
0.03
TT
8
0.02
0
0








MEGA-1
1665
0.9
TC
265
0.19
86
0.05
TT
13
0.01
5
0.003








MEGA-2
2646
0.9
TC
235
0.185
140
0.05
TT
8
0.01
2
7E−04


hCV12066124
F11
rs2036914
C
T
C
LETS
138
0.3
TC
215
0.485
216
0.48
TT
69
0.16
99
0.219








MEGA-1
482
0.3
TC
682
0.49
865
0.49
TT
233
0.17
406
0.232








MEGA-2
744
0.3
TC
602
0.484
1369
0.49
TT
197
0.16
653
0.236


hCV15860433

rs2070006
C
T
T
LETS
161
0.4
TC
211
0.478
217
0.48
TT
95
0.22
72
0.16








MEGA-1
623
0.4
TC
689
0.496
832
0.47
TT
296
0.21
297
0.17








MEGA-2
1042
0.4
TC
603
0.483
1288
0.47
TT
255
0.2
428
0.155


hCV16180170
SERPINC1
rs2227589
C
T
T
LETS
378
0.8
TC
93
0.21
70
0.15
TT
6
0.01
4
0.009








MEGA-1
1457
0.8
TC
259
0.186
283
0.16
TT
22
0.02
15
0.009








MEGA-2
2325
0.8
TC
278
0.215
483
0.17
TT
15
0.01
28
0.01


hCV233148
KT3/SDCCAG
rs1417121
G
C
C
LETS
247
0.5
CG
202
0.456
174
0.38
CC
50
0.11
32
0.071








MEGA-1
882
0.5
CG
573
0.413
745
0.42
CC
163
0.12
129
0.073








MEGA-2
1458
0.5
CG
494
0.396
1074
0.39
CC
126
0.1
214
0.078


hCV25990131
CYP4V2
rs13146272
A
C
A
LETS
199
0.4
CA
207
0.469
190
0.42
CC
32
0.07
64
0.141








MEGA-1
720
0.4
CA
600
0.429
804
0.46
CC
149
0.11
229
0.131








MEGA-2
1094
0.4
CA
478
0.412
1178
0.45
CC
121
0.1
352
0.134


hCV27474895
F11
rs3756011
C
A
A
LETS
160
0.4
AC
208
0.47
200
0.44
AA
107
0.24
92
0.204








MEGA-1
597
0.3
AC
692
0.502
838
0.48
AA
326
0.24
312
0.179








MEGA-2
1022
0.4
AC
612
0.489
1296
0.47
AA
297
0.24
451
0.163


hCV27477533
F11
rs3756008
A
T
T
LETS
164
0.4
TA
212
0.48
200
0.44
TT
101
0.23
88
0.195








MEGA-1
623
0.4
TA
691
0.495
832
0.48
TT
307
0.22
296
0.169








MEGA-2
1048
0.4
TA
619
0.496
1283
0.46
TT
282
0.23
434
0.157


hCV8241630
F11
rs925451
G
A
A
LETS
171
0.4
AG
212
0.481
194
0.43
AA
95
0.22
87
0.192








MEGA-1
661
0.4
AG
666
0.49
816
0.47
AA
289
0.21
272
0.156








MEGA-2
1107
0.4
AG
622
0.496
1258
0.45
AA
259
0.21
405
0.146


hCV8717873
GP6/RDH13
rs1613662
A
G
A
LETS
291
0.6
GA
117
0.264
143
0.32
GG
10
0.02
19
0.042








MEGA-1
1135
0.6
GA
368
0.265
553
0.32
GG
45
0.03
61
0.035








MEGA-2
1924
0.7
GA
355
0.273
835
0.29
GG
29
0.02
89
0.031


hCV8726802
F2
rs1799963
G
A
A
LETS
440
1
AG
28
0.063
10
0.02
AA
0
0
0
0








MEGA-1
1715
1
AG
80
0.058
37
0.02
AA
0
0
0
0








MEGA-2
2794
1
AG
76
0.059
55
0.02
AA
0
0
0
0


hCV8919444
F5
rs4524
T
C
T
LETS
251
0.6
CT
130
0.293
169
0.37
CC
24
0.05
32
0.071








MEGA-1
964
0.6
CT
440
0.317
680
0.39
CC
76
0.05
107
0.061








MEGA-2
1502
0.5
CT
415
0.333
1033
0.38
CC
59
0.05
218
0.079


hCV15949414
XYLB
rs2234628
G
A
G
LETS
397
0.9
AG
31
0.07
51
0.11
AA
1
0
0
0








MEGA-1
1580
0.9
AG
89
0.065
172
0.1
AA
5
0
1
6E−04








MEGA-2
2479
0.9
AG
98
0.078
270
0.1
AA
2
0
13
0.005


hCV15968043
CYP4V2
rs2292423
T
A
A
LETS
153
0.3
AT
224
0.506
208
0.46
AA
97
0.22
92
0.203








MEGA-1
604
0.3
AT
698
0.504
839
0.48
AA
292
0.21
300
0.172








MEGA-2
958
0.3
AT
632
0.515
1339
0.49
AA
264
0.22
447
0.163


hCV263841
NR1I2
rs1523127
A
C
C
LETS
205
0.5
CA
191
0.432
196
0.43
CC
91
0.21
52
0.115








MEGA-1
643
0.4
CA
684
0.49
850
0.48
CC
250
0.18
261
0.149








MEGA-2
1097
0.4
CA
598
0.461
1340
0.47
CC
220
0.17
409
0.144


hCV916107
RGS7
rs670659
C
T
C
LETS
192
0.4
TC
185
0.419
200
0.44
TT
41
0.09
61
0.135








MEGA-1
738
0.4
TC
620
0.446
772
0.44
TT
149
0.11
238
0.136








MEGA-2
1153
0.4
TC
615
0.476
1326
0.47
TT
129
0.1
355
0.125


hCV1841975
PROC
rs1799810
A
T
T
LETS
147
0.3
TA
215
0.486
224
0.5
TT
100
0.23
81
0.179








MEGA-1
554
0.3
TA
655
0.472
864
0.49
TT
323
0.23
329
0.188








MEGA-2
918
0.3
TA
654
0.524
1331
0.48
TT
259
0.21
522
0.188


hCV25474413
F11
rs3822057
C
A
C
LETS
124
0.3
AC
214
0.483
213
0.47
AA
91
0.21
116
0.256








MEGA-1
422
0.2
AC
690
0.505
875
0.5
AA
269
0.2
457
0.261








MEGA-2
650
0.2
AC
617
0.492
1363
0.49
AA
247
0.2
761
0.274


hCV2892877
FGA
rs6050
T
C
C
LETS
227
0.5
CT
249
0.562
226
0.5
CC
0
0
0
0








MEGA-1
889
0.5
CT
807
0.581
859
0.49
CC
0
0
0
0








MEGA-2
1348
0.5
CT
554
0.517
1095
0.44
CC
7
0.01
19
0.008


hCV3230038
F11
rs2289252
C
T
T
LETS
158
0.4
TC
204
0.463
200
0.44
TT
107
0.24
93
0.206








MEGA-1
600
0.3
TC
689
0.512
840
0.48
TT
314
0.23
309
0.177








MEGA-2
1026
0.4
TC
618
0.492
1301
0.47
TT
295
0.23
447
0.161


hCV596331
F9
rs6048
A
G
A
LETS
244
0.5
GA
99
0.223
122
0.27
GG
70
0.16
87
0.192








MEGA-1
1037
0.6
GA
295
0.215
347
0.2
GG
233
0.17
355
0.204








MEGA-2
1682
0.6
GA
278
0.214
621
0.22
GG
222
0.17
545
0.191


hCV11786258
KLKB1
rs4253303
G
A
A
LETS
159
0.4
AG
227
0.514
210
0.46
AA
83
0.19
83
0.184








MEGA-1
655
0.4
AG
686
0.493
815
0.47
AA
271
0.19
282
0.161








MEGA-2
1007
0.4
AG
628
0.503
1347
0.49
AA
257
0.21
414
0.15


hCV3230096
CYP4V2
rs3817184
C
T
T
LETS
149
0.3
TC
227
0.514
211
0.47
TT
95
0.21
92
0.204








MEGA-1
600
0.3
TC
680
0.489
831
0.48
TT
301
0.22
309
0.178








MEGA-2
946
0.3
TC
636
0.506
1358
0.49
TT
282
0.22
473
0.17


hCV11541681
NAT8B
rs2001490
G
C
C
LETS
165
0.4
CG
220
0.497
228
0.5
CC
81
0.18
60
0.132








MEGA-1
697
0.4
CG
662
0.476
815
0.46
CC
228
0.16
242
0.138








MEGA-2
1122
0.4
CG
603
0.465
1334
0.47
CC
205
0.16
394
0.138


hCV1859855

text missing or illegible when filed OLGA3/POLtext missing or illegible when filed

rs2291260
T
C
C
LETS
295
0.7
CT
148
0.336
141
0.31
CC
24
0.05
17
0.038








MEGA-1
1052
0.6
CT
485
0.351
627
0.36
CC
99
0.07
71
0.041








MEGA-2
1705
0.6
CT
469
0.364
978
0.35
CC
76
0.06
122
0.043


hCV1874482
ZDHHC6
rs2306158
G
A
G
LETS
171
0.4
AG
187
0.428
200
0.45
AA
53
0.12
78
0.174








MEGA-1
692
0.4
AG
641
0.465
833
0.48
AA
167
0.12
214
0.123








MEGA-2
921
0.4
AG
485
0.448
891
0.42
AA
135
0.12
323
0.151


hCV15793897
KLKB1
rs3087505
G
A
G
LETS
363
0.8
AG
71
0.161
85
0.19
AA
1
0
3
0.007








MEGA-1
1379
0.8
AG
246
0.177
353
0.2
AA
5
0
22
0.013








MEGA-2
2206
0.8
AG
193
0.154
506
0.18
AA
11
0.01
54
0.02


hCV15871021
EBF1
rs2072495
G
A
G
LETS
149
0.3
AG
191
0.432
238
0.53
AA
70
0.16
66
0.146








MEGA-1
643
0.4
AG
699
0.502
834
0.48
AA
168
0.12
269
0.154








MEGA-2
1004
0.4
AG
592
0.471
1347
0.49
AA
174
0.14
421
0.152


hCV22272267
KLKB1
rs3733402
A
G
A
LETS
135
0.3
GA
210
0.475
226
0.5
GG
90
0.2
91
0.201








MEGA-1
437
0.2
GA
692
0.498
912
0.52
GG
254
0.18
403
0.23








MEGA-2
741
0.3
GA
638
0.515
1361
0.49
GG
212
0.17
653
0.237


hCV2303891
APOH
rs1801690
C
G
C
LETS
404
0.9
GC
28
0.064
44
0.1
GG
0
0
1
0.002








MEGA-1
1559
0.9
GC
106
0.076
192
0.11
GG
4
0
4
0.002








MEGA-2
2464
0.9
GC
109
0.087
289
0.1
GG
4
0
2
7E−04


hCV25620145
PROCR
rs867186
A
G
G
LETS
347
0.8
GA
113
0.255
96
0.21
GG
10
0.02
8
0.018








MEGA-1
1354
0.8
GA
340
0.245
373
0.21
GG
30
0.02
28
0.016








MEGA-2
2160
0.8
GA
310
0.239
637
0.22
GG
27
0.02
38
0.013


hCV8827309
SUMF1
rs1110796
C
T
T
LETS
364
0.8
TC
107
0.244
83
0.18
TT
11
0.03
5
0.011








MEGA-1
1335
0.8
TC
339
0.245
368
0.21
TT
21
0.02
24
0.014








MEGA-2
2103
0.8
TC
266
0.214
591
0.22
TT
32
0.03
47
0.017


hCV8957432
RAC2
rs6572
G
C
C
LETS
126
0.3
CG
225
0.51
249
0.55
CC
99
0.22
77
0.17








MEGA-1
557
0.3
CG
676
0.487
862
0.49
CC
308
0.22
334
0.191








MEGA-2
882
0.3
CG
665
0.512
1380
0.48
CC
265
0.2
587
0.206


hCV2086329
SPARC
rs4958487
A
G
A
MEGA-2
870
0.3
GA
641
0.51
1341
0.48
GG
221
0.18
564
0.203







G
LETS
150
0.3
GA
205
0.463
227
0.5
GG
104
0.23
76
0.168








MEGA-1
570
0.3
GA
631
0.456
887
0.51
GG
298
0.22
296
0.169


hCV25768636

text missing or illegible when filed CDC36/USP1

rs4279134
G
A
A
LETS
204
0.5
AG
197
0.446
199
0.44
AA
68
0.15
48
0.106








MEGA-1
739
0.4
AG
639
0.461
821
0.47
AA
188
0.14
194
0.111







G
MEGA-2
1171
0.4
AG
535
0.426
1223
0.44
AA
140
0.11
372
0.134


hCV29821005
LOC728284
rs6552970
C
T
C
MEGA-2
1919
0.7
TC
220
0.188
635
0.24
TT
38
0.03
90
0.034







T
LETS
284
0.6
TC
170
0.386
147
0.33
TT
20
0.05
19
0.042








MEGA-1
1149
0.7
TC
463
0.344
528
0.3
TT
62
0.05
77
0.044


hCV31199195
KCTD10
rs10850234
A
C
A
MEGA-2
1905
0.7
CA
321
0.257
778
0.28
CC
33
0.03
81
0.029







C
LETS
328
0.7
CA
142
0.321
111
0.25
CC
12
0.03
14
0.031








MEGA-1
1214
0.7
CA
423
0.305
486
0.28
CC
52
0.04
52
0.03


hCV11975651
SERPINC1
rs677
C
G
C
LETS
363
0.8
GC
96
0.218
77
0.17
GG
3
0.01
11
0.024







C
MEGA-2
2115
0.8
GC
252
0.201
620
0.22
GG
13
0.01
42
0.015







G
LETS
363
0.8
GC
96
0.218
77
0.17
GG
3
0.01
11
0.024






text missing or illegible when filed indicates data missing or illegible when filed














