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

Abstract
The present invention provides compositions and methods based on genetic polymorphisms that are associated with response to statin treatment (particularly for reducing the risk of venous thrombosis). For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules 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 disease risk and drug response, particularly genetic polymorphisms that are associated with risk for developing venous thrombosis (VT) and/or response to statins, especially statin treatment for the prevention or treatment of VT and related pathologies. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with risk for developing VT and/or variability in responsiveness to statin treatment (including preventive treatment) in reducing VT risk between different individuals. The SNPs disclosed herein can be used, for example, as targets for diagnostic reagents and for the development of therapeutic agents. In particular, the SNPs of the present invention are useful for such uses as predicting an individual's response to therapeutic agents such as evaluating the likelihood of an individual differentially responding positively to statins, particularly for the treatment or prevention of VT (including recurrent VT), identifying an individual who has an increased or decreased risk of developing VT (including recurrent VT), for early detection of VT, for providing clinically important information for the prevention and/or treatment of VT, for predicting recurrence of VT, and for screening and selecting therapeutic agents. Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided.


BACKGROUND OF THE INVENTION

The present invention relates to SNPs that are associated with risk for developing venous thrombosis (VT) and/or variability between individuals in their response to statins, particularly for reducing the risk of VT.


VT, which may also be referred to as venous thromboembolism (VTE), includes deep vein thrombosis (DVT) and pulmonary embolism (PE). VT can further include a first occurrence of VT (i.e., primary VT) or recurrent VT.


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 0:14-8 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 deep vein thrombosis (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, IX 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 0:14-8 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 a need for novel genetic markers that are predictive of predisposition to VT (as well as response to statin treatment for preventing VT), particularly for individuals who are unrecognized as having a predisposition to developing the disease based on conventional risk factors, as well as genetic markers that are predictive of recurrent VT in individuals who have already experienced a VT event. 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, statins as well as anticoagulant agents). Moreover, the discovery of genetic markers associated with VT may provide novel targets for therapeutic intervention or preventive treatments.


HMG-CoA Reductase Inhibitors (Statins)


HMG-CoA reductase inhibitors (statins) can be used for the prevention and treatment of VT, in addition to their use for the prevention and treatment of other cardiovascular diseases (CVD), particularly coronary heart disease (CHD) (including coronary events, such as myocardial infarction (MI), and cerebrovascular events, such as stroke and transient ischemic attack (TIA)). Reduction of MI, stroke, and other coronary and cerebrovascular events and total mortality by treatment with HMG-CoA reductase inhibitors has been demonstrated in a number of randomized, double-blinded, placebo-controlled prospective trials (D. D. Waters, Clin Cardiol 24(8 Suppl): III3-7 (2001); B. K. Singh and J. L. Mehta, Curr Opin Cardiol 17(5):503-11 (2002)). These drugs are thought to typically have their primary effect through the inhibition of hepatic cholesterol synthesis, thereby upregulating LDL receptors in the liver. The resultant increase in LDL catabolism results in decreased circulating LDL, a major risk factor for cardiovascular disease.


Examples of statins include, but are not limited to, atorvastatin (Lipitor®), rosuvastatin (Crestor®), pravastatin (Pravachol®), simvastatin (Zocor®), fluvastatin (Lescol®), and lovastatin (Mevacor®), as well as combination therapies that include a statin such as simvastatin+ezetimibe (Vytorin®), lovastatin+niacin (Advicor®), atorvastatin+amlodipine besylate (Caduet®), and simvastatin+niacin (Simcor®).


Statins can be divided into two types according to their physicochemical and pharmacokinetic properties. Statins such as atorvastatin, simvastatin, lovastatin, and cerivastatin are lipophilic in nature and, as such, diffuse across membranes and thus are highly cell permeable. Hydrophilic statins such as pravastatin are more polar, such that they require specific cell surface transporters for cellular uptake. K. Ziegler and W. Stunkel, Biochim Biophys Acta 1139(3):203-9 (1992); M. Yamazaki et al., Am J Physiol 264(1 Pt 1):G36-44 (1993); T. Komai et al., Biochem Pharmacol 43(4):667-70 (1992). The latter statins utilizes a transporter, OATP2, whose tissue distribution is confined to the liver and, therefore, they are relatively hepato-specific inhibitors. B. Hsiang et al., J Biol Chem 274(52):37161-37168 (1999). The former statins, not requiring specific transport mechanisms, are available to all cells and they can directly impact a much broader spectrum of cells and tissues. These differences in properties may influence the spectrum of activities that each statin possesses. Pravastatin, for instance, has a low myopathic potential in animal models and myocyte cultures compared to lipophilic statins. B. A. Masters et al., Toxicol Appl Pharmacol 131(1):163-174 (1995); K. Nakahara et al., Toxicol Appl Pharmacol 152(1):99-106 (1998); J. C. Reijneveld et al., Pediatr Res 39(6):1028-1035 (1996). Statins are reviewed in Vaughan et al., “Update on Statins: 2003”, Circulation 2004; 110; 886-892.


Evidence from gene association studies is accumulating to indicate that responses to drugs are, indeed, at least partly under genetic control. As such, pharmacogenetics—the study of variability in drug responses attributed to hereditary factors in different populations—may significantly assist in providing answers toward meeting this challenge. A. D. Roses, Nature 405(6788):857-865 (2000); V. Mooser et al., J Thromb Haemost 1(7):1398-1402 (2003); L. M. Humma and S. G. Terra, Am J Health Syst Pharm 59(13):1241-1252 (2002). Associations have been reported between specific genotypes, as defined by SNPs and other genetic sequence variations, and specific responses to cardiovascular drugs. For example, a polymorphism in the KIF6 gene is associated with response to statin treatment (Iakoubova et al., “Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study”, J Am Coll Cardiol. 2008 Jan. 29; 51(4):449-55; Iakoubova et al., “Association of the 719Arg variant of KIF6 with both increased risk of coronary events and with greater response to statin therapy”, J Am Coll Cardiol. 2008 Jun. 3; 51(22):2195; Iakoubova et al., “KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study”, Eur J Cardiovasc Prev Rehabil. 2010 Apr. 20; and Shiffman et al., “Effect of pravastatin therapy on coronary events in carriers of the KIF6 719Arg allele from the cholesterol and recurrent events trial”, Am J Cardiol. 2010 May 1; 105(9):1300-5).


There is a need for genetic markers that can be used to predict an individual's responsiveness to statins. For example, there is a growing need to better identify people who have a high chance of benefiting from statins, and those who have a low risk of developing side-effects. For example, severe myopathies represent a significant risk for a low percentage of the patient population, and this may be a particular concern for patients who are treated more aggressively with statins. Furthermore, different patients may have the same risk for adverse events but are more likely to benefit from a drug (such as statins) and this may justify use of the drug in those individuals who are more likely to benefit. Similarly, in individuals who are less likely to benefit from a drug but are at risk for adverse events, use of the drug in these individuals can be de-prioritized or delayed.


An example of a large trial which analyzed the benefits of statin treatment for reducing the risk of CVD in a large population was the JUPITER Study (described in Ridker et al., “Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein”, N Engl J Med. 2008 Nov. 20; 359(21):2195-207), which demonstrated that rosuvastatin (Crestor®) significantly reduced the incidence of major cardiovascular events (including MI, stroke, arterial revascularization, hospitalization for unstable angina, and death from cardiovascular causes) in a study of 17,802 individuals.


Use of HMG-CoA Reductase Inhibitors (Statins) for Venous Thrombosis (VT)


HMG-CoA reductase inhibitors (statins) can be used to reduce the risk of VT. For example, the following three case-control studies reported the association of statin use with a reduction in the number of VT events:


Simvastatin use was associated with a reduced risk of VT [OR=0.51 (0.29-0.91)] in a Group Health Cooperative study of postmenopausal women, which contained about 500 DVT cases and 2000 controls of whom about 5% were statin users (Doggen et al., “HMG CoA reductase inhibitors and the risk of venous thrombosis among postmenopausal women”, J Thromb Haemost 2004; 2: 700-1).


Current use of statins was associated with a reduced risk of venous thromboembolism [relative risk=0.74 (95% CI, 0.63-0.85)] in a VT study which contained 3366 adult patients (18-89 years) diagnosed with primary incident venous thromboembolism (2310 with venous thrombosis and 1056 with pulmonary embolism) (Sorenson et al., “Arterial cardiovascular events, statins, low-dose aspirin and subsequent risk of venous thromboembolism: a population based case-control study”, J Thromb Haemost 2009; 7: 521-8).