TABLE 25





Age- and sex-adjusted association of 52 SNPs with isolated PE in MEGA (p <= 0.05)
































Gene


NonRef
Risk
Control







Case

Control-


Marker
Symbol
RS number
RefAllele
Allele
Allele
RAF
Model
Parameter
P-value
OddsRatio
OR95l
OR95u
Genot
Count3
CaseFreq3
Count3





hCV11503414
FGG
rs2066865
G
A
A
0.265941
general
hCV11503414.AA
7.9E−07
1.7644
1.40836
2.21043
GG
548
0.4656
2426









recessive
hCV11503414.AA.rec
2.65E−05
1.5897
1.28058
1.97356
GG
548
0.4656
2426









dominant
hCV11503414.GG.dom
9.06E−06
1.3387
1.17692
1.5228
GG
548
0.4656
2426









additive
hCV11503414.AA.AG.adtv
1.38E−07
1.3027
1.18064
1.43736
GG
548
0.4656
2426









general
hCV11503414.AG
0.000825
1.2612
1.1008
1.44487
GG
548
0.4656
2426


hCV11503469
FGG
rs2066854
T
A
A
0.266985
general
hCV11503469.AA
2.7E−06
1.7154
1.36923
2.14908
TT
551
0.4677
2423









recessive
hCV11503469.AA.rec
6.76E−05
1.5525
1.25045
1.92746
TT
551
0.4677
2423









dominant
hCV11503469.TT.dom
2.15E−05
1.3219
1.16224
1.50354
TT
551
0.4677
2423









additive
hCV11503469.AA.AT.adtv
  5E−07
1.2867
1.16622
1.41954
TT
551
0.4677
2423









general
hCV11503469.AT
0.001332
1.2492
1.09047
1.43109
TT
551
0.4677
2423


hCV11503470

rs1800788
C
T
T
0.208112
general
hCV11503470.TC
0.003347
1.2266
1.07016
1.40596
CC
693
0.5868
2864









dominant
hCV11503470.CC.dom
0.003532
1.2149
1.06597
1.38472
CC
693
0.5868
2864









additive
hCV11503470.TT.TC.adtv
0.010682
1.1492
1.03283
1.2787
CC
693
0.5868
2864


hCV11786258
KLKB1
rs4253303
G
A
A
0.393142
general
hCV11786258.AA
0.041072
1.2175
1.00801
1.47061
GG
410
0.348
1662









recessive
hCV11786258.AA.rec
0.048475
1.1868
1.00115
1.40687
GG
410
0.348
1662


hCV11975250
F5
rs6025
C
T
T
0.026408
dominant
hCV11975250.CC.dom
9.91E−08
1.9003
1.50059
2.4065
CC
1084
0.9071
4311









general
hCV11975250.TC
2.06E−07
1.8887
1.48577
2.40092
CC
1084
0.9071
4311









additive
hCV11975250.TT.TC.adtv
1.25E−07
1.8329
1.46414
2.29465
CC
1084
0.9071
4311


hCV1202883
MTHFR
rs1801133
G
A
G
0.69837
general
hCV1202883.AA
0.025299
0.7168
0.53542
0.95963
GG
582
0.4818
2132









recessive
hCV1202883.AA.rec
0.031062
0.7312
0.55017
0.97191
GG
582
0.4818
2132


hCV12066124
F11
rs2036914
C
T
C
0.518478
general
hCV12066124.TT
0.00048
0.7255
0.6059
0.8687
CC
389
0.3316
1226









dominant
hCV12066124.CC.dom
4.11E−05
0.7487
0.65205
0.85979
CC
389
0.3316
1226









general
hCV12066124.TC
0.000273
0.7598
0.65525
0.88093
CC
389
0.3316
1226









additive
hCV12066124.TT.TC.adtv
0.000208
0.8423
0.76928
0.92226
CC
389
0.3316
1226


hCV12092542
CASP5
rs507879
T
C
T
0.548201
recessive
hCV12092542.CC.rec
0.006664
0.7876
0.66284
0.93587
TT
353
0.3046
1170









general
hCV12092542.CC
0.03597
0.8101
0.66544
0.98631
TT
353
0.3046
1170


hCV15860433

rs2070006
C
T
T
0.395787
general
hCV15860433.TT
0.001749
1.3524
1.11945
1.63385
CC
369
0.314
1665









dominant
hCV15860433.CC.dom
0.0005
1.2764
1.11253
1.46444
CC
369
0.314
1665









general
hCV15860433.TC
0.002575
1.2504
1.08131
1.44596
CC
369
0.314
1665









recessive
hCV15860433.TT.rec
0.045925
1.1859
1.00309
1.40199
CC
369
0.314
1665









additive
hCV15860433.TT.TC.adtv
0.000548
1.1753
1.07241
1.28797
CC
369
0.314
1665


hCV15949414
XYLB
rs2234628
G
A
G
0.947951
general
hCV15949414.AG
0.01515
0.744
0.58608
0.94452
GG
1087
0.9204
4059









dominant
hCV15949414.GG.dom
0.027067
0.7696
0.6102
0.97075
GG
1087
0.9204
4059


hCV15968043
CYP4V2
rs2292423
T
A
A
0.409182
general
hCV15968043.AA
0.036009
1.2214
1.01314
1.47241
TT
383
0.329
1562









recessive
hCV15968043.AA.rec
0.040079
1.1899
1.0079
1.40466
TT
383
0.329
1562


hCV16180170
SERPINC1
rs2227589
C
T
T
0.09279
general
hCV16180170.TT
0.024575
1.8494
1.08198
3.16127
CC
941
0.7842
3782









recessive
hCV16180170.TT.rec
0.035841
1.7737
1.03862
3.02895
CC
941
0.7842
3782









dominant
hCV16180170.CC.dom
0.001751
1.2856
1.09842
1.5046
CC
941
0.7842
3782









additive
hCV16180170.TT.TC.adtv
0.000708
1.2794
1.10936
1.47544
CC
941
0.7842
3782









general
hCV16180170.TC
0.006258
1.2536
1.06609
1.4742
CC
941
0.7842
3782


hCV1842260
LOC642043
rs2281390
G
T
T
0.171422
general
hCV1842260.TG
0.02393
1.1745
1.02147
1.35049
GG
796
0.6589
3177









dominant
hCV1842260.GG.dom
0.03773
1.1535
1.00813
1.31976
GG
796
0.6589
3177


hCV1859855
GOLGA3/
rs2291260
T
C
C
0.218551
recessive
hCV1859855.CC.rec
0.000395
1.6269
1.24298
2.12951
TT
742
0.622
2757



POLE





general
hCV1859855.CC
0.001859
1.5434
1.17426
2.02848
TT
742
0.622
2757







T
0.781449
general
hCV1859855.CT
0.034049
0.8603
0.74856
0.98874
TT
742
0.622
2757


hCV2103346
DKFZP564J102
rs11733307
T
C
C
0.441711
additive
hCV2103346.CC.CT.adtv
0.043311
1.0967
1.00278
1.19951
TT
343
0.2917
1450


hCV22272267
KLKB1
rs3733402
A
G
A
0.513535
general
hCV22272267.GA
3.14E−05
0.7277
0.62658
0.84518
AA
378
0.3206
1178









dominant
hCV22272267.AA.dom
4.55E−05
0.7483
0.65098
0.86023
AA
378
0.3206
1178









general
hCV22272267.GG
0.010202
0.7927
0.66394
0.94642
AA
378
0.3206
1178









additive
hCV22272267.GG.GA.adtv
0.004727
0.8775
0.80143
0.96077
AA
378
0.3206
1178


hCV233148
AKT3/SDCCAG8
rs1417121
G
C
C
0.27821
general
hCV233148.CC
0.027568
1.2973
1.02917
1.6352
GG
585
0.497
2340









recessive
hCV233148.CC.rec
0.036974
1.2684
1.01448
1.58595
GG
585
0.497
2340


hCV25474413
F11
rs3822057
A
C
C
0.483878
general
hCV25474413.CC
0.000165
1.4124
1.18018
1.6902
AA
273
0.2312
1218









recessive
hCV25474413.CC.rec
0.000395
1.2968
1.12318
1.49737
AA
273
0.2312
1218









dominant
hCV25474413.AA.dom
0.007883
1.2264
1.055
1.42566
AA
273
0.2312
1218









additive
hCV25474413.CC.CA.adtv
0.000155
1.1902
1.08754
1.30266
AA
273
0.2312
1218


hCV25615302
CUEDC1
rs17762338
C
T
T
0.178556
general
hCV25615302.TC
0.01558
1.1856
1.03281
1.36102
CC
774
0.645
3107









dominant
hCV25615302.CC.dom
0.032234
1.1572
1.01246
1.32268
CC
774
0.645
3107


hCV25620145
PROCR
rs867186
A
G
G
0.124401
additive
hCV25620145.GG.GA.adtv
0.013407
1.179
1.03473
1.34333
AA
884
0.7354
3514









dominant
hCV25620145.AA.dom
0.026984
1.1783
1.01886
1.36277
AA
884
0.7354
3514


hCV25748719
NAP5
NONE
C
T
C
0.7673
general
hCV25748719.TT
0.033944
0.705
0.51043
0.97385
CC
738
0.6165
2693









additive
hCV25748719.TT.TC.adtv
0.021016
0.8782
0.78644
0.98061
CC
738
0.6165
2693


hCV25768636
CCDC36/
rs4279134
G
A
G
0.648673
recessive
hCV25768636.AA.rec
0.032703
0.7973
0.64757
0.98153
GG
502
0.4265
1910



USP19


hCV2590858
ADCY9
rs2230738
C
T
C
0.733461
general
hCV2590858.TT
0.022606
0.7254
0.55052
0.95594
CC
654
0.5566
2418









recessive
hCV2590858.TT.rec
0.020267
0.726
0.55407
0.95138
CC
654
0.5566
2418


hCV25990131
CYP4V2
rs13146272
A
C
A
0.64085
general
hCV25990131.CC
0.009124
0.7483
0.60174
0.93053
AA
515
0.4522
1814









recessive
hCV25990131.CC.rec
0.029035
0.7944
0.64605
0.97675
AA
515
0.4522
1814









dominant
hCV25990131.AA.dom
0.021499
0.8571
0.7516
0.97752
AA
515
0.4522
1814









additive
hCV25990131.CC.CA.adtv
0.006142
0.8728
0.79182
0.962
AA
515
0.4522
1814


hCV26175114
TUBA4A
rs3731892
A
G
G
0.108496
recessive
hCV26175114.GG.rec
0.010391
1.6966
1.13236
2.54198
AA
936
0.7939
3655









general
hCV26175114.GG
0.011269
1.6893
1.12616
2.53402
AA
936
0.7939
3655


hCV27474895
F11
rs3756011
C
A
A
0.405226
general
hCV27474895.AA
 1.4E−05
1.5002
1.24929
1.80148
CC
357
0.3036
1619









recessive
hCV27474895.AA.rec
0.000287
1.344
1.14551
1.57678
CC
357
0.3036
1619









dominant
hCV27474895.CC.dom
0.000437
1.2822
1.11632
1.47271
CC
357
0.3036
1619









additive
hCV27474895.AA.AC.adtv
1.39E−05
1.2226
1.11666
1.33868
CC
357
0.3036
1619









general
hCV27474895.AC
0.013465
1.2044
1.03922
1.3958
CC
357
0.3036
1619


hCV27474984
PIK3R1
rs3756668
G
A
A
0.448895
general
hCV27474984.AA
0.003924
1.3009
1.08794
1.55547
GG
329
0.2769
1416









recessive
hCV27474984.AA.rec
0.013232
1.2106
1.04073
1.40818
GG
329
0.2769
1416









dominant
hCV27474984.GG.dom
0.024908
1.1763
1.02069
1.35558
GG
329
0.2769
1416









additive
hCV27474984.AA.AG.adtv
0.004131
1.1397
1.04227
1.24624
GG
329
0.2769
1416


hCV27477533
F11
rs3756008
A
T
T
0.395815
general
hCV27477533.TT
5.37E−05
1.4656
1.21747
1.76441
AA
369
0.3132
1671









recessive
hCV27477533.TT.rec
0.00183
1.2972
1.10137
1.52774
AA
369
0.3132
1671









dominant
hCV27477533.AA.dom
0.000252
1.2923
1.12649
1.48254
AA
369
0.3132
1671









general
hCV27477533.TA
0.004944
1.2326
1.06535
1.42618
AA
369
0.3132
1671









additive
hCV27477533.TT.TA.adtv
3.06E−05
1.2135
1.10796
1.32902
AA
369
0.3132
1671


hCV27902808
CYP4V2
rs4253236
C
T
C
0.636333
general
hCV27902808.TT
0.037699
0.8022
0.65157
0.98755
CC
529
0.4494
1838









dominant
hCV27902808.CC.dom
0.007416
0.838
0.73623
0.95372
CC
529
0.4494
1838









general
hCV27902808.TC
0.01876
0.8484
0.73967
0.97306
CC
529
0.4494
1838









additive
hCV27902808.TT.TC.adtv
0.009101
0.8808
0.80074
0.96896
CC
529
0.4494
1838


hCV2892877
FGA
rs6050
T
C
C
0.23658
dominant
hCV2892877.TT.dom
2.84E−05
1.3303
1.16388
1.52044
TT
503
0.4594
2237









general
hCV2892877.CT
3.74E−05
1.3257
1.15939
1.51579
TT
503
0.4594
2237









additive
hCV2892877.CC.CT.adtv
2.16E−05
1.3265
1.16435
1.51125
TT
503
0.4594
2237


hCV2915511
OBSL1/STK11IP
rs627530
T
C
C
0.036056
general
hCV2915511.CC
0.018869
2.8308
1.18768
6.74695
TT
1103
0.9154
4284









recessive
hCV2915511.CC.rec
0.020235
2.7975
1.17396
6.66633
TT
1103
0.9154
4284









additive
hCV2915511.CC.CT.adtv
0.027831
1.2706
1.02644
1.57275
TT
1103
0.9154
4284


hCV29821005
LOC728284
rs6552970
C
T
C
0.829809
general
hCV29821005.TC
0.013769
0.8228
0.70448
0.96093
CC
827
0.7267
3068


hCV30562347
F11
rs4253418
G
A
G
0.956444
general
hCV30562347.AG
0.04875
0.7731
0.59856
0.99859
GG
1098
0.9313
4119


hCV3180954
PTCRA
rs9471966
G
A
G
0.734992
general
hCV3180954.AA
0.043289
0.7611
0.58411
0.9918
GG
685
0.5689
2507


hCV32291301
KLKB1
rs4253302
A
G
A
0.837091
general
hCV32291301.GA
5.63E−05
0.727
0.62248
0.84899
AA
893
0.7568
3177









dominant
hCV32291301.AA.dom
0.000204
0.756
0.65222
0.87625
AA
893
0.7568
3177









additive
hCV32291301.GG.GA.adtv
0.00251
0.8204
0.72152
0.93278
AA
893
0.7568
3177


hCV3230038
F11
rs2289252
C
T
T
0.403825
general
hCV3230038.TT
5.16E−06
1.5316
1.27506
1.83965
CC
355
0.3014
1626









recessive
hCV3230038.TT.rec
0.000163
1.3601
1.15911
1.59587
CC
355
0.3014
1626









dominant
hCV3230038.CC.dom
0.000187
1.3025
1.13389
1.49618
CC
355
0.3014
1626









additive
hCV3230038.TT.TC.adtv
 4.8E−06
1.2359
1.12865
1.3533
CC
355
0.3014
1626









general
hCV3230038.TC
0.007754
1.2218
1.05429
1.41601
CC
355
0.3014
1626


hCV3230096
CYP4V2
rs3817184
C
T
T
0.415431
general
hCV3230096.TT
0.021851
1.2411
1.03187
1.49283
CC
374
0.3175
1546









recessive
hCV3230096.TT.rec
0.036521
1.1894
1.01093
1.39932
CC
374
0.3175
1546









additive
hCV3230096.TT.TC.adtv
0.026457
1.109
1.01216
1.215
CC
374
0.3175
1546


hCV3230113
CYP4V2
rs1053094
A
T
T
0.490487
recessive
hCV3230113.TT.rec
0.007751
1.2185
1.05354
1.40928
AA
286
0.2436
1158









general
hCV3230113.TT
0.030129
1.22
1.0193
1.46022
AA
286
0.2436
1158









additive
hCV3230113.TT.TA.adtv
0.029142
1.1067
1.01035
1.21226
AA
286
0.2436
1158


hCV3272537
TIAM1
rs497689
T
A
A
0.442161
general
hCV3272537.AT
0.003248
1.2507
1.07759
1.45156
TT
330
0.2782
1449









dominant
hCV3272537.TT.dom
0.012334
1.1982
1.03998
1.38055
TT
330
0.2782
1449


hCV540410
LASP1
rs609529
T
A
A
0.063164
general
hCV540410.AA
0.007939
2.6467
1.29008
5.42985
TT
1037
0.8649
3967









recessive
hCV540410.AA.rec
0.008389
2.6271
1.28109
5.38731
TT
1037
0.8649
3967


hCV596331
F9
rs6048
A
G
A
0.698278
general
hCV596331.GG
0.005303
0.7741
0.64659
0.92677
AA
759
0.6309
2719









recessive
hCV596331.GG.rec
0.011347
0.7941
0.66432
0.94926
AA
759
0.6309
2719









dominant
hCV596331.AA.dom
0.001786
0.8083
0.70723
0.92377
AA
759
0.6309
2719









additive
hCV596331.GG.GA.adtv
0.001633
0.8731
0.80244
0.95003
AA
759
0.6309
2719


hCV7422466
C9orf103
rs1052690
A
C
A
0.803646
general
hCV7422466.CA
0.001726
0.7929
0.68582
0.91676
AA
815
0.6901
2630









dominant
hCV7422466.AA.dom
0.002711
0.8083
0.70328
0.92892
AA
815
0.6901
2630









additive
hCV7422466.CC.CA.adtv
0.011048
0.8557
0.75881
0.96499
AA
815
0.6901
2630


hCV7581501
USP45
rs1323717
G
C
G
0.879567
general
hCV7581501.CG
0.043619
0.8471
0.72094
0.99526
GG
956
0.796
3528


hCV7625318
PLEKHG4
rs3868142
G
A
A
0.084256
general
hCV7625318.AA
0.002718
2.0943
1.29169
3.39574
GG
992
0.8267
3877









recessive
hCV7625318.AA.rec
0.002865
2.0835
1.28604
3.37549
GG
992
0.8267
3877


hCV8241630
F11
rs925451
G
A
A
0.379287
general
hCV8241630.AA
3.67E−05
1.4822
1.22955
1.78668
GG
394
0.3333
1768









recessive
hCV8241630.AA.rec
0.001099
1.3212
1.11769
1.56172
GG
394
0.3333
1768









dominant
hCV8241630.GG.dom
0.00023
1.2889
1.12609
1.4753
GG
394
0.3333
1768









general
hCV8241630.AG
0.005449
1.2259
1.06187
1.41517
GG
394
0.3333
1768









additive
hCV8241630.AA.AG.adtv
2.03E−05
1.2188
1.11277
1.33486
GG
394
0.3333
1768


hCV8361354
PANX1
rs1138800
C
A
A
0.374456
recessive
hCV8361354.AA.rec
0.011342
1.254
1.05247
1.49423
CC
464
0.3863
1774









general
hCV8361354.AA
0.046424
1.2139
1.00308
1.46897
CC
464
0.3863
1774


hCV8717873
GP6/RDH13
rs1613662
A
G
A
0.816402
dominant
hCV8717873.AA.dom
0.00637
0.8245
0.71782
0.94713
AA
849
0.7063
3059









general
hCV8717873.GA
0.011484
0.8311
0.72009
0.95931
AA
849
0.7063
3059









additive
hCV8717873.GG.GA.adtv
0.006619
0.845
0.74824
0.95422
AA
849
0.7063
3059


hCV8726802
F2
rs1799963
G
A
A
0.009998
additive
hCV8726802.AA.AG.adtv
0.001832
1.7876
1.24051
2.57599
GG
1154
0.9649
4509









dominant
hCV8726802.GG.dom
0.002881
1.7586
1.21319
2.54921
GG
1154
0.9649
4509









general
hCV8726802.AG
0.004755
1.7145
1.17921
2.49277
GG
1154
0.9649
4509


hCV8911768
SERPINC1
rs941988
C
T
T
0.095461
additive
hCV8911768.TT.TC.adtv
0.045997
1.2308
1.0037
1.50923
CC
432
0.7869
2274


hCV8919444
F5
rs4524
T
C
T
0.737678
general
hCV8919444.CC
0.00142
0.6217
0.46423
0.83249
TT
703
0.5993
2466









recessive
hCV8919444.CC.rec
0.005126
0.6634
0.49765
0.88423
TT
703
0.5993
2466









dominant
hCV8919444.TT.dom
0.001654
0.8105
0.71104
0.92383
TT
703
0.5993
2466









additive
hCV8919444.CC.CT.adtv
0.000259
0.8188
0.73558
0.91152
TT
703
0.5993
2466









general
hCV8919444.CT
0.016842
0.8466
0.73854
0.97047
TT
703
0.5993
2466


hCV9102827
GPATCH4
rs3795733
T
C
C
0.258025
general
hCV9102827.CC
0.038395
1.2746
1.01305
1.6037
TT
614
0.5217
2331









dominant
hCV9102827.TT.dom
0.0061
1.1997
1.05332
1.36641
TT
614
0.5217
2331









general
hCV9102827.CT
0.018086
1.1819
1.02896
1.35755
TT
614
0.5217
2331









additive
hCV9102827.CC.CT.adtv
0.005678
1.1485
1.04116
1.26683
TT
614
0.5217
2331


hDV70683382
RABGAP1L
rs16846815
G
C
C
0.061982
general
hDV70683382.CC
0.040966
3.2342
1.04937
9.96795
GG
468
0.854
2439









recessive
hDV70683382.CC.rec
0.044861
3.1627
1.02675
9.74207
GG
468
0.854
2439





























Gene


NonRef
Risk
Control

Control-

Case
Case-
Control-
Control-

Case

Control-
Control-


Marker
Symbol
RS number
RefAllele
Allele
Allele
RAF
Model
Freq3
Genot2
Count4
Freq4
Count4
Freq4
Genot3
Count5
CaseFreq5
Count5
Freq5





hCV11503414
FGG
rs2066865
G
A
A
0.265941
general
0.539
AG
501
0.426
1756
0.3901
AA
128
0.1088
319
0.071









recessive
0.539
AG
501
0.426
1756
0.3901
AA
128
0.1088
319
0.071









dominant
0.539
AG
501
0.426
1756
0.3901
AA
128
0.1088
319
0.071









additive
0.539
AG
501
0.426
1756
0.3901
AA
128
0.1088
319
0.071









general
0.539
AG
501
0.426
1756
0.3901
AA
128
0.1088
319
0.071


hCV11503469
FGG
rs2066854
T
A
A
0.266985
general
0.538
AT
500
0.424
1757
0.3901
AA
127
0.1078
324
0.072









recessive
0.538
AT
500
0.424
1757
0.3901
AA
127
0.1078
324
0.072









dominant
0.538
AT
500
0.424
1757
0.3901
AA
127
0.1078
324
0.072









additive
0.538
AT
500
0.424
1757
0.3901
AA
127
0.1078
324
0.072









general
0.538
AT
500
0.424
1757
0.3901
AA
127
0.1078
324
0.072


hCV11503470

rs1800788
C
T
T
0.208112
general
0.6331
TC
426
0.361
1437
0.3176
TT
62
0.0525
223
0.049









dominant
0.6331
TC
426
0.361
1437
0.3176
TT
62
0.0525
223
0.049









additive
0.6331
TC
426
0.361
1437
0.3176
TT
62
0.0525
223
0.049


hCV11786258
KLKB1
rs4253303
G
A
A
0.393142
general
0.3677
AG
559
0.475
2162
0.4783
AA
209
0.1774
696
0.154









recessive
0.3677
AG
559
0.475
2162
0.4783
AA
209
0.1774
696
0.154


hCV11975250
F5
rs6025
C
T
T
0.026408
dominant
0.9487
TC
107
0.09
226
0.0497
TT
4
0.0033
7
0.002









general
0.9487
TC
107
0.09
226
0.0497
TT
4
0.0033
7
0.002









additive
0.9487
TC
107
0.09
226
0.0497
TT
4
0.0033
7
0.002


hCV1202883
MTHFR
rs1801133
G
A
G
0.69837
general
0.4635
AG
566
0.469
2161
0.4698
AA
60
0.0497
307
0.067









recessive
0.4635
AG
566
0.469
2161
0.4698
AA
60
0.0497
307
0.067


hCV12066124
F11
rs2036914
C
T
C
0.518478
general
0.2713
TC
540
0.46
2234
0.4944
TT
244
0.208
1059
0.234









dominant
0.2713
TC
540
0.46
2234
0.4944
TT
244
0.208
1059
0.234









general
0.2713
TC
540
0.46
2234
0.4944
TT
244
0.208
1059
0.234









additive
0.2713
TC
540
0.46
2234
0.4944
TT
244
0.208
1059
0.234


hCV12092542
CASP5
rs507879
T
C
T
0.548201
recessive
0.3008
CT
610
0.526
1925
0.4949
CC
196
0.1691
795
0.204