In another study, 154 of 4538 patients used statins (3.3%), as did 354 of 5914 control subjects (5.7%). The use of statins [odds ratio (OR) 0.45; 95% confidence interval (CI) 0.36-0.56] but not other lipid-lowering medications (OR 1.22; 95% CI 0.62-2.43), was associated with reduced VT risk as compared with individuals who did not use any lipid-lowering medication, after adjustment for age, sex, body mass index, atherosclerotic disease, anti-platelet therapy and use of vitamin K antagonists. Different types and various durations of statin therapy were all associated with reduced VT risk (Ramcharan et al., “HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis”, J Thromb Haemost 2009; 7: 514-20).


Identification of individuals who will respond to statin therapy for the prevention or treatment of VT has the further benefit of enabling these individuals to be targeted for statin treatment as an alternative to anticoagulant therapy, which has a high risk of bleeding events, thus providing a safer course of treatment.


Single Nucleotide Polymorphisms (SNPs)


The genomes of all organisms undergo spontaneous mutations 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 individual members of a 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 environment. 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 segregating at appreciable frequencies is defined as a genetic polymorphism, which includes single nucleotide polymorphisms (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 (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 71(4):854-62 (October 2002).


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 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 (July 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., Clinical Chemistry 43:254 (1997); Marshall, Nature Biotechnology 15:1249 (1997); International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et al., Nature Biotechnology 16:3 (1998).


SUMMARY OF THE INVENTION

Exemplary embodiments of the present invention relate to the identification of SNPs that are associated with risk for developing venous thrombosis (VT) and/or variability between individuals in their response to statins, particularly for the prevention or treatment of VT. These SNPs are useful for determining risk and/or statin response for primary and recurrent VT. Accordingly, the polymorphisms disclosed herein are directly useful as targets for the design of diagnostic and prognostic reagents and the development of therapeutic and preventive agents for use in the diagnosis, prognosis, treatment, and/or prevention of VT, as well as for predicting a patient's response to therapeutic agents such as statins, particularly for the treatment or prevention of VT.


Based on the identification of SNPs associated with risk for developing VT and/or variability between individuals in their response to statins, particularly for reducing the risk of VT, exemplary embodiments of the present invention also provide 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, SNPs associated with VT risk and/or responsiveness to statin treatment for reducing VT risk, isolated nucleic acid molecules (including 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, methods for determining the risk of an individual for developing recurrent VT, methods of treating an individual who has an increased risk for VT, and methods for identifying individuals (e.g., determining a particular individual's likelihood) who have an altered (i.e., increased or decreased) likelihood of responding to drug treatment (especially statin treatment), particularly drug treatment of 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 such as statins, methods of screening for compounds useful in the treatment or prevention of VT, compounds identified by these methods, methods of treating or preventing VT, etc.


Exemplary embodiments of the present invention further provide methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer statin treatment to an individual having VT, or who is at risk for developing VT in the future, or who has previously had VT, methods for selecting a particular statin-based treatment regimen such as dosage and frequency of administration of statin, or a particular form/type of statin such as a particular pharmaceutical formulation or statin compound, methods for administering an alternative, non-statin-based treatment (such as warfarin or other anticoagulants, e.g., direct thrombin inhibitors such as dabigatran, or direct factor Xa inhibitors such as rivaroxaban or apixaban) to individuals who are predicted to be unlikely to respond positively to statin treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from statin treatment, etc. Various embodiments of the present invention also provide methods for selecting individuals to whom a statin or other therapeutic will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a statin or other therapeutic agent based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the statin treatment and/or excluding individuals from the trial who are unlikely to respond positively from the statin treatment based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to statins based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them). Further embodiments of the present invention provide methods for reducing an individual's risk of developing VT using statin treatment, including preventing recurrent VT using statin treatment, when said individual carries one or more SNPs identified herein as being associated with statin response.


Tables 1 and 2 provides gene information, references to the identification of transcript sequences (SEQ ID NOS:1-84), encoded amino acid sequences (SEQ ID NOS:85-168), genomic sequences (SEQ ID NOS:338-500), transcript-based context sequences (SEQ ID NOS:169-337) and genomic-based context sequences (SEQ ID NOS:501-3098) that contain the SNPs of the present application, 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:1-84), amino acid sequences (SEQ ID NOS:85-168), genomic sequences (SEQ ID NOS:338-500), transcript-based SNP context sequences (SEQ ID NOS:169-337), and genomic-based SNP context sequences (SEQ ID NOS:501-3098) are provided in the Sequence Listing.


In certain exemplary embodiments, the invention provides methods for identifying an individual who has an altered risk for developing VT (including, for example, a first incidence and/or a recurrence of the disease, such as primary or recurrent VT), in which the method comprises detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-84, SEQ ID NOS:169-337, SEQ ID NOS:338-500, and SEQ ID NOS:501-3098 in said individual's nucleic acids, wherein the SNP is specified in Table 1 and/or Table 2, and the presence of the SNP is indicative of an altered risk for VT in said individual. In certain embodiments, the VT is deep vein thrombosis (DVT) or pulmonary embolism (PE). In certain embodiments, the VT is recurrent VT. In certain exemplary embodiments of the invention, SNPs that occur naturally in the human genome are provided within isolated nucleic acid molecules. These SNPs are associated with response to statin treatment thereby reducing the risk of VT, such that they can have a variety of uses in the diagnosis, prognosis, treatment, and/or prevention of VT, and particularly in the treatment or prevention of VT using statins. 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 further embodiments of the invention, reagents for detecting a SNP in the context of its naturally-occurring flanking nucleotide sequences (which can be, e.g., either DNA or mRNA) are 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 the SNP detection reagents. An exemplary embodiment of the present invention provides a kit comprising a SNP detection reagent for use in determining whether a human's risk for VT is reduced by treatment with statins based upon the presence or absence of a particular allele of one or more SNPs disclosed herein.


In various embodiments, the present invention provides methods for evaluating whether an individual is likely (or unlikely) to respond to statin treatment (i.e., benefit from statin treatment)), particularly statin treatment for reducing the risk of VT (including recurrent VT), by detecting the presence or absence of one or more SNP alleles disclosed herein. In certain embodiments, the VT is DVT or PE. In certain embodiments, the VT is recurrent VT. The present invention also provides methods of identifying an individual having an increased or decreased risk of developing VT (including recurrent VT) by detecting the presence or absence of one or more SNP alleles disclosed herein. In certain embodiments, the VT is DVT or PE. In other embodiments, a method for diagnosis or prognosis 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 or prevention of VT.


An aspect of this invention is a method for treating or preventing VT (including, for example, a first occurrence and/or a recurrence of the disease, such as primary or recurrent VT), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 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 a gene, transcript, and/or encoded protein identified in Tables 1 and 2.


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 and 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 or preventing VT, in a human subject, in which the method comprises:


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


Another aspect of the invention is a method for identifying a human who is likely to benefit from statin treatment, in which the method comprises detecting an allele of one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele indicates that said human is likely to benefit from statin treatment.


Another aspect of the invention is a method for identifying a human who is likely to benefit from statin treatment, in which the method comprises detecting an allele of one or more SNPs that are in LD with one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele of the LD SNP indicates that said human is likely to benefit from statin treatment.


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 exemplary 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_CD0000290RD.txt provides the Sequence Listing. The Sequence Listing provides the transcript sequences (SEQ ID NOS:1-84) and protein sequences (SEQ ID NOS:85-168) as referred to in Table 1, and genomic sequences (SEQ ID NOS:338-500) as referred to in Table 2, for each gene (or genomic region for intergenic SNPs) that contains one or more statin response-associated 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:169-337) and genomic-based context sequences as referred to in Table 2 (SEQ ID NOS:501-3098). 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. File SEQLIST_CD0000290RD.txt is 22,428 KB in size, and was created on Oct. 31, 2011.









LENGTHY TABLES




The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).






2) File TABLE1_CD0000290RD.txt provides Table 1, which is 172 KB in size and was created on Oct. 28, 2011.


3) File TABLE2—CD0000290RD.txt provides Table 2, which is 1,843 KB in size and was created on Oct. 28, 2011.


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





DESCRIPTION OF THE FIGURE

The FIGURE shows two SNP in the F11 gene significantly associated with statin response for reducing VT risk: F11 SNP rs2036914 and F11 SNP rs2289252. The FIGURE shows risk of VT according to statin use for rs2289252, rs2036914, and Factor V Leiden genotypes. The odds ratios (shown with 95% confidence intervals) were adjusted for sex and age.