general
0.3008
CT
610
0.526
1925
0.4949
CC
196
0.1691
795
0.204


hCV15860433

rs2070006
C
T
T
0.395787
general
0.3692
TC
588
0.5
2120
0.4701
TT
218
0.1855
725
0.161









dominant
0.3692
TC
588
0.5
2120
0.4701
TT
218
0.1855
725
0.161









general
0.3692
TC
588
0.5
2120
0.4701
TT
218
0.1855
725
0.161









recessive
0.3692
TC
588
0.5
2120
0.4701
TT
218
0.1855
725
0.161









additive
0.3692
TC
588
0.5
2120
0.4701
TT
218
0.1855
725
0.161


hCV15949414
XYLB
rs2234628
G
A
G
0.947951
general
0.899
AG
88
0.075
442
0.0979
AA
6
0.0051
14
0.003









dominant
0.899
AG
88
0.075
442
0.0979
AA
6
0.0051
14
0.003


hCV15968043
CYP4V2
rs2292423
T
A
A
0.409182
general
0.3481
AT
558
0.479
2178
0.4854
AA
223
0.1916
747
0.166









recessive
0.3481
AT
558
0.479
2178
0.4854
AA
223
0.1916
747
0.166


hCV16180170
SERPINC1
rs2227589
C
T
T
0.09279
general
0.8238
TC
239
0.199
766
0.1668
TT
20
0.0167
43
0.009









recessive
0.8238
TC
239
0.199
766
0.1668
TT
20
0.0167
43
0.009









dominant
0.8238
TC
239
0.199
766
0.1668
TT
20
0.0167
43
0.009









additive
0.8238
TC
239
0.199
766
0.1668
TT
20
0.0167
43
0.009









general
0.8238
TC
239
0.199
766
0.1668
TT
20
0.0167
43
0.009


hCV1842260
LOC642043
rs2281390
G
T
T
0.171422
general
0.692
TG
372
0.308
1254
0.2731
TT
40
0.0331
160
0.035









dominant
0.692
TG
372
0.308
1254
0.2731
TT
40
0.0331
160
0.035


hCV1859855
GOLGA3/
rs2291260
T
C
C
0.218551
recessive
0.6053
CT
371
0.311
1605
0.3524
CC
80
0.0671
193
0.042



POLE





general
0.6053
CT
371
0.311
1605
0.3524
CC
80
0.0671
193
0.042







T
0.781449
general
0.6053
CT
371
0.311
1605
0.3524
CC
80
0.0671
193
0.042


hCV2103346
DKFZP564J102
rs11733307
T
C
C
0.441711
additive
0.3214
CT
571
0.486
2138
0.4738
CC
262
0.2228
924
0.205


hCV22272267
KLKB1
rs3733402
A
G
A
0.513535
general
0.2614
GA
532
0.451
2273
0.5043
GG
269
0.2282
1056
0.234









dominant
0.2614
GA
532
0.451
2273
0.5043
GG
269
0.2282
1056
0.234









general
0.2614
GA
532
0.451
2273
0.5043
GG
269
0.2282
1056
0.234









additive
0.2614
GA
532
0.451
2273
0.5043
GG
269
0.2282
1056
0.234


hCV233148
AKT3/SDCCAG8
rs1417121
G
C
C
0.27821
general
0.5198
CG
479
0.407
1819
0.404
CC
113
0.096
343
0.076









recessive
0.5198
CG
479
0.407
1819
0.404
CC
113
0.096
343
0.076


hCV25474413
F11
rs3822057
A
C
C
0.483878
general
0.269
CA
570
0.483
2238
0.4943
CC
338
0.2862
1072
0.237









recessive
0.269
CA
570
0.483
2238
0.4943
CC
338
0.2862
1072
0.237









dominant
0.269
CA
570
0.483
2238
0.4943
CC
338
0.2862
1072
0.237









additive
0.269
CA
570
0.483
2238
0.4943
CC
338
0.2862
1072
0.237


hCV25615302
CUEDC1
rs17762338
C
T
T
0.178556
general
0.6778
TC
389
0.324
1317
0.2873
TT
37
0.0308
160
0.035









dominant
0.6778
TC
389
0.324
1317
0.2873
TT
37
0.0308
160
0.035


hCV25620145
PROCR
rs867186
A
G
G
0.124401
additive
0.7656
GA
292
0.243
1010
0.22
GG
26
0.0216
66
0.014









dominant
0.7656
GA
292
0.243
1010
0.22
GG
26
0.0216
66
0.014


hCV25748719
NAP5
NONE
C
T
C
0.7673
general
0.5879
TC
412
0.344
1644
0.3589
TT
47
0.0393
244
0.053









additive
0.5879
TC
412
0.344
1644
0.3589
TT
47
0.0393
244
0.053


hCV25768636
CCDC36/
rs4279134
G
A
G
0.648673
recessive
0.4226
AG
554
0.471
2044
0.4522
AA
121
0.1028
566
0.125



USP19


hCV2590858
ADCY9
rs2230738
C
T
C
0.733461
general
0.5441
TC
454
0.386
1683
0.3787
TT
67
0.057
343
0.077









recessive
0.5441
TC
454
0.386
1683
0.3787
TT
67
0.057
343
0.077


hCV25990131
CYP4V2
rs13146272
A
C
A
0.64085
general
0.4144
CA
501
0.44
1982
0.4528
CC
123
0.108
581
0.133









recessive
0.4144
CA
501
0.44
1982
0.4528
CC
123
0.108
581
0.133









dominant
0.4144
CA
501
0.44
1982
0.4528
CC
123
0.108
581
0.133









additive
0.4144
CA
501
0.44
1982
0.4528
CC
123
0.108
581
0.133


hCV26175114
TUBA4A
rs3731892
A
G
G
0.108496
recessive
0.8003
GA
208
0.176
833
0.1824
GG
35
0.0297
79
0.017









general
0.8003
GA
208
0.176
833
0.1824
GG
35
0.0297
79
0.017


hCV27474895
F11
rs3756011
C
A
A
0.405226
general
0.3585
AC
567
0.482
2134
0.4725
AA
252
0.2143
763
0.169









recessive
0.3585
AC
567
0.482
2134
0.4725
AA
252
0.2143
763
0.169









dominant
0.3585
AC
567
0.482
2134
0.4725
AA
252
0.2143
763
0.169









additive
0.3585
AC
567
0.482
2134
0.4725
AA
252
0.2143
763
0.169









general
0.3585
AC
567
0.482
2134
0.4725
AA
252
0.2143
763
0.169


hCV27474984
PIK3R1
rs3756668
G
A
A
0.448895
general
0.3099
AG
573
0.482
2204
0.4824
AA
286
0.2407
949
0.208









recessive
0.3099
AG
573
0.482
2204
0.4824
AA
286
0.2407
949
0.208









dominant
0.3099
AG
573
0.482
2204
0.4824
AA
286
0.2407
949
0.208









additive
0.3099
AG
573
0.482
2204
0.4824
AA
286
0.2407
949
0.208


hCV27477533
F11
rs3756008
A
T
T
0.395815
general
0.37
TA
574
0.487
2115
0.4683
TT
235
0.1995
730
0.162









recessive
0.37
TA
574
0.487
2115
0.4683
TT
235
0.1995
730
0.162









dominant
0.37
TA
574
0.487
2115
0.4683
TT
235
0.1995
730
0.162









general
0.37
TA
574
0.487
2115
0.4683
TT
235
0.1995
730
0.162









additive
0.37
TA
574
0.487
2115
0.4683
TT
235
0.1995
730
0.162


hCV27902808
CYP4V2
rs4253236
C
T
C
0.636333
general
0.4065
TC
508
0.432
2079
0.4598
TT
140
0.1189
605
0.134









dominant
0.4065
TC
508
0.432
2079
0.4598
TT
140
0.1189
605
0.134









general
0.4065
TC
508
0.432
2079
0.4598
TT
140
0.1189
605
0.134









additive
0.4065
TC
508
0.432
2079
0.4598
TT
140
0.1189
605
0.134


hCV2892877
FGA
rs6050
T
C
C
0.23658
dominant
0.5314
CT
584
0.533
1954
0.4641
CC
8
0.0073
19
0.005









general
0.5314
CT
584
0.533
1954
0.4641
CC
8
0.0073
19
0.005









additive
0.5314
CT
584
0.533
1954
0.4641
CC
8
0.0073
19
0.005


hCV2915511
OBSL1/STK11IP
rs627530
T
C
C
0.036056
general
0.9305
CT
93
0.077
308
0.0669
CC
9
0.0075
12
0.003









recessive
0.9305
CT
93
0.077
308
0.0669
CC
9
0.0075
12
0.003









additive
0.9305
CT
93
0.077
308
0.0669
CC
9
0.0075
12
0.003


hCV29821005
LOC728284
rs6552970
C
T
C
0.829809
general
0.6976
TC
259
0.228
1163
0.2644
TT
52
0.0457
167
0.038


hCV30562347
F11
rs4253418
G
A
G
0.956444
general
0.9153
AG
76
0.064
370
0.0822
AA
5
0.0042
11
0.002


hCV3180954
PTCRA
rs9471966
G
A
G
0.734992
general
0.5473
AG
445
0.37
1720
0.3755
AA
74
0.0615
354
0.077


hCV32291301
KLKB1
rs4253302
A
G
A
0.837091
general
0.7023
GA
250
0.212
1220
0.2697
GG
37
0.0314
127
0.028









dominant
0.7023
GA
250
0.212
1220
0.2697
GG
37
0.0314
127
0.028









additive
0.7023
GA
250
0.212
1220
0.2697
GG
37
0.0314
127
0.028


hCV3230038
F11
rs2289252
C
T
T
0.403825
general
0.3595
TC
571
0.485
2141
0.4734
TT
252
0.2139
756
0.167









recessive
0.3595
TC
571
0.485
2141
0.4734
TT
252
0.2139
756
0.167









dominant
0.3595
TC
571
0.485
2141
0.4734
TT
252
0.2139
756
0.167









additive
0.3595
TC
571
0.485
2141
0.4734
TT
252
0.2139
756
0.167









general
0.3595
TC
571
0.485
2141
0.4734
TT
252
0.2139
756
0.167


hCV3230096
CYP4V2
rs3817184
C
T
T
0.415431
general
0.3423
TC
569
0.483
2189
0.4846
TT
235
0.1995
782
0.173









recessive
0.3423
TC
569
0.483
2189
0.4846
TT
235
0.1995
782
0.173









additive
0.3423
TC
569
0.483
2189
0.4846
TT
235
0.1995
782
0.173


hCV3230113
CYP4V2
rs1053094
A
T
T
0.490487
recessive
0.2562
TA
565
0.481
2290
0.5066
TT
323
0.2751
1072
0.237









general
0.2562
TA
565
0.481
2290
0.5066
TT
323
0.2751
1072
0.237









additive
0.2562
TA
565
0.481
2290
0.5066
TT
323
0.2751
1072
0.237


hCV3272537
TIAM1
rs497689
T
A
A
0.442161
general
0.3169
AT
630
0.531
2204
0.482
AA
226
0.1906
920
0.201









dominant
0.3169
AT
630
0.531
2204
0.482
AA
226
0.1906
920
0.201


hCV540410
LASP1
rs609529
T
A
A
0.063164
general
0.8777
AT
149
0.124
535
0.1184
AA
13
0.0108
18
0.004









recessive
0.8777
AT
149
0.124
535
0.1184
AA
13
0.0108
18
0.004


hCV596331
F9
rs6048
A
G
A
0.698278
general
0.5928
GA
259
0.215
968
0.211
GG
185
0.1538
900
0.196









recessive
0.5928
GA
259
0.215
968
0.211
GG
185
0.1538
900
0.196









dominant
0.5928
GA
259
0.215
968
0.211
GG
185
0.1538
900
0.196









additive
0.5928
GA
259
0.215
968
0.211
GG
185
0.1538
900
0.196


hCV7422466
C9orf103
rs1052690
A
C
A
0.803646
general
0.6435
CA
323
0.273
1309
0.3203
CC
43
0.0364
148
0.036









dominant
0.6435
CA
323
0.273
1309
0.3203
CC
43
0.0364
148
0.036









additive
0.6435
CA
323
0.273
1309
0.3203
CC
43
0.0364
148
0.036


hCV7581501
USP45
rs1323717
G
C
G
0.879567
general
0.7718
CG
227
0.189
985
0.2155
CC
18
0.015
58
0.013


hCV7625318
PLEKHG4
rs3868142
G
A
A
0.084256
general
0.8419
AG
182
0.152
680
0.1477
AA
26
0.0217
48
0.01









recessive
0.8419
AG
182
0.152
680
0.1477
AA
26
0.0217
48
0.01


hCV8241630
F11
rs925451
G
A
A
0.379287
general
0.3912
AG
565
0.478
2074
0.459
AA
223
0.1887
677
0.15









recessive
0.3912
AG
565
0.478
2074
0.459
AA
223
0.1887
677
0.15









dominant
0.3912
AG
565
0.478
2074
0.459
AA
223
0.1887
677
0.15









general
0.3912
AG
565
0.478
2074
0.459
AA
223
0.1887
677
0.15









additive
0.3912
AG
565
0.478
2074
0.459
AA
223
0.1887
677
0.15


hCV8361354
PANX1
rs1138800
C
A
A
0.374456
recessive
0.3863
AC
541
0.45
2197
0.4784
AA
196
0.1632
621
0.135