DESCRIPTION OF TABLE 1 AND TABLE 2

Table 1 and Table 2 (both submitted electronically via EFS-Web as part of the instant application) 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 NO), 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 NO) 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 be readily cross-referenced between all Tables based on their Celera hCV (or, in some instances, hDV) identification numbers and/or public rs 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 gene symbol, along with an Entrez gene identification number (Entrez Gene database, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health) (if Entrez gene information is unavailable, then Ensembl gene information is used instead)
    • a gene name,
    • an accession number for the transcript (e.g., RefSeq NM number and/or a Celera hCT identification number) (Table 1 only) (if RefSeq transcript information is unavailable, then Ensembl transcript information is used instead),
    • an accession number for the protein (e.g., RefSeq NP number and/or a Celera hCP identification number) (Table 1 only) (if RefSeq protein information is unavailable, then Ensembl protein information is used instead),
    • the chromosome number of the chromosome on which the gene is located,
    • an OMIM (“Online Mendelian Inheritance in Man” database, Johns Hopkins University/NCBI) public reference number for the gene, and OMIM information such as alternative gene/protein name(s) and/or symbol(s) in the OMIM 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 (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:169-337); SEQ ID NOs are indicated in Table 2 for the genomic-based context sequences (SEQ ID NOS:501-3098).


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:169-337; the genomic-based SNP context sequences in Table 2 are provided in the Sequence Listing as SEQ ID NOS:501-3098).
    • 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 Chromosome Position” indicates the nucleotide position of the SNP along the entire sequence of the chromosome as provided in NCBI Genome Build 37.
    • SNP position (nucleotide position of the SNP within the given transcript sequence (Table 1) or within the given genomic sequence (Table 2)).
    • “Related Interrogated SNP” is 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.

    • 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 six 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, six male and six female.


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) [“MIS-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, codon1) (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 a list of LD SNPs that are related to and derived from certain interrogated SNPs. The interrogated SNPs, which are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 3, are statistically significantly associated with VT risk (particularly risk for recurrent VT) and/or statin response for reducing VT risk, as described and shown herein, particularly in Tables 4-9 and in the Examples sections below. The LD SNPs are provided as an example of SNPs which can also serve as markers for disease association based on their being in LD with an interrogated SNP. The criteria and process of selecting such LD SNPs, including the calculation of the r2 value and the threshold r2 value, are described in Example 7, below.


In Table 3, the column labeled “Interrogated SNP” presents each marker as identified by its unique hCV identification number. The column labeled “Interrogated rs” presents the publicly known rs identification 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 identification number for the corresponding hCV number. The column labeled “Power” presents the level of power where the r2 threshold is set. For example, when power is set at 0.51, 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 r2” 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 Tables 4-9


Tables 4-9 provide the results of analyses for SNPs disclosed in Tables 1 and 2 (SNPs can be cross-referenced between all the tables herein based on their hCV and/or rs identification numbers).


The analyses in Tables 4-6 are further described in Example 1 below.


The analysis in Table 7 is further described in Example 3 below.


The analysis in Table 8 is further described in Example 4 below.


The analysis in Table 9 is further described in Example 5 below.


The results shown in Tables 4-9 provide support for the association of these SNPs with VT risk, particularly risk for recurrent VT, and/or response to statin treatment for reducing the risk of VT.


In Tables 4-6, “statin1” or “statin user” are equivalent designations that refer to individuals who were using statins, and “statin0” or “statin nonuser” are equivalent designations that refer to individuals who were not using statins.


Throughout Tables 4-9, “P” or “P-value” indicates the p-value, “p(int)” indicates the p(interaction) value, “OR” refers to the odds ratio, “HR” refers to the hazard ratio, and “95% CI” refers to the 95% confidence interval for the odds ratio or hazard ratio.


In Tables 7-9, “P_DF2” indicates the two degrees of freedom Wald Test p-value.


In Tables 8-9, “HW(control)pExact” indicates the Hardy-Weinberg p-value for all controls in the study.


With respect to drug response (e.g., response to a statin), if the OR or HR of those treated with the drug (e.g., a statin) compared with those treated with a placebo within a particular genotype (or with a particular allele) is less than one, this indicates that an individual with this particular genotype or allele would benefit from the drug (an OR or HR equal to one would indicate that the drug has no effect). In contrast, with respect to drug response, if the OR or HR is greater than one for a particular allele, then this indicates that an individual with the other alternative allele would benefit from the drug. 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 administering 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.


With respect to disease risk, an OR or HR that is greater than one indicates that a given allele is a risk allele (which may also be referred to as a susceptibility allele), whereas an OR or HR that is less than one indicates 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, if the OR or HR 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 OR 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.


DETAILED DESCRIPTION OF THE INVENTION

Exemplary embodiments of the present invention provide SNPs associated with risk for developing venous thrombosis (VT) (interchangeably referred to as venous thromboembolism (VTE)) and/or response to statin treatment, particularly statin treatment for reducing the risk of VT, and methods for their use. The present invention further provides nucleic acid molecules containing these 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 statin response-associated SNPs disclosed herein are particularly useful for predicting, screening for, and evaluating response to statin treatment, particularly for prevention or treatment of VT using statins, in humans. The SNPs disclosed herein are also useful for diagnosing, prognosing, screening for, and evaluating predisposition to VT in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic and preventive agents.


Thus, exemplary embodiments of the present invention provide individual SNPs associated with risk for developing VT and/or response to statin treatment, particularly statin treatment for reducing the risk of VT, as well as combinations of SNPs and haplotypes, polymorphic/variant transcript sequences (SEQ ID NOS:1-84) and genomic sequences (SEQ ID NOS:338-500) containing SNPs, encoded amino acid sequences (SEQ ID NOS:85-168), and both transcript-based SNP context sequences (SEQ ID NOS:169-337) and genomic-based SNP context sequences (SEQ ID NOS:501-3098) (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 an individual's risk for developing VT, methods of determining if an individual is likely to respond to a particular treatment such as statins (particularly for treating or preventing VT), methods of screening for compounds useful for treating VT, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment/preventive strategy or therapeutic agent, and methods of treating or preventing VT.


Exemplary embodiments of the present invention further provide methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer statin treatment to an individual having VT, or who is at risk for developing VT in the future, or who has previously had VT, methods for selecting a particular statin-based treatment regimen such as dosage and frequency of administration of statin, or a particular form/type of statin such as a particular pharmaceutical formulation or statin compound, methods for administering an alternative, non-statin-based treatment (such as warfarin or other anticoagulants, e.g., direct thrombin inhibitors such as dabigatran, or direct factor Xa inhibitors such as rivaroxaban or apixaban) to individuals who are predicted to be unlikely to respond positively to statin treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from statin treatment, etc. The present invention also provides methods for selecting individuals to whom a statin or other therapeutic will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a statin or other therapeutic agent based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the statin treatment and/or excluding individuals from the trial who are unlikely to respond positively from the statin treatment based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to statins based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them).


Exemplary embodiments of the present invention may include novel SNPs associated with VT risk and/or response to statin treatment, as well as SNPs that were previously known in the art, but were not previously known to be associated with VT risk and/or response to statin treatment. Accordingly, the present invention may provide novel compositions and methods based on novel SNPs disclosed herein, and may also provide novel methods of using known, but previously unassociated, SNPs in methods relating to, for example, methods relating to evaluating an individual's likelihood of responding to statin treatment (particularly statin treatment, including preventive treatment, of VT, including recurrent VT), evaluating an individual's likelihood of having or developing VT, and predicting the likelihood of an individual experiencing a recurrence of VT. In Tables 1 and 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).


Particular alleles of the SNPs disclosed herein can be associated with either an increased likelihood of responding to statin treatment (particularly for reducing the risk of VT) or increased risk of developing VT, or a decreased likelihood of responding to statin treatment or a decreased risk of developing VT. 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 likelihood of responding to statin treatment or an increased risk of developing VT, other SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of a decreased likelihood of responding to statin treatment or a decreased risk of developing VT. Similarly, particular alleles of the SNPs disclosed herein can be associated with either an increased or decreased likelihood of having a recurrence of VT, or of experiencing toxic effects from a particular treatment or therapeutic compound such as statins, etc. The term “altered” may be used herein to encompass either of these two possibilities (e.g., either an increased or a decreased likelihood/risk). 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”.