general
0.3863
AC
541
0.45
2197
0.4784
AA
196
0.1632
621
0.135


hCV8717873
GP6/RDH13
rs1613662
A
G
A
0.816402
dominant
0.6654
GA
321
0.267
1388
0.3019
GG
32
0.0266
150
0.033









general
0.6654
GA
321
0.267
1388
0.3019
GG
32
0.0266
150
0.033









additive
0.6654
GA
321
0.267
1388
0.3019
GG
32
0.0266
150
0.033


hCV8726802
F2
rs1799963
G
A
A
0.009998
additive
0.98
AG
41
0.034
92
0.02
AA
1
0.0008
0
0









dominant
0.98
AG
41
0.034
92
0.02
AA
1
0.0008
0
0









general
0.98
AG
41
0.034
92
0.02
AA
1
0.0008
0
0


hCV8911768
SERPINC1
rs941988
C
T
T
0.095461
additive
0.8192
TC
107
0.195
474
0.1707
TT
10
0.0182
28
0.01


hCV8919444
F5
rs4524
T
C
T
0.737678
general
0.5475
CT
412
0.351
1713
0.3803
CC
58
0.0494
325
0.072









recessive
0.5475
CT
412
0.351
1713
0.3803
CC
58
0.0494
325
0.072









dominant
0.5475
CT
412
0.351
1713
0.3803
CC
58
0.0494
325
0.072









additive
0.5475
CT
412
0.351
1713
0.3803
CC
58
0.0494
325
0.072









general
0.5475
CT
412
0.351
1713
0.3803
CC
58
0.0494
325
0.072


hCV9102827
GPATCH4
rs3795733
T
C
C
0.258025
general
0.5669
CT
448
0.381
1440
0.3502
CC
115
0.0977
341
0.083









dominant
0.5669
CT
448
0.381
1440
0.3502
CC
115
0.0977
341
0.083









general
0.5669
CT
448
0.381
1440
0.3502
CC
115
0.0977
341
0.083









additive
0.5669
CT
448
0.381
1440
0.3502
CC
115
0.0977
341
0.083


hDV70683382
RABGAP1L
rs16846815
G
C
C
0.061982
general
0.8789
CG
75
0.137
328
0.1182
CC
5
0.0091
8
0.003









recessive
0.8789
CG
75
0.137
328
0.1182
CC
5
0.0091
8
0.003
















TABLE 26





Age- and sex-adjusted association of 31 SNPs with cancer-related DVT in MEGA (p <= 0.05)
































Gene


Non
Risk
Control







Case
Case-
Control-


Marker
Symbol
RS number
RefAllele
RefAllele
Allele
RAF
Model
Parameter
P-value
OddsRatio
OR95l
OR95u
Genot
Count3
Freq3
Count3





hCV11466393
TACR1
rs881
C
G
C
0.830716
additive
hCV11466393.GG.GC.adtv
0.0301
0.80141
0.6561
0.97891
CC
346
0.7425
3125


hCV11503414
FGG
rs2066865
G
A
A
0.265941
general
hCV11503414.AA
0.0001
1.96423
1.3869
2.78179
GG
196
0.4242
2426









dominant
hCV11503414.GG.dom
3E−06
1.61356
1.3218
1.96967
GG
196
0.4242
2426









recessive
hCV11503414.AA.rec
0.0056
1.59724
1.147
2.22421
GG
196
0.4242
2426









general
hCV11503414.AG
4E−05
1.55126
1.259
1.91134
GG
196
0.4242
2426









additive
hCV11503414.AA.AG.adtv
1E−06
1.4539
1.2513
1.68933
GG
196
0.4242
2426


hCV11503469
FGG
rs2066854
T
A
A
0.266985
general
hCV11503469.AA
0.0004
1.87504
1.3257
2.65193
TT
199
0.428
2423









dominant
hCV11503469.TT.dom
5E−06
1.58923
1.303
1.9383
TT
199
0.428
2423









general
hCV11503469.AT
5E−05
1.53661
1.2481
1.89177
TT
199
0.428
2423









recessive
hCV11503469.AA.rec
0.0112
1.53311
1.1021
2.13262
TT
199
0.428
2423









additive
hCV11503469.AA.AT.adtv
3E−06
1.42741
1.2297
1.65692
TT
199
0.428
2423


hCV11503470

rs1800788
C
T
T
0.208112
general
hCV11503470.TT
0.0413
1.52638
1.0168
2.29142
CC
271
0.5815
2864









dominant
hCV11503470.CC.dom
0.0227
1.26127
1.0329
1.54013
CC
271
0.5815
2864









additive
hCV11503470.TT.TC.adtv
0.0118
1.22802
1.0466
1.44086
CC
271
0.5815
2864


hCV11786258
KLKB1
rs4253303
G
A
A
0.393142
general
hCV11786258.AA
0.0038
1.51355
1.1429
2.00443
GG
147
0.3148
1662









recessive
hCV11786258.AA.rec
0.0109
1.37826
1.0768
1.76415
GG
147
0.3148
1662









dominant
hCV11786258.GG.dom
0.0322
1.25844
1.0198
1.55299
GG
147
0.3148
1662









additive
hCV11786258.AA.AG.adtv
0.0046
1.22332
1.064
1.40651
GG
147
0.3148
1662


hCV11975250
F5
rs6025
C
T
T
0.026408
general
hCV11975250.TC
1E−06
2.37719
1.6784
3.36683
CC
428
0.8992
4311









dominant
hCV11975250.CC.dom
1E−06
2.35148
1.6662
3.31854
CC
428
0.8992
4311









additive
hCV11975250.TT.TC.adtv
2E−06
2.20614
1.5871
3.06664
CC
428
0.8992
4311


hCV15860433

rs2070006
C
T
T
0.395787
general
hCV15860433.TT
0.0099
1.47193
1.0975
1.97415
CC
135
0.2922
1665









dominant
hCV15860433.CC.dom
0.0013
1.42291
1.1477
1.76413
CC
135
0.2922
1665









general
hCV15860433.TC
0.0031
1.4064
1.1218
1.76314
CC
135
0.2922
1665









additive
hCV15860433.TT.TC.adtv
0.0031
1.2365
1.0744
1.42304
CC
135
0.2922
1665


hCV15968043
CYP4V2
rs2292423
T
A
A
0.409182
general
hCV15968043.AA
0.0076
1.458
1.1056
1.92265
TT
143
0.3102
1562









recessive
hCV15968043.AA.rec
0.0042
1.42227
1.1178
1.80962
TT
143
0.3102
1562









additive
hCV15968043.AA.AT.adtv
0.015 
1.1906
1.0345
1.37025
TT
143
0.3102
1562


hCV1841975
PROC
rs1799810
A
T
T
0.431275
general
hCV1841975.TA
0.0452
1.26045
1.005
1.58086
AA
134
0.2888
1472


hCV1859855
GOLGA3/POLE
rs2291260
T
C
C
0.218551
general
hCV1859855.CC
5E−05
2.20173
1.5067
3.21731
TT
263
0.5445
2757









recessive
hCV1859855.CC.rec
0.0001
2.07661
1.434
3.00721
TT
263
0.5445
2757









additive
hCV1859855.CC.CT.adtv
0.0005
1.3222
1.1293
1.54809
TT
263
0.5445
2757









dominant
hCV1859855.TT.dom
0.0148
1.27396
1.0486
1.54776
TT
263
0.5445
2757


hCV1874482
ZDHHC6
rs2306158
G
A
G
0.638875
general
hCV1874482.AA
0.003 
0.57869
0.403
0.83098
GG
205
0.4586
1613









recessive
hCV1874482.AA.rec
0.0049
0.6086
0.4307
0.86006
GG
205
0.4586
1613









additive
hCV1874482.AA.AG.adtv
0.0068
0.81053
0.6962
0.94361
GG
205
0.4586
1613


hCV2144411
NDUFB8/SEC31B
rs3763695
A
G
A
0.773979
dominant
hCV2144411.AA.dom
0.0498
0.81788
0.669
0.99986
AA
310
0.6418
2736


hCV2211618
DDT
rs12483950
C
G
G
0.429318
general
hCV2211618.GG
0.0431
1.32796
1.0088
1.74808
CC
144
0.3013
1478









recessive
hCV2211618.GG.rec
0.0494
1.26949
1.0006
1.61058
CC
144
0.3013
1478


hCV2303891
APOH
rs1801690
C
G
G
0.054656
general
hCV2303891.GG
0.0001
11.0922
3.2537
37.8146
CC
402
0.8701
4023









recessive
hCV2303891.GG.rec
0.0001
10.9845
3.2237
37.4293
CC
402
0.8701
4023


hCV25990131
CYP4V2
rs13146272
A
C
A
0.64085
dominant
hCV25990131.AA.dom
0.0243
0.79512
0.6513
0.97074
AA
213
0.4702
1814









additive
hCV25990131.CC.CA.adtv
0.0198
0.83799
0.7222
0.97232
AA
213
0.4702
1814


hCV26175114
TUBA4A
rs3731892
A
G
G
0.108496
general
hCV26175114.GG
0.0039
2.45516
1.3332
4.52126
AA
371
0.7762
3655









recessive
hCV26175114.GG.rec
0.0049
2.39667
1.3042
4.40436
AA
371
0.7762
3655









additive
hCV26175114.GG.GA.adtv
0.0226
1.26882
1.034
1.55701
AA
371
0.7762
3655


hCV27474895
F11
rs3756011
C
A
A
0.405226
general
hCV27474895.AA
0.0382
1.35187
1.0165
1.79786
CC
141
0.3045
1619









dominant
hCV27474895.CC.dom
0.0202
1.28699
1.0402
1.59237
CC
141
0.3045
1619









general
hCV27474895.AC
0.0425
1.26294
1.0079
1.5825
CC
141
0.3045
1619









additive
hCV27474895.AA.AC.adtv
0.0234
1.1738
1.0219
1.34829
CC
141
0.3045
1619


hCV27477533
F11
rs3756008
A
T
T
0.395815
general
hCV27477533.TT
0.0337
1.35365
1.0236
1.79005
AA
152
0.3269
1671









additive
hCV27477533.TT.TA.adtv
0.0358
1.15943
1.0099
1.33116
AA
152
0.3269
1671


hCV27502514
KLF3
rs3796533
G
A
A
0.164108
general
hCV27502514.AA
0.0467
1.71209
1.0078
2.90852
GG
308
0.6681
3134









additive
hCV27502514.AA.AG.adtv
0.0227
1.23385
1.0298
1.47838
GG
308
0.6681
3134


hCV2892877
FGA
rs6050
T
C
C
0.23658
dominant
hCV2892877.TT.dom
0.0003
1.47541
1.1978
1.81744
TT
183
0.441
2237









additive
hCV2892877.CC.CT.adtv
0.0002
1.46842
1.1983
1.79943
TT
183
0.441
2237









general
hCV2892877.CT
0.0003
1.46956
1.1923
1.8113
TT
183
0.441
2237


hCV30040828
TNFSF4
rs6700269
C
T
T
0.099423
general
hCV30040828.TC
0.0374
1.39291
1.0194
1.90319
CC
213
0.7662
2257









dominant
hCV30040828.CC.dom
0.0342
1.38941
1.0247
1.88389
CC
213
0.7662
2257









additive
hCV30040828.TT.TC.adtv
0.0421
1.32817
1.0101
1.74635
CC
213
0.7662
2257


hCV3230038
F11
rs2289252
C
T
T
0.403825
general
hCV3230038.TT
0.0241
1.38491
1.0436
1.83792
CC
143
0.3082
1626









dominant
hCV3230038.CC.dom
0.0236
1.27762
1.0334
1.57953
CC
143
0.3082
1626









additive
hCV3230038.TT.TC.adtv
0.017 
1.18364
1.0307
1.35933
CC
143
0.3082
1626


hCV3230096
CYP4V2
rs3817184
C
T
T
0.415431
general
hCV3230096.TT
0.0064
1.46092
1.1125
1.91853
CC
144
0.3103
1546









recessive
hCV3230096.TT.rec
0.0039
1.41651
1.1182
1.7944
CC
144
0.3103
1546









additive
hCV3230096.TT.TC.adtv
0.0117
1.19499
1.0405
1.37242
CC
144
0.3103
1546


hCV3230113
CYP4V2
rs1053094
A
T
T
0.490487
recessive
hCV3230113.TT.rec
0.0189
1.30142
1.0444
1.62169
AA
111
0.2403
1158


hCV596331
F9
rs6048
A
G
A
0.698278
general
hCV596331.GG
0.0476
0.76464
0.5863
0.99719
AA
313
0.644
2719









dominant
hCV596331.AA.dom
0.0411
0.8085
0.6593
0.99142
AA
313
0.644
2719









additive
hCV596331.GG.GA.adtv
0.0334
0.87259
0.7696
0.98931
AA
313
0.644
2719


hCV7422466
C9orf103
rs1052690
A
C
C
0.196354
recessive
hCV7422466.CC.rec
0.0402
1.59328
1.021
2.4864
AA
311
0.6466
2630