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 “represented by”, “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). In other words, it is recognized that the context sequence of SEQ ID NO:X in this example may contain one or more polymorphic nucleotide positions outside of position 101 and therefore an exact match over the full-length of SEQ ID NO:X is irrelevant since SEQ ID NO:X is only meant to provide context for referring to the SNP at position 101 of SEQ ID NO:X. Likewise, the length of the context sequence is also irrelevant (100 nucleotides on each side of a SNP position has been arbitrarily used in the present application as the length for context sequences merely for convenience and because 201 nucleotides of total length is expected to provide sufficient uniqueness to unambiguously identify a given nucleotide sequence). Thus, since a SNP is a variation at a single nucleotide position, 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). For example, in the instant application, “rs2036914”, “hCV12066124”, and “position 101 of SEQ ID NO:713” all refer to the same SNP.


As used herein, the term “benefit” (with respect to a preventive or therapeutic drug treatment, such as statin 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).


Examples of statins (also known as HMG-CoA reductase inhibitors) include, but are not limited to, atorvastatin (Lipitor®), rosuvastatin (Crestor®), pravastatin (Pravachol®), simvastatin (Zocor®), fluvastatin (Lescol®), and lovastatin (Mevacor®), as well as combination therapies that include a statin such as simvastatin+ezetimibe (Vytorin®), lovastatin+niacin (Advicor®), atorvastatin+amlodipine besylate (Caduet®), and simvastatin+niacin (Simcor®).


Certain exemplary embodiments of the invention provide the following compositions and uses: (1) a reagent (such as an allele-specific probe or primer, or any other oligonucleotide or other reagent suitable for detecting a polymorphism disclosed herein, which can include detection of any allele of the polymorphism) for use as a diagnostic or predictive agent for determining VT risk and/or statin response, particularly for reducing the risk of VT; (2) a kit, device, array, or assay component that includes or is coupled with the reagent of (1) above for use in determining VT risk and/or statin response, particularly for reducing the risk of VT; (3) the use of the reagent of (1) above for the manufacture of a kit, device, array, or assay component for determining VT risk and/or statin response, particularly for reducing the risk of VT; and (4) the use of a polymorphism disclosed herein for the manufacture of a reagent for use as a diagnostic or predictive agent for determining VT risk and/or statin response, particularly for reducing the risk of VT.


The various methods described herein, such as correlating the presence or absence of a polymorphism with the predicted response of an individual to a drug such as a statin, particularly for reducing the risk for VT, and/or correlating the presence or absence of a polymorphism with an altered (e.g., increased or decreased) risk (or no altered risk) for developing 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) response (or no altered response) to statin treatment for reducing the risk for VT, and/or correlating the presence or absence of a polymorphism with an altered (e.g., increased or decreased) risk (or no altered risk) for developing VT. Accordingly, certain embodiments of the invention provide a computer (or other apparatus/device) programmed to carry out any of the methods described herein.


Reagants, and kits containing the reagents, for detecting a SNP disclosed herein can be manufactured in compliance with regulatory requirements for clinical diagnostic use, such as those set forth by the United States Food and Drug Administration (FDA). Reagents and kits can be manufactured in compliance with “good manufacturing practice” (GMP) guidelines, such as “current good manufacturing practices” (cGMP) guidelines in the United States. Furthermore, reagents and kits can be registered with the FDA (such as by satisfying 510(k) Pre-Market Notification (PMN) requirements or obtaining Pre-Market Approval (PMA)). Reagents (particularly reagents for clinical diagnostic use) for detecting a SNP disclosed herein can be classified by the FDA (or other agency) as an analyte specific reagent (ASR) (or similar classification), and kits (particularly kits for clinical diagnostic use) containing reagents for detecting a SNP disclosed herein can be classified by the FDA (or other agency) as in vitro diagnostic (IVD) kits or laboratory developed tests (LDTs) (or similar classifications), including in vitro diagnostic multivariate index assays (IVDMIAs). Furthermore, reagents and kits can be classified by the FDA (or other agency) as Class I, Class II, or Class III medical devices. Reagents and kits can also be registered with (e.g., approved by) and/or manufactured in compliance with regulatory requirements set forth by the Clinical Laboratory Improvement Amendments Act (CLIA), which is administered by the Centers for Medicare and Medicaid Services (CMS), or other agencies in the United States or throughout the rest of the world.


Reports, Programmed Computers, Business Methods, and Systems


The results of a test (e.g., an individual's predicted responsiveness to statin treatment, or an individual's risk for developing VT, 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 practitioners 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 predicted risk for developing DVT and/or predicted responsiveness to statin treatment (e.g., whether the individual will benefit from statin treatment by having their risk for VT reduced), 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 statin response and/or VT risk, for individuals having a certain allele/genotype at the SNP). Thus, for example, the report can include drug responsiveness, disease risk, and/or other medical/biological significance, as well as optionally also including the allele/genotype information, or the report may just include allele/genotype information without including drug responsiveness, disease risk, or other medical/biological significance (such that an individual viewing the report can use the allele/genotype information to determine the associated drug response, disease risk, or other medical/biological significance from a source outside of the report itself, such as from a medical practitioner, 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/sending 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 (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 predicted statin responsiveness or risk for developing VT) or other result 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 predicted response to statin treatment (e.g., for reducing their risk for VT) or their risk for developing 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, a kit for collecting a biological sample (e.g., a buccal swab for collecting buccal cells, or other sample collection device) is provided to a medical practitioner (e.g., a physician) which the medical practitioner uses to obtain a sample (e.g., buccal cells, saliva, blood, etc.) from a patient, the sample is then sent to a laboratory (e.g., a CLIA-certified laboratory) or other facility that tests the sample for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the patient's predicted response to statin treatment for reducing their risk for VT, and/or their risk for developing VT), and the results of the test (e.g., the patient's genotype at one or more SNPs disclosed herein and/or the patient's predicted statin response or VT risk based on their SNP genotype) are provided back to the medical practitioner (and/or directly to the patient and/or to another party such as a hospital, medical insurance company, genetic counselor, etc.) who may then provide or otherwise convey the results to the patient. The results are typically provided in the form of a report, such as described above.


In certain further exemplary methods of doing business, kits for collecting a biological sample from a customer (e.g., a buccal swab for collecting buccal cells, or other sample collection device) 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 (e.g., a CLIA-certified laboratory) or other facility which tests the samples for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the customer's predicted response to statin treatment for reducing their risk for VT, and/or their risk for developing VT) and provides the results of the test (e.g., of the customer's genotype at one or more SNPs disclosed herein and/or the customer's statin response or VT risk based on their SNP genotype) back to the customer and/or to a third party (e.g., a physician or other medical practitioner, hospital, medical insurance company, genetic counselor, etc.). The results are typically provided in the form of a report, such as described above. If the results of the test are provided to a third party, then this third party may optionally provide another report to the customer based on the results of the test (e.g., the result of the test from the laboratory may provide the customer's genotype at one or more SNPs disclosed herein without statin response or VT risk information, and the third party may provide a report of the customer's statin response or VT risk based on this genotype result).


Certain further embodiments of the invention provide a system for determining whether an individual will benefit from statin treatment (or other therapy) in reducing VT risk, or for determining an individual's risk for developing VT. Certain exemplary systems comprise an integrated “loop” in which an individual (or their medical practitioner) requests a determination of such individual's predicted statin response (or VT risk, 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., buccal cells, saliva, blood, etc.) 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 practitioner, 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 predicted statin response (or VT risk, 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 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 statin or other drug for reducing VT 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 VT risk, this may include any means used in the art for improving aspects of an individual's health relevant to reducing VT risk. Thus, in exemplary embodiments, the system is controlled by the individual and/or their medical practitioner in that the individual and/or their medical practitioner 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 system.


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 risk for developing VT and/or response to statin treatment (particularly for reducing an individual's risk for VT), including the transcript sequences (SEQ ID NOS:1-84), genomic sequences (SEQ ID NOS:338-500), and protein sequences (SEQ ID NOS:85-168) 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:169-337 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS:501-3098 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


Exemplary embodiments of the invention provide isolated nucleic acid molecules that contain one or more SNPs disclosed herein, particularly SNPs disclosed in Table 1 and/or Table 2. Isolated nucleic acid molecules containing one or more SNPs disclosed herein (such as in at least one of Tables 1 and 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:1-84), and polymorphic genomic sequences are referred to in Table 2 and provided in the Sequence Listing (SEQ ID NOS:338-500). 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 and 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-84, genomic sequences are referred to in Table 2 as SEQ ID NOS:338-500, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:169-337, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:501-3098) 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. Furthermore, a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 nucleotides in length (or any other number in between). 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 and 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:1-84, genomic sequences are referred to in Table 2 as SEQ ID NOS:338-500, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:169-337, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:501-3098), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:85-168). 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:1-84, genomic sequences are referred to in Table 2 as SEQ ID NOS:338-500, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:169-337, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:501-3098), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:85-168). 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:1-84, genomic sequences are referred to in Table 2 as SEQ ID NOS:338-500, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:169-337, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:501-3098), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:85-168). 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, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).


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, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000). 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; and 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 15(6):224-9 (June 1997), and Hyrup et al., “Peptide nucleic acids (PNA): synthesis, properties and potential applications,” Bioorg Med Chem 4(1):5-23) (January 1996). 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); WO 96/04000. 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 and 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 and 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 and 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, A. M. Lesk, ed., Oxford University Press, N.Y (1988); Biocomputing: Informatics and Genome Projects, D. W. Smith, ed., Academic Press, N.Y. (1993); Computer Analysis of Sequence Data, Part 1, A. M. Griffin and H. G. Griffin, eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology, G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence Analysis Primer, M. Gribskov and J. Devereux, eds., M. Stockton Press, N.Y. (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 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. J. Devereux et al., Nucleic Acids Res. 12(1):387 (1984). 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; for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0). 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. 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 20(12):1269-71 (December 2002)). 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:1-84), genomic sequences (referred to in Table 2 as SEQ ID NOS:338-500), and context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:169-337; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:501-3098), 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:169-337; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:501-3098). 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:1-84), genomic sequences (SEQ ID NOS:338-500), and SNP context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:169-337; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:501-3098) disclosed in the Sequence Listing and in Tables 1 and 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, Cotton et al., eds., 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 not limited to, the phosphotriester method described by Narang et al., Methods in Enzymology 68:90 (1979); the phosphodiester method described by Brown et al., Methods in Enzymology 68:109 (1979); the diethylphosphoamidate method described by Beaucage et al., Tetrahedron Letters 22:1859 (1981); 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, Nucleic Acid Res 17:2427-2448 (1989). 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., PCR Method Appl 4:357-362 (1995); Tyagi et al., Nature Biotechnology 14:303-308 (1996); Nazarenko et al., Nucl Acids Res 25:2516-2521 (1997); 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.


Exemplary kits of the invention can comprise a container containing a SNP detection reagent which detects a SNP disclosed herein, said container can optionally be enclosed in a package (e.g., a box for commercial sale), and said package can further include other containers containing any or all of the following: enzyme (e.g., polymerase or ligase, any of which can be thermostable), dNTPs and/or ddNTPs (which can optionally be detectably labeled, such as with a fluorescent label or mass tag, and such label can optionally differ between any of the dATPs, dCTPs, dGTPs, dTTPs, ddATPs, ddCTPs, ddGTPs, and/or ddTTPs, so that each of these dNTPs and/or ddNTPs can be distinguished from each other by detection of the label, and any of these dNTPs and/or ddNTPs can optionally be stored in the same container or each in separate containers), buffer, controls (e.g., positive control nucleic acid, or a negative control), reagent(s) for extracting nucleic acid from a test sample, and instructions for using the kit (such as instructions for correlating the presence or absence of a particular allele or genotype with an increased or decreased risk for disease such as VT, or an increased or decreased likelihood of responding to a drug such as a statin). The SNP detection reagent can comprise, for example, at least one primer and/or probe, any of which can optionally be allele-specific, and any of which can optionally be detectably labeled (e.g., with a fluorescent label).


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 Chee et al., U.S. Pat. No. 5,837,832 and PCT application WO95/11995; D. J. Lockhart et al., Nat Biotech 14:1675-1680 (1996); and M. Schena et al., Proc Natl Acad Sci 93:10614-10619 (1996), 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 8:85-101 (2002); Sosnowski et al., “Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications,” Psychiatr Genet 12(4):181-92 (December 2002); Heller, “DNA microarray technology: devices, systems, and applications,” Annu Rev Biomed Eng 4:129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al., “Analysis of SNPs and other genomic variations using gel-based chips,” Hum Mutat 19(4):343-60 (April 2002); and McGall et al., “High-density genechip oligonucleotide probe arrays,” Adv Biochem Eng Biotechnol 77:21-42 (2002).


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 6.3.1-6.3.6, John Wiley & Sons, N.Y. (1989).


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 applications that describe chemiluminescent approaches for microarray detection: Ser. No. 10/620,332 and Ser. No. 10/620,333. U.S. patents that describe methods and compositions of dioxetane for performing chemiluminescent 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 5,773,628. And the U.S. published application that discloses methods and compositions for microarray controls: US2002/0110828.


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) such as buccal cells (e.g., as obtained by buccal swabs), biopsies, 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 55(3):349-77 (February 2003). 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. No. 6,153,073, Dubrow et al., and U.S. Pat. No. 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, particularly for predicting whether an individual will benefit from statin treatment by reducing their risk for VT in response to the statin treatment, as well as for the diagnosis, prognosis, treatment, and prevention of VT. For example, the nucleic acid molecules of the invention are useful for determining the likelihood of an individual who currently or previously has or has had VT or who is at increased risk for developing VT (such as an individual who has not yet had VT but is at increased risk for having VT in the future) of responding to treatment (or prevention) of VT with statins (such as by reducing their risk of developing primary or recurrent VT in the future), predicting the likelihood that the individual will experience toxicity or other undesirable side effects from the statin treatment, predicting an individual's risk for developing VT, etc. 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, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).


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 the likelihood that an individual will respond positively to statin treatment for reducing the risk of VT, or whether an individual with the polymorphism(s) is at risk for developing VT (or has already 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 allows, 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 nucleotide(s) is/are present at each of one or more SNP positions (such as a SNP position disclosed in Table 1 and/or Table 2), for either or both alleles, may be referred to by such phrases as SNP genotyping, determining the “identity” of a SNP, determining the “content” of a SNP, or determining which nucleotide(s)/allele(s) is/are present at a SNP position. Thus, these terms can refer to detecting a single allele (nucleotide) at a SNP position or can encompass detecting both alleles (nucleotides) at a SNP position (such as to determine the homozygous or heterozygous state of a SNP position). Furthermore, these terms may also refer to detecting an amino acid residue encoded by a SNP (such as alternative amino acid residues that are encoded by different codons created by alternative nucleotides at a missense SNP position, for example).


The present invention provides methods of SNP genotyping, such as for use in implementing a preventive or treatment regimen for an individual based on that individual having an increased susceptibility for developing VT and/or an increased likelihood of benefiting from statin treatment for reducing the risk of VT, in evaluating an individual's likelihood of responding to statin treatment (particularly for treating or preventing VT), in selecting a treatment or preventive regimen (e.g., in deciding whether or not to administer statin treatment to an individual having VT, or who is at increased risk for developing VT in the future), or in formulating or selecting a particular statin-based treatment or preventive regimen such as dosage and/or frequency of administration of statin treatment or choosing which form/type of statin to be administered, such as a particular pharmaceutical composition or compound, etc.), determining the likelihood of experiencing toxicity or other undesirable side effects from statin treatment, or selecting individuals for a clinical trial of a statin (e.g., selecting individuals to participate in the trial who are most likely to respond positively from the statin treatment and/or excluding individuals from the trial who are unlikely to respond positively from the statin treatment based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to statins based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them), etc. The SNP genotyping methods of the invention can also be useful for evaluating an individual's risk for developing VT and for predicting the likelihood that an individual who has previously had VT will have a recurrence of VT again in the future (recurrent VT).


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 3(2):77-96 (2003); Kwok et al., “Detection of single nucleotide polymorphisms,” Curr Issues Mol Biol 5(2):43-60 (April 2003); Shi, “Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes,” Am J Pharmacogenomics 2(3):197-205 (2002); and Kwok, “Methods for genotyping single nucleotide polymorphisms,” Annu Rev Genomics Hum Genet 2:235-58 (2001). Exemplary techniques for high-throughput SNP genotyping are described in Marnellos, “High-throughput SNP analysis for genetic association studies,” Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). 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, for example, screening individuals for their likelihood of responding to statin treatment (i.e., benefiting from statin treatment), particularly individuals who have or are susceptible to VT, or in screening for individuals who are susceptible to developing VT. These probes and primers 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. The following U.S. patents describe OLA strategies for performing SNP detection: U.S. Pat. Nos. 6,027,889; 6,268,148; 5,494,810; 5,830,711 and 6,054,564. 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 Ser. No. 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 17(11):1195-202 (2003).