hCV7459627
WBP11P1
rs1985293
A
G
G
0.30776
recessive
hCV7459627.GG.rec
0.0057
1.50827
1.1268
2.01898
AA
225
0.463
2189









general
hCV7459627.GG
0.0117
1.48469
1.092
2.01856
AA
225
0.463
2189


hCV8726802
F2
rs1799963
G
A
A
0.009998
additive
hCV8726802.AA.AG.adtv
5E−06
2.86622
1.8273
4.49576
GG
454
0.9419
4509









dominant
hCV8726802.GG.dom
8E−06
2.85006
1.8019
4.50807
GG
454
0.9419
4509









general
hCV8726802.AG
2E−05
2.75908
1.7344
4.38918
GG
454
0.9419
4509


hCV8919444
F5
rs4524
T
C
T
0.737678
general
hCV8919444.CT
0.0322
0.79363
0.6424
0.9805
TT
272
0.5849
2466









dominant
hCV8919444.TT.dom
0.0388
0.8105
0.664
0.98929
TT
272
0.5849
2466


hCV8957432
RAC2
rs6572
G
C
G
0.55628
general
hCV8957432.CC
0.032 
0.72918
0.5464
0.97313
GG
169
0.3499
1439









additive
hCV8957432.CC.CG.adtv
0.0353
0.86194
0.7506
0.98985
GG
169
0.3499
1439


hCV9102827
GPATCH4
rs3795733
T
C
C
0.258025
general
hCV9102827.CT
0.0224
1.27189
1.0347
1.56351
TT
246
0.5136
2331









dominant
hCV9102827.TT.dom
0.0202
1.26146
1.037
1.53456
TT
246
0.5136
2331









additive
hCV9102827.CC.CT.adtv
0.0424
1.16745
1.0054
1.35567
TT
246
0.5136
2331





























Gene


Non
Risk
Control

Control-

Case
Case-
Control-
Control-

Case
Case-
Control-
Control-


Marker
Symbol
RS number
RefAllele
RefAllele
Allele
RAF
Model
Freq3
Genot2
Count4
Freq4
Count4
Freq4
Genot3
Count5
Freq5
Count5
Freq5





hCV11466393
TACR1
rs881
C
G
C
0.830716
additive
0.691
GC
113
0.2425
1263
0.2793
GG
7
0.015
134
0.0296


hCV11503414
FGG
rs2066865
G
A
A
0.265941
general
0.539
AG
217
0.4697
1756
0.3901
AA
49
0.1061
319
0.0709









dominant
0.539
AG
217
0.4697
1756
0.3901
AA
49
0.1061
319
0.0709









recessive
0.539
AG
217
0.4697
1756
0.3901
AA
49
0.1061
319
0.0709









general
0.539
AG
217
0.4697
1756
0.3901
AA
49
0.1061
319
0.0709









additive
0.539
AG
217
0.4697
1756
0.3901
AA
49
0.1061
319
0.0709


hCV11503469
FGG
rs2066854
T
A
A
0.266985
general
0.538
AT
217
0.4667
1757
0.3901
AA
49
0.1054
324
0.0719









dominant
0.538
AT
217
0.4667
1757
0.3901
AA
49
0.1054
324
0.0719









general
0.538
AT
217
0.4667
1757
0.3901
AA
49
0.1054
324
0.0719









recessive
0.538
AT
217
0.4667
1757
0.3901
AA
49
0.1054
324
0.0719









additive
0.538
AT
217
0.4667
1757
0.3901
AA
49
0.1054
324
0.0719


hCV11503470

rs1800788
C
T
T
0.208112
general
0.633
TC
163
0.3498
1437
0.3176
TT
32
0.0687
223
0.0493









dominant
0.633
TC
163
0.3498
1437
0.3176
TT
32
0.0687
223
0.0493









additive
0.633
TC
163
0.3498
1437
0.3176
TT
32
0.0687
223
0.0493


hCV11786258
KLKB1
rs4253303
G
A
A
0.393142
general
0.368
AG
224
0.4797
2162
0.4783
AA
96
0.2056
696
0.154









recessive
0.368
AG
224
0.4797
2162
0.4783
AA
96
0.2056
696
0.154









dominant
0.368
AG
224
0.4797
2162
0.4783
AA
96
0.2056
696
0.154









additive
0.368
AG
224
0.4797
2162
0.4783
AA
96
0.2056
696
0.154


hCV11975250
F5
rs6025
C
T
T
0.026408
general
0.949
TC
47
0.0987
226
0.0497
TT
1
0.0021
7
0.0015









dominant
0.949
TC
47
0.0987
226
0.0497
TT
1
0.0021
7
0.0015









additive
0.949
TC
47
0.0987
226
0.0497
TT
1
0.0021
7
0.0015


hCV15860433

rs2070006
C
T
T
0.395787
general
0.369
TC
242
0.5238
2120
0.4701
TT
85
0.184
725
0.1608









dominant
0.369
TC
242
0.5238
2120
0.4701
TT
85
0.184
725
0.1608









general
0.369
TC
242
0.5238
2120
0.4701
TT
85
0.184
725
0.1608









additive
0.369
TC
242
0.5238
2120
0.4701
TT
85
0.184
725
0.1608


hCV15968043
CYP4V2
rs2292423
T
A
A
0.409182
general
0.348
AT
215
0.4664
2178
0.4854
AA
103
0.2234
747
0.1665









recessive
0.348
AT
215
0.4664
2178
0.4854
AA
103
0.2234
747
0.1665









additive
0.348
AT
215
0.4664
2178
0.4854
AA
103
0.2234
747
0.1665


hCV1841975
PROC
rs1799810
A
T
T
0.431275
general
0.326
TA
249
0.5366
2195
0.4858
TT
81
0.1746
851
0.1884


hCV1859855
GOLGA3/POLE
rs2291260
T
C
C
0.218551
general
0.605
CT
179
0.3706
1605
0.3524
CC
41
0.0849
193
0.0424









recessive
0.605
CT
179
0.3706
1605
0.3524
CC
41
0.0849
193
0.0424









additive
0.605
CT
179
0.3706
1605
0.3524
CC
41
0.0849
193
0.0424









dominant
0.605
CT
179
0.3706
1605
0.3524
CC
41
0.0849
193
0.0424


hCV1874482
ZDHHC6
rs2306158
G
A
G
0.638875
general
0.416
AG
202
0.4519
1724
0.445
AA
40
0.0895
537
0.1386









recessive
0.416
AG
202
0.4519
1724
0.445
AA
40
0.0895
537
0.1386









additive
0.416
AG
202
0.4519
1724
0.445
AA
40
0.0895
537
0.1386


hCV2144411
NDUFB8/SEC31B
rs3763695
A
G
A
0.773979
dominant
0.598
GA
152
0.3147
1613
0.3524
GG
21
0.0435
228
0.0498


hCV2211618
DDT
rs12483950
C
G
G
0.429318
general
0.329
GC
230
0.4812
2179
0.4843
GG
104
0.2176
842
0.1872









recessive
0.329
GC
230
0.4812
2179
0.4843
GG
104
0.2176
842
0.1872


hCV2303891
APOH
rs1801690
C
G
G
0.054656
general
0.892
GC
54
0.1169
481
0.1067
GG
6
0.013
6
0.0013









recessive
0.892
GC
54
0.1169
481
0.1067
GG
6
0.013
6
0.0013


hCV25990131
CYP4V2
rs13146272
A
C
A
0.64085
dominant
0.414
CA
190
0.4194
1982
0.4528
CC
50
0.1104
581
0.1327









additive
0.414
CA
190
0.4194
1982
0.4528
CC
50
0.1104
581
0.1327


hCV26175114
TUBA4A
rs3731892
A
G
G
0.108496
general
0.8
GA
93
0.1946
833
0.1824
GG
14
0.0293
79
0.0173









recessive
0.8
GA
93
0.1946
833
0.1824
GG
14
0.0293
79
0.0173









additive
0.8
GA
93
0.1946
833
0.1824
GG
14
0.0293
79
0.0173


hCV27474895
F11
rs3756011
C
A
A
0.405226
general
0.359
AC
230
0.4968
2134
0.4725
AA
92
0.1987
763
0.169









dominant
0.359
AC
230
0.4968
2134
0.4725
AA
92
0.1987
763
0.169









general
0.359
AC
230
0.4968
2134
0.4725
AA
92
0.1987
763
0.169









additive
0.359
AC
230
0.4968
2134
0.4725
AA
92
0.1987
763
0.169


hCV27477533
F11
rs3756008
A
T
T
0.395815
general
0.37
TA
218
0.4688
2115
0.4683
TT
95
0.2043
730
0.1616









additive
0.37
TA
218
0.4688
2115
0.4683
TT
95
0.2043
730
0.1616


hCV27502514
KLF3
rs3796533
G
A
A
0.164108
general
0.697
AG
135
0.2928
1245
0.277
AA
18
0.039
115
0.0256









additive
0.697
AG
135
0.2928
1245
0.277
AA
18
0.039
115
0.0256


hCV2892877
FGA
rs6050
T
C
C
0.23658
dominant
0.531
CT
229
0.5518
1954
0.4641
CC
3
0.0072
19
0.0045









additive
0.531
CT
229
0.5518
1954
0.4641
CC
3
0.0072
19
0.0045









general
0.531
CT
229
0.5518
1954
0.4641
CC
3
0.0072
19
0.0045


hCV30040828
TNFSF4
rs6700269
C
T
T
0.099423
general
0.815
TC
61
0.2194
477
0.1721
TT
4
0.0144
37
0.0134









dominant
0.815
TC
61
0.2194
477
0.1721
TT
4
0.0144
37
0.0134









additive
0.815
TC
61
0.2194
477
0.1721
TT
4
0.0144
37
0.0134


hCV3230038
F11
rs2289252
C
T
T
0.403825
general
0.359
TC
227
0.4892
2141
0.4734
TT
94
0.2026
756
0.1671









dominant
0.359
TC
227
0.4892
2141
0.4734
TT
94
0.2026
756
0.1671









additive
0.359
TC
227
0.4892
2141
0.4734
TT
94
0.2026
756
0.1671


hCV3230096
CYP4V2
rs3817184
C
T
T
0.415431
general
0.342
TC
212
0.4569
2189
0.4846
TT
108
0.2328
782
0.1731









recessive
0.342
TC
212
0.4569
2189
0.4846
TT
108
0.2328
782
0.1731









additive
0.342
TC
212
0.4569
2189
0.4846
TT
108
0.2328
782
0.1731


hCV3230113
CYP4V2
rs1053094
A
T
T
0.490487
recessive
0.256
TA
218
0.4719
2290
0.5066
TT
133
0.2879
1072
0.2372


hCV596331
F9
rs6048
A
G
A
0.698278
general
0.593
GA
92
0.1893
968
0.211
GG
81
0.1667
900
0.1962









dominant
0.593
GA
92
0.1893
968
0.211
GG
81
0.1667
900
0.1962









additive
0.593
GA
92
0.1893
968
0.211
GG
81
0.1667
900
0.1962


hCV7422466
C9orf103
rs1052690
A
C
C
0.196354
recessive
0.644
CA
144
0.2994
1309
0.3203
CC
26
0.0541
148
0.0362


hCV7459627
WBP11P1
rs1985293
A
G
G
0.30776
recessive
0.478
GA
197
0.4053
1956
0.4275
GG
64
0.1317
430
0.094









general
0.478
GA
197
0.4053
1956
0.4275
GG
64
0.1317
430
0.094


hCV8726802
F2
rs1799963
G
A
A
0.009998
additive
0.98
AG
27
0.056
92
0.02
AA
1
0.0021
0
0









dominant
0.98
AG
27
0.056
92
0.02
AA
1
0.0021
0
0









general
0.98
AG
27
0.056
92
0.02
AA
1
0.0021
0
0


hCV8919444
F5
rs4524
T
C
T
0.737678
general
0.548
CT
158
0.3398
1713
0.3803
CC
35
0.0753
325
0.0722









dominant
0.548
CT
158
0.3398
1713
0.3803
CC
35
0.0753
325
0.0722


hCV8957432
RAC2
rs6572
G
C
G
0.55628
general
0.313
CG
236
0.4886
2242
0.4872
CC
78
0.1615
921
0.2001









additive
0.313
CG
236
0.4886
2242
0.4872
CC
78
0.1615
921
0.2001


hCV9102827
GPATCH4
rs3795733
T
C
C
0.258025
general
0.567
CT
193
0.4029
1440
0.3502
CC
40
0.0835
341
0.0829









dominant
0.567
CT
193
0.4029
1440
0.3502
CC
40
0.0835
341
0.0829









additive
0.567
CT
193
0.4029
1440
0.3502
CC
40
0.0835
341
0.0829
















TABLE 27







Additive association for 123 finemapping SNPs with DVT in LETS, with LD data from Hapmap


(p-value cutoff <=0.1 in LETS)



















Additive










Model



Distance






Compar-

R-
D-
Between


marker
annotation
P Value
OR (95% CI)
ison
Finemapping target
Squared
Prime
Targets



















hDV70683187
(rs16846561)
0.022041
1.43
(1.05-1.93)
G_vs_C
SERPINC1 (hCV16180170)
1
1
17106


hCV16135173
(rs2146372)
0.033754
1.39
(1.03-1.89)
C_vs_G
SERPINC1 (hCV16180170)
1
1
16648


hCV15956077
SERPINC1 (rs2227611)
0.093487
6.14
(0.74-51.16)
G_vs_A
SERPINC1 (hCV16180170)
not
not
not









hapmap
hapmap
hapmap


hCV8911768
SERPINC1 (rs941988)
0.017019
1.46
(1.07-1.98)
T_vs_C
SERPINC1 (hCV16180170)
1
1
4324


hCV15956034
SERPINC1 (rs2227603)
0.077266
1.71
(0.94-3.09)
A_vs_C
SERPINC1 (hCV16180170)
0.0129
0.2026
3669


hCV15956059
SERPINC1 (rs2227592)
0.022768
1.44
(1.05-1.96)
T_vs_C
SERPINC1 (hCV16180170)
1
1
505


hCV16180170
SERPINC1 (rs2227589)
0.025749
1.42
(1.04-1.94)
T_vs_C
SERPINC1 (hCV16180170)
1
1
1


hCV11975658
(rs1951626)
0.078232
1.2
(0.98-1.47)
A_vs_G
SERPINC1 (hCV16180170)
0.204
1
5886


hDV70683212
RC3H1 (rs16846593)
0.044415
1.45
(1.01-2.07)
G_vs_C
SERPINC1 (hCV16180170)
0.425
1
12002


hCV30440155
(rs6699146)
0.061774
1.19
(0.99-1.43)
C_vs_G
SERPINC1 (hCV16180170)
0.1123
1
173307


hCV30205817
RABGAP1L
0.073088
1.42
(0.97-2.09)
T_vs_C
SERPINC1 (hCV16180170)
0.3247
0.7784
311586



(rs10489254)


hCV25932979
RABGAP1L
0.096111
1.38
(0.94-2.02)
G_vs_A
SERPINC1 (hCV16180170)
0.2519
0.7228
333183



(rs16846809)


hDV70683382
RABGAP1L
0.040023
1.49
(1.02-2.18)
C_vs_G
SERPINC1 (hCV16180170)
0.3247
0.7784
334327



(rs16846815)


hCV815038
RGS7 (rs390488)
0.096645
1.18
(0.97-1.43)
T_vs_C
RGS7 (hCV916107)
0.1298
0.6645
92924


hCV1703855
RGS7 (rs261828)
0.082919
1.19
(0.98-1.44)
C_vs_T
RGS7 (hCV916107)
0.1108
0.6027
90577


hCV1703867
RGS7 (rs261861)
0.028305
1.24
(1.02-1.5)
T_vs_C
RGS7 (hCV916107)
0.0283
0.2557
66200


hCV29269378
RGS7 (rs6657406)
0.085115
1.49
(0.95-2.36)
G_vs_A
RGS7 (hCV916107)
0.0129
1
56263


hCV30626715
RGS7 (rs6690744)
0.058389
1.2
(0.99-1.45)
G_vs_T
RGS7 (hCV916107)
0.2435
0.7882
28216


hCV31714450
RGS7 (rs6429232)
0.039477
1.22
(1.01-1.48)
T_vs_C
RGS7 (hCV916107)
0.2201
0.7854
27206


hCV26887403
RGS7 (rs6682084)
0.054414
1.2
(1-1.44)
C_vs_A
RGS7 (hCV916107)
0.279
0.6754
26666


hCV1703892
RGS7 (rs3893179)
0.086181
1.18
(0.98-1.43)
T_vs_A
RGS7 (hCV916107)
0.2315
0.7973
26412


hCV27878067
RGS7 (rs4660016)
0.069991
1.19
(0.99-1.44)
G_vs_A
RGS7 (hCV916107)
0.2315
0.7973
26331


hCV27956129
RGS7 (rs4659585)
0.072323
1.19
(0.98-1.44)
A_vs_C
RGS7 (hCV916107)
0.2315
0.7973
26266


hCV8857351
RGS7 (rs2341021)
0.073263
1.19
(0.98-1.43)
T_vs_C
RGS7 (hCV916107)
0.2315
0.7973
21760


hCV1703910
RGS7 (rs3911618)
0.033677
1.23
(1.02-1.48)
A_vs_G
RGS7 (hCV916107)
0.263
0.8034
16533


hCV26887434
RGS7 (rs12723522)
0.056937
1.2
(0.99-1.45)
C_vs_A
RGS7 (hCV916107)
0.2787
0.8674
14037


hCV8856223
RGS7 (rs1382243)
0.039025
1.22
(1.01-1.47)
G_vs_C
RGS7 (hCV916107)
0.3276
0.7273
7275


hCV916106
RGS7 (rs575226)
0.021282
1.26
(1.04-1.54)
A_vs_G
RGS7 (hCV916107)
1
1
128


hCV916107
LOC729138 (rs670659)
0.017944
1.27
(1.04-1.54)
C_vs_T
RGS7 (hCV916107)
1
1
1


hCV26887464
RGS7 (rs6669640)
0.092625
1.18
(0.97-1.43)
A_vs_G
RGS7 (hCV916107)
0.6131
0.874
6356


hCV31056155
SDCCAG8 (rs12131952)
0.018087
1.74
(1.1-2.75)
G_vs_C
AKT3 (hCV233148)
0.0258
1
81464


hCV15755949
SDCCAG8 (rs2997494)
0.098814
1.35
(0.94-1.94)
G_vs_A
AKT3 (hCV233148)
0.0403
1
54670


hCV26338482
SDCCAG8 (rs10803143)
0.050211
1.23
(1-1.51)
T_vs_C
AKT3 (hCV233148)
0.1943
0.4617
53762


hCV26338512
SDCCAG8 (rs2994339)
0.002976
1.41
(1.12-1.77)
G_vs_A
AKT3 (hCV233148)
0.4321
0.8476
27931


hCV26338513
AKT3 (rs3006917)
0.004793
1.39
(1.1-1.74)
T_vs_C
AKT3 (hCV233148)
0.4774
0.8689
27380


hCV26034157
LOC729199 (rs2994329)
0.012253
1.32
(1.06-1.64)
T_vs_C
AKT3 (hCV233148)
0.5147
0.8759
21430


hCV30690784
SDCCAG8 (rs4658574)
0.01138
1.32
(1.06-1.64)
C_vs_T
AKT3 (hCV233148)
0.7442
0.9033
18635


hCV26034142
AKT3 (rs9428576)
0.024681
1.23
(1.03-1.47)
C_vs_T
AKT3 (hCV233148)
0.4446
1
7324


hCV12073840
AKT3 (rs14403)
0.005929
1.36
(1.09-1.69)
T_vs_C
AKT3 (hCV233148)
0.8697
1
5458


hCV9493081
AKT3 (rs1058304)
0.000379
1.45
(1.18-1.78)
T_vs_C
AKT3 (hCV233148)
1
1
4494


hCV233148
AKT3 (rs1417121)
0.000345
1.45
(1.18-1.78)
C_vs_G
AKT3 (hCV233148)
1
1
1


hCV30690777
AKT3 (rs12045585)
0.035416
1.32
(1.02-1.72)
A_vs_G
AKT3 (hCV233148)
0.3153
0.8291
3750


hCV30690778
AKT3 (rs12140414)
0.002597
1.44
(1.14-1.82)
C_vs_T
AKT3 (hCV233148)
0.5904
0.9381
5038


hCV97631
AKT3 (rs1538773)
9.68E−05
1.55
(1.24-1.92)
G_vs_T
AKT3 (hCV233148)
0.6656
0.9434
5333


hCV30690780
AKT3 (rs10737888)
3.78E−05
1.58
(1.27-1.96)
C_vs_A
AKT3 (hCV233148)
0.6656
0.9434
9134


hCV8688111
AKT3 (rs1578275)
0.001215
1.49
(1.17-1.89)
C_vs_G
AKT3 (hCV233148)
0.5904
0.9381
11093


hCV26719108
AKT3 (rs10927035)
0.001896
1.36
(1.12-1.66)
C_vs_T
AKT3 (hCV233148)
0.2417
0.7058
34633


hCV29210363
AKT3 (rs6656918)
5.24E−05
1.56
(1.26-1.94)
G_vs_A
AKT3 (hCV233148)
0.656
0.941
36875


hCV26719113
AKT3 (rs7517340)
0.000163
1.58
(1.24-2)
T_vs_C
AKT3 (hCV233148)
0.3991
0.9147
40841


hCV26719121
AKT3 (rs10927041)
0.000111
1.59
(1.26-2)
C_vs_T
AKT3 (hCV233148)
0.5615
1
62541


hCV31523608
AKT3 (rs12744297)
0.005758
1.32
(1.08-1.61)
G_vs_A
AKT3 (hCV233148)
0.1547
0.4381
64947


hCV31523638
AKT3 (rs12037013)
0.002893
1.49
(1.15-1.93)
A_vs_G
AKT3 (hCV233148)
0.382
0.9142
114858


hCV31523643
AKT3 (rs6671475)
0.000377
1.52
(1.21-1.91)
G_vs_A
AKT3 (hCV233148)
0.4875
0.9224
119993


hCV31523557
AKT3 (rs10754807)
0.000179
1.57
(1.24-1.98)
A_vs_G
AKT3 (hCV233148)
0.4481
0.9239
134809


hCV15885425
AKT3 (rs2290754)
0.000145
1.57
(1.24-1.97)
C_vs_A
AKT3 (hCV233148)
0.4499
0.9244
136919


hCV1678682
AKT3 (rs320339)
0.00034
1.51
(1.21-1.9)
T_vs_G
AKT3 (hCV233148)
0.3838
0.9147
201561


hCV1678674
AKT3 (rs1458023)
0.000408
1.5
(1.2-1.88)
C_vs_T
AKT3 (hCV233148)
0.3517
0.9089
217324


hCV26719227
AKT3 (rs10927065)
0.009997
1.4
(1.08-1.8)
A_vs_C
AKT3 (hCV233148)
0.3517
0.9089
245262


hCV26719154
AKT3 (rs11588042)
0.025097
1.79
(1.08-2.98)
T_vs_C
AKT3 (hCV233148)
0.0097
1
265282


hCV31523650
AKT3 (rs12048930)
0.000974
1.47
(1.17-1.86)
T_vs_C
AKT3 (hCV233148)
0.3459
0.7848
270727


hCV31523658
AKT3 (rs12047209)
0.006153
1.43
(1.11-1.85)
C_vs_A
AKT3 (hCV233148)
0.317
0.8314
285058


hCV15953063
(rs2953331)
0.041925
1.22
(1.01-1.48)
A_vs_G
AKT3 (hCV233148)
0.0556
0.2841
354919


hCV134275
C3orf15 (rs9847068)
0.065868
1.21
(0.99-1.48)
G_vs_A
NR1I2 (hCV263841)
0.5453
0.8675
76427


hCV134278
C3orf15 (rs9848716)
0.085183
1.19
(0.98-1.46)
T_vs_C
NR1I2 (hCV263841)
0.329
0.8118
74733


hCV30699692
C3orf15 (rs6781992)
0.078978
1.66
(0.94-2.94)
C_vs_T
NR1I2 (hCV263841)
0.1035
1
47857


hCV1834242
C3orf15 (rs11712308)
0.005499
1.3
(1.08-1.56)
G_vs_A
NR1I2 (hCV263841)
0.5486
0.9531
17773


hCV1833991
NR1I2 (rs11926554)
0.057578
1.25
(0.99-1.58)
C_vs_T
NR1I2 (hCV263841)
0.5548
1
5484


hCV263841
NR1I2 (rs1523127)
0.000146
1.44
(1.19-1.73)
C_vs_A
NR1I2 (hCV263841)
1
1
1


hCV30747430
NR1I2 (rs11712211)
0.014443
1.35
(1.06-1.71)
T_vs_C
NR1I2 (hCV263841)
0.176
1
3102


hCV11503470
(rs1800788)
0.013778
1.32
(1.06-1.65)
T_vs_C
FGG (hCV11503469)
0.3992
0.7151
51268


hCV15860433
(rs2070006)
0.023913
1.24
(1.03-1.5)
T_vs_C
FGG (hCV11503469)
0.5455
1
21316


hCV2892869
(rs13109457)
0.002493
1.37
(1.12-1.68)
A_vs_G
FGG (hCV11503469)
0.9149
0.9565
20303


hCV27020269
(rs7659613)
0.027027
1.24
(1.02-1.49)
C_vs_G
FGG (hCV11503469)
0.5455
1
19766


hCV31863982
(rs7659024)
0.000205
1.48
(1.2-1.82)
A_vs_G
FGG (hCV11503469)
0.9579
1
14252


hCV7429782
FGG (rs1118823)
0.014285
1.3
(1.05-1.6)
T_vs_A
FGG (hCV11503469)
0.1442
1
11336


hCV11503414
FGG (rs2066865)
0.000446
1.45
(1.18-1.78)
A_vs_G
FGG (hCV11503469)
0.9579
1
9906


hCV11503431
FGG (rs2066861)
0.000351
1.46
(1.19-1.8)
T_vs_C
FGG (hCV11503469)
0.9579
1
7746