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 19 Suppl 1:144-153 (July 2003); Storm et al., “MALDI-TOF mass spectrometry-based SNP genotyping,” Methods Mol Biol 212:241-62 (2003); Jurinke et al., “The use of Mass ARRAY technology for high throughput genotyping,” Adv Biochem Eng Biotechnol 77:57-74 (2002); and Jurinke et al., “Automated genotyping using the DNA MassArray technology,” Methods Mol Biol 187:179-92 (2002).


SNPs can also be scored by direct DNA sequencing. A variety of automated sequencing procedures can be utilized (e.g. Biotechniques 19:448 (1995)), including sequencing by mass spectrometry. See, e.g., PCT International Publication No. WO 94/16101; 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. PCR Technology: Principles and Applications for DNA Amplification Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y. (1992).


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 patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent, and predicting the likelihood that an individual will experience toxic side effects from a therapeutic agent.


Analysis of Genetic Associations 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 609-622, Lippincott, Williams & Wilkins (1998). 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.


Case-only studies are an alternative to case-control studies when gene-environment interaction is the association of interest (Piegorsch et al., “Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies”, Statistics in Medicine 13 (1994) pp 153-162). In a typical case-only study of gene-environment interaction, genotypes are obtained only from cases who are often selected from an existing cohort study. The association between genotypes and the environmental factor is then assessed and a significant association implies that the effect of the environmental factor on the endpoint of interest (the case definition) differs by genotype. The primary assumption underlying the test of association in case-only studies is that the environmental effect of interest is independent of genotype (e.g., allocation to statin therapy is independent of genotype) and it has been shown that the case-only design has more power than the case-control design to detect gene-environment interaction when this assumption is true in the population (Yang et al., “Sample Size Requirements in Case-Only Designs to Detect Gene-Environment Interaction”, American Journal of Epidemiology 146:9 (1997) pp 713-720). Selecting cases from a randomized clinical trial may be an ideal setting in which to perform a case-only study since genotypes will be independent of treatment by design.


In 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. B. Weir, Genetic Data Analysis, 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 or allelic (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). Hosmer and Lemeshow, Applied Logistic Regression, 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 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. Daly et al, Nature Genetics 29:232-235 (2001). 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 that score tests can be done on haplotypes using the program “haplo.score.” Schaid et al, Am J Hum Genet 70:425-434 (2002). 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. Westfall et al., Multiple comparisons and multiple tests, 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); Westfall and Young, Resampling-based Multiple Testing, 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 643-673, Lippincott, Williams & Wilkins (1998). 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 when prevalence of the disease is associated with different subpopulation groups. Ewens and Spielman, Am J Hum Genet 62:450-458 (1995). Such bias can also lead to a loss of statistical power in genetic association studies. To detect population stratification, Pritchard and Rosenberg 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. Pritchard et al., Am J Hum Gen 65:220-228 (1999). When stratification is detected, the genomic control (GC) method as proposed by Devlin and Roeder can be used to adjust for the inflation of test statistics due to population stratification. Devlin et al., Biometrics 55:997-1004 (1999). The GC method is robust to changes in population structure levels as well as being applicable to DNA pooling designs. Devlin et al., Genet Epidem 21:273-284 (2001).


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 that about 60-70 biallelic markers are sufficient to estimate the inflation factor for the test statistics due to population stratification. Bacanu et al., Am J Hum Genet 66:1933-1944 (2000). Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicated in a genome scan. Kehoe et al., Hum Mol Genet 8:237-245 (1999).


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. Draper and Smith, Applied Regression Analysis, 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).


For further information about genetic association studies, see Balding, “A tutorial on statistical methods for population association studies”, Nature Reviews Genetics 7, 781 (2006).


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 responsiveness of an individual to statin treatment, or to the development of VT, 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/predictive screening (i.e., determining whether an individual has an increased or decreased risk of developing VT in the future), predicting recurrence of VT in an individual, determining a particular type or subclass of VT in an individual who currently or previously had VT, confirming or reinforcing a previously made diagnosis of VT, evaluating an individual's likelihood of responding positively to a particular treatment or therapeutic agent (i.e., benefiting) such as statin treatment (particularly treatment or prevention of VT using statins), determining or selecting a therapeutic or preventive strategy that an individual is most likely to positively respond to (e.g., selecting a particular therapeutic agent such as a statin, or combination of therapeutic agents, or selecting a particular statin from among other statins, or determining a dosing regimen or selecting a dosage formulation, etc.), classifying (or confirming/reinforcing) an individual as a responder/non-responder (or determining a particular subtype of responder/non-responder) with respect to the individual's response to a drug treatment such as statin treatment, and predicting whether a patient is likely to experience toxic effects from a particular treatment or therapeutic compound. Such diagnostic uses can be based on the SNPs individually or a unique combination or SNPs disclosed herein, as well as SNP haplotypes.


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


As discussed above, an aspect of the present invention relates to SNPs that are in LD with an interrogated SNP and which can also be used as valid markers for determining an individual's likelihood of benefiting from statin treatment, or whether an individual has an increased or decreased risk of having or developing VT. As used herein, the term “interrogated SNP” refers to SNPs that have been found to be associated with statin response, particularly for reducing VT risk, 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 associated with statin response or an increased or decreased risk of VT 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.


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 B2/A2B1. 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 a will be deemed statistically significant). Define the standard Gaussian distribution function as Φ(•). Mathematically,










Φ


(
x
)


=


1


2

π








-


x






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(
28
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Alternatively, the following error function notation (Erf) may also be used,










Φ


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1
+

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(

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(
29
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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
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q

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,
cs


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;




(
30
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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, one obtains Z0.975=1.95996. Next, setting power equal to a threshold of a minimum power of T,









T
=

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r
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(
31
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and solving for r2, the following threshold r2 is obtained:











r
T
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=




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n


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Or
,





(
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r
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(
33
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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.


Imputation


Genotypes of SNPs can be imputed without actually having to be directly genotyped (referred to as “imputation”), by using known haplotype information. Imputation is a process to provide “missing” data, either missing individual genotypes or missing SNPs and concomitant genotypes, which have not been directly genotyped (i.e., assayed). Imputation is particularly useful for identifying disease associations for specific ungenotyped SNPs by inferring the missing genotypes to these ungenotyped SNPs. Although the process uses similar information to LD, since the phasing and imputation process uses information from multiple SNPs at the same time, the phased haplotype, it is able to infer the genotype and achieve high identifiable accuracy. Genotype information (such as from the HapMap project by The International HapMap Consortium) can be used to infer haplotype phase and impute genotypes for SNPs that are not directly genotyped in a given individual or sample set (such as for a disease association study). In general, imputation uses a reference dataset in which the genotypes of potential SNPs that are to be tested for disease association have been determined in multiple individuals (such as in HapMap); the individuals in the reference dataset are then haplotype phased. This phasing can be done with independent programs such as fastPHASE (Sheet and Stephens, Am J Hum Genet (2006) 76: 629-644) or a combination program such as BEAGLE which does both the phasing and the imputation. The reference phased haplotypes and process can be checked using the children of the HapMap individual parents, among other mechanisms. Once the reference phased haplotypes have been created, the imputation of additional individuals for SNPs genotyped or complete sets of SNPs that have not been directly genotyped can then proceed. The HapMap dataset is particularly useful as the reference dataset, however other datasets can be used. Since the imputation creates new concommitant phased haplotypes for individuals in the association study and these contain other SNPs within the genomic region, these ungenotyped but imputed SNPs can also be tested for disease associations (or other traits). Certain exemplary methods for haplotype phase inference and imputation of missing genotypes utilize the BEAGLE genetic analysis program, (Browning, Hum Genet (2008) 124:439-450).


Thus, SNPs for which genotypes are imputed can be tested for association with a disease or other trait even though these SNPs are not directly genotyped. The SNPs for which genotypes are imputed have genotype data available in the reference dataset, e.g. HapMap individuals, but they are not directly genotyped in a particular individual or sample set (such as in a particular disease association study).


In addition to using a reference dataset (e.g., HapMap) to impute genotypes of SNPs that are not directly genotyped in a study, imputation can provide genotypes of SNPs that were directly genotyped in a study but for which the genotypes are missing, in some or most of the individuals, for some reason, such as because they failed to pass quality control. Imputation can also be used to combine genotyping results from multiple studies in which different sets of SNPs were genotyped to construct a complete meta-analysis. For example, genotyped and imputed genotyped SNP results from multiple different studies can be combined, and the overlapping SNP genotypes (e.g., genotyped in one study, imputed in another study or imputed in both or genotyped in both) can be analyzed across all of the studies (Browning, Hum Genet (2008) 124:439-450).


For a review of imputation (as well as the BEAGLE program), see Browning, “Missing data imputation and haplotype phase inference for genome-wide association studies”, Hum Genet (2008) 124:439-450 and Browning et al. “A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals”, Am J Hum Genet. (2009) February; 84(2):210-23, each of which is incorporated herein by reference in its entirety.


The contribution or association of particular SNPs with statin response or 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 reduced risk for VT in response to statin treatment, 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 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 benefit from statin treatment or individuals who are at risk (or less at risk) of developing VT, but rather to indicate a certain increased (or decreased) degree or likelihood of responding to statin therapy or developing VT based on statistically significant association results. However, this information is extremely valuable as it can be used to, for example, encourage individuals to comply with their statin regimens as prescribed by their doctors (even though the benefit of maintaining statin therapy may not be overtly apparent, which often leads to lack of compliance with prescribed statin treatment), to 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 combination of SNPs 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 or drug response.


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.


Therapeutics, Pharmacogenomics, and Drug Development


Therapeutic Methods and Compositions


In certain aspects of the invention, there are provided methods of assaying (i.e., testing) one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a therapeutic or preventive agent to the individual based on the allele(s) present at the SNP(s) having indicated that the individual can benefit from the therapeutic or preventive agent.


In further aspects of the invention, there are provided methods of assaying one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a diagnostic agent (e.g., an imaging agent), or otherwise carrying out further diagnostic procedures on the individual, based on the allele(s) present at the SNP(s) having indicated that the diagnostic agents or diagnostics procedures are justified in the individual.


In yet other aspects of the 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 an individual who has been tested for one or more SNPs provided by the present invention.


Pharmacogenomics


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


Clinical Trials


In certain aspects of the invention, there are provided methods of using the SNPs disclosed herein to identify or stratify patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent.


For instance, an aspect of the present invention includes selecting individuals for clinical trials based on their SNP genotype, such as selecting individuals for inclusion in a clinical trial and/or assigning individuals to a particular group within a clinical trial (e.g., an “arm” or “cohort” of the trial). 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. Further, one can stratify a prospective trial with patients with different SNP variants to determine the impact of differential drug treatment.


Thus, 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 within a clinical trial based on the presence or absence of one or more SNPs disclosed herein. In certain embodiments, the therapeutic agent is a statin.


In certain exemplary embodiments, SNPs of the invention can be used to select individuals who are unlikely to respond positively to a particular therapeutic agent (or class of therapeutic agents) based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them. Thus, in certain embodiments, the SNPs of the invention can be used to identify patient populations who do not adequately respond to current treatments and are therefore in need of new therapies. This not only benefits the patients themselves, but also benefits organizations such as pharmaceutical companies by enabling the identification of populations that represent markets for new drugs, and enables the efficacy of these new drugs to be tested during clinical trials directly in individuals within these markets.


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, particularly in a treatment regimen or in clinical trials. 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.


Furthermore, the SNPs of the present invention may have utility in determining 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 patient population (e.g., particular VT patients) that can benefit from it.


Identification, Screening, and Use of Therapeutic Agents


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 invention further provides methods 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.


Pharmaceutical Compositions and Administration Thereof


Any of the statin response-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating or preventing VT, 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 18th ed., E. W. Martin, ed., Mack Publishing Company (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 a 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 effects of VT.


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


Nucleic Acid-Based Therapeutic Agents


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


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 22(3):326-30 (March 2004); Epub Feb. 1, 2004; 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 6(6):829-34 (December 2002); Layery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July 2003); Shi, “Mammalian RNAi for the masses,” Trends Genet 19(1):9-12 (January 2003); Shuey et al., “RNAi: gene-silencing in therapeutic intervention,” Drug Discovery Today 7(20):1040-1046 (October 2002); McManus et al., Nat Rev Genet 3(10):737-47 (October 2002); Xia et al., Nat Biotechnol 20(10):1006-10 (October 2002); Plasterk et al., Curr Opin Genet Dev 10(5):562-7 (October 2000); Bosher et al., Nat Cell Biol 2(2):E31-6 (February 2000); and Hunter, Curr Biol 17; 9(12):R440-2 (June 1999).


Other Therapeutic Aspects


SNPs have many important uses in drug discovery, screening, and development, and thus the SNPs of the present invention are useful for improving many different aspects of the drug development process.


For example, 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 S30-S36 (March 2002).


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 19(3):209-11 (March 2001). 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 S30-S36 (March 2002).


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 and 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 and 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.


A subject suffering from a pathological condition ascribed to a SNP, such as VT, 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.


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:85-168 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, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).


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 60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al., “Designing proteins that work using recombinant technologies,” Curr Pharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al., “Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins,” Protein Expr Purif 11(1):1-16 (October 1997).


In certain embodiments, novel compositions of the present invention also relate to further obvious variants of the variant polypeptides of the present invention, such as naturally-occurring mature forms (e.g., allelic 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.


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, for example, in 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, particularly using the amino acid sequence and polymorphism information provided in Table 1. Cunningham et al., Science 244:1081-1085 (1989). 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. Particularly common modifications, for example glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, are described in most basic texts, such as Proteins—Structure and Molecular Properties 2nd Ed., T. E. Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold, Posttranslational Covalent Modification of Proteins 1-12, B. C. Johnson, ed., Academic Press, N.Y. (1983); Seifter et al., Meth Enzymol 182:626-646 (1990); and Rattan et al., Ann NY 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, Sambrook and Russell, Cold Spring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology: Guide to Molecular Cloning Techniques, S. L. Berger and A. R. Kimmel, eds., Academic Press (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:85-168. 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 aspect of the invention, variant proteins of the present invention can be used as targets for predicting an individual's response to statin treatment (particularly for reducing the risk of VT), for determining predisposition to VT, for diagnosing VT, or for treating and/or preventing VT, etc. 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 statin response 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 15; 71(12):294R-304R (June 1999).


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, 10(9), 973-80 (September 1992).


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 to identify other proteins that bind to or interact with the variant protein and are involved in variant protein activity. See, e.g., U.S. Pat. No. 5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J Biol Chem 268:12046-12054 (1993); Bartel et al., Biotechniques 14:920-924 (1993); Iwabuchi et al., Oncogene 8:1693-1696 (1993); and Brent, WO 94/10300. 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, N.Y. (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, which immortalizes cells secreting a specific monoclonal antibody. Kohler and Milstein, Nature 256:495 (1975). 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 (1):53-9 (February 2003); Ross et al., “Anticancer antibodies,” Am J Clin Pathol 119(4):472-85 (April 2003); Goldenberg, “Advancing role of radiolabeled antibodies in the therapy of cancer,” Cancer Immunol Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003; Ross et al., “Antibody-based therapeutics in oncology,” Expert Rev Anticancer Ther 3(1):107-21 (February 2003); Cao et al., “Bispecific antibody conjugates in therapeutics,” Adv Drug Deliv Rev 55(2):171-97 (February 2003); von Mehren et al., “Monoclonal antibody therapy for cancer,” Annu Rev Med 54:343-69 (2003); Epub Dec. 3, 2001; Hudson et al., “Engineered antibodies,” Nat Med 9(1):129-34 (January 2003); Brekke et al., “Therapeutic antibodies for human diseases at the dawn of the twenty-first century,” Nat Rev Drug Discov 2(1):52-62 (January 2003); Erratum in: Nat Rev Drug Discov 2(3):240 (March 2003); Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Andreakos et al., “Monoclonal antibodies in immune and inflammatory diseases,” Curr Opin Biotechnol 13(6):615-20 (December 2002); Kellermann et al., “Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics,” Curr Opin Biotechnol 13(6):593-7 (December 2002); Pini et al., “Phage display and colony filter screening for high-throughput selection of antibody libraries,” Comb Chem High Throughput Screen 5(7):503-10 (November 2002); Batra et al., “Pharmacokinetics and biodistribution of genetically engineered antibodies,” Curr Opin Biotechnol 13(6):603-8 (December 2002); and Tangri et al., “Rationally engineered proteins or antibodies with absent or reduced immunogenicity,” Curr Med Chem 9(24):2191-9 (December 2002).