hCV11503469
FGG (rs2066854)
0.000205
1.48
(1.2-1.83)
A_vs_T
FGG (hCV11503469)
1
1
1


hCV11853483
FGG (rs12644950)
0.000278
1.47
(1.19-1.81)
A_vs_G
FGG (hCV11503469)
0.9545
1
2141


hCV2892855
FGG (rs6536024)
0.0009
1.39
(1.14-1.68)
C_vs_T
FGG (hCV11503469)
0.2597
1
8189


hCV11853496
FGG (rs7654093)
0.000364
1.46
(1.18-1.79)
T_vs_A
FGG (hCV11503469)
0.9576
1
9892


hCV25990131
CYP4V2 (rs13146272)
0.04894
1.22
(1-1.49)
A_vs_C
CYP4V2 (hCV25990131)
1
1
1


hCV3230099
CYP4V2 (rs3736456)
0.075392
1.49
(0.96-2.32)
T_vs_C
CYP4V2 (hCV25990131)
0.119
1
2145


hCV3230016
KLKB1 (rs4253325)
0.044164
1.37
(1.01-1.86)
G_vs_A
CYP4V2 (hCV25990131)
0.0097
0.2187
58263


hCV25634754
KLKB1 (rs4253331)
0.005773
1.7
(1.17-2.48)
C_vs_T
CYP4V2 (hCV25990131)
0.0545
1
58925


hCV27477533
(rs3756008)
0.030992
1.22
(1.02-1.46)
T_vs_A
CYP4V2 (hCV25990131)
0.1626
0.6312
65175


hCV8241630
F11 (rs925451)
0.045183
1.2
(1-1.44)
A_vs_G
CYP4V2 (hCV25990131)
0.1371
0.6445
67359


hCV25474414
F11 (rs4253399)
0.023178
1.23
(1.03-1.48)
G_vs_T
CYP4V2 (hCV25990131)
0.1211
0.5547
67884


hCV25474413
F11 (rs3822057)
0.066697
1.19
(0.99-1.42)
C_vs_A
CYP4V2 (hCV25990131)
0.1545
0.4747
67942


hCV12066124
F11 (rs2036914)
0.013274
1.27
(1.05-1.53)
C_vs_T
CYP4V2 (hCV25990131)
0.1525
0.456
72271


hCV3230030
F11 (rs4253408)
0.04234
1.43
(1.01-2.01)
A_vs_G
CYP4V2 (hCV25990131)
0.0486
1
73648


hCV27474895
F11 (rs3756011)
0.035267
1.21
(1.01-1.45)
A_vs_C
CYP4V2 (hCV25990131)
0.1303
0.6017
86039


hCV3230038
F11 (rs2289252)
0.061325
1.19
(0.99-1.42)
T_vs_C
CYP4V2 (hCV25990131)
0.1185
0.5845
87171


hCV3230136
LOC728284
0.092188
1.2
(0.97-1.48)
G_vs_A
CYP4V2 (hCV25990131)
0.0006
0.0282
97676



(rs13116273)


hCV29821005
LOC728284 (rs6552970)
0.088436
1.22
(0.97-1.53)
T_vs_C
CYP4V2 (hCV25990131)
0.0012
0.0582
118016


hCV32209620
LOC728284 (rs6552972)
0.088796
1.21
(0.97-1.52)
C_vs_T
CYP4V2 (hCV25990131)
0.0012
0.0582
118194


hCV32209605
LOC728284 (rs6829128)
0.097805
1.17
(0.97-1.42)
T_vs_C
CYP4V2 (hCV25990131)
0.0101
0.204
136794


hCV1376207
NLRP2 (rs11672113)
0.081881
1.18
(0.98-1.43)
G_vs_C
GP6 (hCV8717873)
0.112
0.8676
41715


hCV8717949
NLRP2 (rs1654495)
0.079445
1.18
(0.98-1.43)
C_vs_A
GP6 (hCV8717873)
0.1439
0.858
35017


hCV1376227
NLRP2 (rs1671133)
0.071931
1.19
(0.98-1.43)
C_vs_A
GP6 (hCV8717873)
0.1501
0.8785
29547


hCV8717916
NLRP2 (rs1043673)
0.0279
1.24
(1.02-1.5)
A_vs_C
GP6 (hCV8717873)
0.1296
0.8728
24364


hCV8717893
GP6 (rs1671192)
0.085361
1.22
(0.97-1.54)
G_vs_A
GP6 (hCV8717873)
0.8755
1
6663


hCV1376342
GP6 (rs1654416)
0.081328
1.23
(0.97-1.54)
T_vs_C
GP6 (hCV8717873)
0.838
1
6561


hCV8717873
GP6 (rs1613662)
0.01299
1.36
(1.07-1.74)
A_vs_G
GP6 (hCV8717873)
1
1
1


hCV8717752
RDH13 (rs1671217)
0.024278
1.34
(1.04-1.72)
G_vs_A
GP6 (hCV8717873)
0.8868
1
17638


hCV29271569
RDH13 (rs1626971)
0.014499
1.36
(1.06-1.75)
T_vs_C
GP6 (hCV8717873)
0.8868
1
20430


hCV8703249
RDH13 (rs1654444)
0.051859
1.28
(1-1.64)
G_vs_T
GP6 (hCV8717873)
0.8868
1
29860


hCV27904396
(rs4829996)
0.056818
1.19
(1-1.41)
G_vs_A
F9 (hCV596331)
0.2533
0.6172
42147


hCV596663
(rs411017)
0.013879
1.23
(1.04-1.45)
G_vs_A
F9 (hCV596331)
0.2537
0.5796
21179


hCV2288095
F9 (rs378815)
0.01722
1.22
(1.04-1.44)
C_vs_T
F9 (hCV596331)
0.2537
0.5796
21084


hCV2986575
F9 (rs4149674)
0.071573
1.16
(0.99-1.37)
A_vs_T
F9 (hCV596331)
0.6414
0.8782
16480


hCV596669
F9 (rs376165)
0.06633
1.16
(0.99-1.37)
A_vs_G
F9 (hCV596331)
0.7113
0.9583
15548


hCV596326
F9 (rs398101)
0.017442
1.23
(1.04-1.45)
A_vs_G
F9 (hCV596331)
0.8216
0.9064
9324


hCV596330
F9 (rs422187)
0.047525
1.19
(1-1.41)
A_vs_C
F9 (hCV596331)
1
1
422


hCV596331
F9 (rs6048)
0.026883
1.21
(1.02-1.44)
A_vs_G
F9 (hCV596331)
1
1
1


hDV76976792
F9 (rs4149759)
0.05842
1.31
(0.99-1.74)
T_vs_C
F9 (hCV596331)
0.0744
0.596
1775


hCV596335
F9 (rs413957)
0.080856
1.19
(0.98-1.44)
C_vs_G
F9 (hCV596331)
0.4049
0.9319
4237


hCV596336
F9 (rs110583)
0.07609
1.19
(0.98-1.44)
T_vs_C
F9 (hCV596331)
0.4049
0.9319
5252


hCV596337
F9 (rs421766)
0.059328
1.21
(0.99-1.46)
G_vs_C
F9 (hCV596331)
0.4049
0.9319
94835


hDV76976795
F9 (rs4149762)
0.072018
1.34
(0.97-1.85)
A_vs_G
F9 (hCV596331)
0.0065
0.1534
8918


hCV2969899
(rs434144)
0.030535
1.23
(1.02-1.49)
C_vs_G
F9 (hCV596331)
0.343
0.8128
13146


hDV70941043
(rs17342358)
0.056568
4.08
(0.96-17.3)
G_vs_A
F9 (hCV596331)
0.0123
1
21299


hCV15952952
MCF2 (rs2235708)
0.057867
4.05
(0.95-17.15)
G_vs_A
F9 (hCV596331)
0.0123
1
45465








Claims
  • 1. A method of determining whether a human has an altered risk for venous thrombosis (VT), comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:602-1587 or its complement, wherein the polymorphism indicates an altered risk for VT.
  • 2. The method of claim 1, wherein the VT is deep vein thrombosis (DVT).
  • 3. The method of claim 1, wherein said polymorphism is selected from the group consisting of the polymorphisms provided in at least one of Tables 5-9 and 11-30.
  • 4. The method of claim 1, wherein the altered risk is an increased risk.
  • 5. The method of claim 1, wherein the altered risk is a decreased risk.
  • 6. The method of claim 1, wherein said nucleic acid is a nucleic acid extract from a biological sample from said human.
  • 7. The method of claim 6, wherein said biological sample is blood, saliva, or buccal cells.
  • 8. The method of claim 6, further comprising preparing said nucleic acid extract from said biological sample prior to said testing step.
  • 9. The method of claim 8, further comprising obtaining said biological sample from said human prior to said preparing step.
  • 10. The method of claim 1, wherein said testing step comprises nucleic acid amplification.
  • 11. The method of claim 10, wherein said nucleic acid amplification is carried out by polymerase chain reaction.
  • 12. The method of claim 1, further comprising correlating the presence or absence of the polymorphism with an altered risk for VT.
  • 13. The method of claim 12, wherein said correlating step is performed by computer software.
  • 14. The method of claim 1, wherein said testing is performed using sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, or denaturing gradient gel electrophoresis (DGGE).
  • 15. The method of any one of claim 1, wherein said testing is performed using an allele-specific method.
  • 16. The method of claim 15, wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification.
  • 17. The method of claim 16, wherein the method is performed using an allele-specific primer provided in Table 3.
  • 18. The method of claim 1 which is an automated method.
  • 19. The method of claim 1, wherein the VT is recurrent VT.
  • 20. The method of claim 19, wherein the polymorphism is selected from the group consisting of the polymorphisms provided in Table 24.
  • 21. The method of claim 1, wherein the VT includes pulmonary embolism (PE).
  • 22. The method of claim 21, wherein the polymorphism is selected from the group consisting of the polymorphisms provided in Table 25.
  • 23. The method of claim 1, wherein the human has cancer.
  • 24. The method of claim 23, wherein the polymorphism is selected from the group consisting of the polymorphisms provided in Table 26.
  • 25. A method for reducing risk of venous thrombosis (VT) in a human, comprising administering to said human an effective amount of a therapeutic agent, said human having been identified as having an increased risk for VT due to the presence or absence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:602-1587 or its complement.
  • 26. The method of claim 25, wherein the method comprises testing nucleic acid from said human for the presence or absence of said polymorphism.
  • 27. The method of claim 25, wherein the therapeutic agent comprises an anticoagulant agent.
  • 28. The method of claim 27, wherein the anticoagulant agent is selected from the group consisting of coumarines (vitamin K antagonists) such as warfarin (coumadin), acenocoumarol, phenprocoumon, and phenindione; heparin and derivative substances such as low molecular weight heparin; factor Xa inhibitors such as Fondaparinux, Idraparinux, and other synthetic pentasaccharide inhibitors of factor Xa; and thrombin inhibitors such as argatroban, lepirudin, bivalirudin, and dabigatran.
  • 29. The method of claim 25, wherein the therapeutic agent comprises an antiplatelet agent.
  • 30. The method of claim 29, wherein the antiplatelet agent is selected from the group consisting of cyclooxygenase inhibitors such as aspirin, and ADP receptor inhibitors such as clopidogrel (Plavix) and prasugrel (Effient).
  • 31. A method of identifying a human having an increased risk for venous thrombosis (VT), comprising testing a nucleic acid sample from said human for the presence or absence of a first polymorphism which is in linkage disequilibrium with a second polymorphism, wherein the second polymorphism is a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:602-1587 or its complement, and wherein the first polymorphism identifies said human as having an increased risk for VT.
  • 32. The method of claim 31, wherein the linkage disequilibrium is r2=1.
  • 33. The method of claim 31, wherein the first polymorphism is selected from the group consisting of the polymorphisms set forth in Table 4.
  • 34. The method of claim 31, further comprising correlating the presence or absence of said first polymorphism with an increased risk for VT.
  • 35. The method of claim 34, wherein said correlating step is performed by computer software.
  • 36. The method of claim 1, further comprising at least one of: a) selecting said human for inclusion in a clinical trial of a therapeutic agent; andb) assigning said human to a group within a clinical trial.
  • 37. The method of claim 36, wherein the therapeutic agent is an anticoagulant agent or an antiplatelet agent.
  • 38. A kit for determining whether a human has an altered risk for venous thrombosis (VT), wherein the kit comprises at least one container and at least one polynucleotide detection reagent stored in said container, wherein the polynucleotide detection reagent is capable of detecting the presence or absence of a polymorphism selected from the group consisting of the polymorphisms represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:602-1587 or its complement.
  • 39. The kit of claim 38, wherein the polynucleotide detection reagent selectively hybridizes to said nucleic acid in the presence of said polymorphism and does not hybridize to said nucleic acid in the absence of said polymorphism.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. non-provisional application Ser. No. 12/403,552, filed Mar. 13, 2009, which claims priority to U.S. provisional application Ser. No. 61/069,687, filed on Mar. 13, 2008, the contents of each of which are hereby incorporated by reference in their entirety into this application.

Provisional Applications (1)
Number Date Country
61069687 Mar 2008 US
Divisions (1)
Number Date Country
Parent 12403552 Mar 2009 US
Child 13270936 US