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 in VT, or during statin treatment. 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, such as VT, or during the course of a treatment regime, such as during statin treatment. 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 determine an individual's response to statin treatment (particularly for reducing their risk for VT) or to diagnose VT or predisposition/susceptibility 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, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).


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, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).


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, Escherichia coli, Streptomyces spp., and Salmonella typhimurium. Eukaryotic host cells include, but are not limited to, yeast, insect cells such as Drosophila spp., 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 (S. Gottesman, Gene Expression Technology: Methods in Enzymology 185:119-128, Academic Press, Calif. (1990)). 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 (B. Seed, 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, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, N.Y. (2000).


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, for example, in 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 B. Hogan, Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, 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, for example, in I. Wilmut 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 13(6):625-9 (December 2002); Petters et al., “Transgenic animals as models for human disease,” Transgenic Res 9(4-5):347-51, discussion 345-6 (2000); Wolf et al., “Use of transgenic animals in understanding molecular mechanisms of toxicity,” J Pharm Pharmacol 50(6):567-74 (June 1998); Echelard, “Recombinant protein production in transgenic animals,” Curr Opin Biotechnol 7(5):536-40 (October 1996); Houdebine, “Transgenic animal bioreactors,” Transgenic Res 9(4-5):305-20 (2000); Pirity et al., “Embryonic stem cells, creating transgenic animals,” Methods Cell Biol 57:279-93 (1998); and Robl et al., “Artificial chromosome vectors and expression of complex proteins in transgenic animals,” Theriogenology 59(1):107-13 (January 2003).


EXAMPLES

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


Example 1
SNPs Associated with Response to Statins for Reducing VT Risk

27 SNPs were identified that had a significant p(interaction) for statin*SNP of <0.05 (Wald test) for the statin*SNP interaction term in the MEGA sample set (ModelFormula: VTE˜SNP+statin user or nonuser+SNP*statin+age+sex). These 27 SNPs are provided in Table 4. Further, Table 6 provides additional SNPs with P(int)<0.1. Thus, the SNPs provided in Tables 4 and 6 can be assayed to determine whether statin treatment will reduce an individual's risk for VT.


Analysis of SNPs in Statin Subgroups (Statin Users Vs. Statin Nonusers)


75 SNPs genotyped in MEGA had an additive P<0.05 for VT risk in the statin nonusers subgroup. Comparing the risk of VT in the statin users subgroup for these SNPs identifies individuals at risk for VT that benefit from statin therapy and individuals at risk for VT that do not benefit from statin therapy. These 75 SNPs are provided in Table 5. Thus, the SNPs provided in Table 5 can be assayed to determine whether statin treatment will reduce an individual's risk for VT.


MEGA Sample Set


The sample sets used in the present analysis were from a large population-based case-control study referred to as 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), including both the MEGA-1 and MEGA-2 subsets of the MEGA study. 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.


Collection and ascertainment of VT 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 VT (deep vein thrombosis of the leg, venous thrombosis of the arm, or pulmonary embolism) at any of six 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 VT and medication use (including statins), and provided a blood or buccal swab sample. Seven different statins were used by statin users, which are all combined in the current analysis, however 94% of statin users used simvastatin, pravastatin, or atorvastatin. The questionnaire included an item on parent birth country as a proxy for ethnicity.


Two SNPs in particular that were identified in MEGA as being significantly associated with statin response for reducing VT risk were in the F11 gene: F11 SNP rs2036914 (see Tables 4 and 5) and F11 SNP rs2289252 (see Table 5).


Example 2
Association of F11 SNPs rs2036914 and rs2289252 with Response to Statin Treatment for Reducing VT Risk

The MEGA study was analyzed to determine whether carriers of the risk alleles of F11 SNPs rs2289252 and rs2036914, compared with noncarriers, were at increased risk for VT among statin users and also among nonusers.


The MEGA study recruited consecutive patients aged 18 to 70 years with a first diagnosis of VT (deep vein thrombosis of the leg, venous thrombosis of the arm, or pulmonary embolism) from six anticoagulation clinics in the Netherlands between Mar. 1, 1999 and May 31, 2004 (Blom et al., JAMA. 2005; 293: 715-22). Partners of patients were invited to take part as control participants. Additional controls were recruited from the same geographical region by a random digit dialing method and were frequency-matched to patients by age and sex (Chinthammitr et al., J Thromb Haemost. 2006; 4: 2587-92). Information on risk factors for VT and medication use (including statins) prior to their VT event for cases or prior to enrollment for controls was obtained from questionnaires completed by the participants. Seven different statins were used by statin users, which are all combined in the current analysis, however 94% of statin users used simvastatin, pravastatin, or atorvastatin. Participants also provided a blood or buccal swab sample for DNA extraction. Genotypes were determined in a core laboratory that was blinded to case-control status (Germer et al., Genome Res. 2000; 10: 258-66). All study participants provided written informed consent. The MEGA study was approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, The Netherlands.


DNA was available for 9803 participants. Because active cancer is a strong risk factor for VT that might mask other associations, participants with a known malignancy or missing malignancy status were excluded from the current analysis (n=708); participants without medication use information were also excluded (n=204); thus, 3698 cases with VT and 4473 controls with no history of VT were investigated in the current study. Of these 8171 study participants, 384 (5%) were self-reported statin users (125 cases and 259 controls). Logistic regression models that adjusted for age and sex were used to assess association between genotype and VT in statin users and nonusers separately using SAS software (version 9.1) (SAS Institute Inc., Cary, N.C., USA).


Cases and controls did not differ appreciably in mean age [cases, 47.2 years (standard deviation, 12.9); controls, 47.6 years (standard deviation, 12.3)] or sex (45.6% of cases and 47.2% of controls were male). In the controls of MEGA, the genotypes frequencies for rs2289252 were 17.1% (TT), 47.1% (TC) and 35.8% (CC) and for rs2036914 were 27.4% (CC), 49.3% (CT) and 23.3% (TT). Genotype distributions for the 2 SNPs in MEGA did not deviate from Hardy-Weinberg expectations among controls (P>0.25) (Weir, Genetic Data Analysis II. Sunderland: Sinauer Associates Inc., 1996). The linkage disequilibrium between rs2289252 and rs2036914 was moderate (r2=0.38) in the HapMap CEPH population (Utah residents with ancestry from northern and western Europe) (Frazer et al., Nature. 2007; 449: 851-61).


Among statin nonusers of MEGA, the rs2289252 and rs2036914 SNPs were associated with VT (FIGURE): for participants carrying two risk alleles, compared with those carrying no risk alleles, the OR for VT was 1.83 (95% CI, 1.60 to 2.08) for rs2289252 and 1.75 (95% CI, 1.54 to 1.98) for rs2036914. For participants with one risk allele, the OR was 1.39 (95% CI, 1.26 to 1.55) for rs2289252 and 1.30 (95% CI, 1.15 to 1.46) for rs2036914, again compared with participants carrying no risk alleles.


In contrast, among statin users, carriers of rs2289252 were not at increased risk for VT. For participants carrying two risk alleles, compared with those carrying no risk alleles, the OR for VT was 1.06 (95% CI, 0.66 to 1.71); for those carrying one risk allele the OR was 1.10 (95% CI, 0.57 to 2.10); and for carriers of 1 or 2 risk alleles, the OR was 1.07 (95% CI, 0.68 to 1.68). Similarly, among statin users, carriers of two rs2036914 risk alleles were also not at increased risk for VT: the OR was 1.03 (95% CI, 0.53 to 1.99).


It was also determined whether the association between factor V Leiden and VT differed according to statin use. For factor V Leiden, the ORs for VT were not appreciably different between statin users and nonusers. Among statin users, for carriers of factor V Leiden, compared with noncarriers, the OR was 4.94 (95% CI, 2.37 to 10.30) and among nonusers the OR was 3.64 (95% CI, 3.09 to 4.29).


Thus, among MEGA participants who were statin nonusers, it was determined that carriers compared with noncarriers of the risk alleles of rs2289252 and rs2036914 had an increased risk for VT. In contrast, among statin users, carriers of two risk alleles were not at increased risk for VT.


Although anticoagulant therapy reduces the risk for VT events by about 80% (Dentali et al., Ann Intern Med. 2007; 146: 278-88), anticoagulant therapy also causes life-threatening bleeding events (Shireman et al., Chest. 2006; 130: 1390-6; Wittkowsky et al., Arch Intern Med. 2005; 165: 703; and Buresly et al., Arch Intern Med. 2005; 165: 784-9). Thus, statin therapy may be a useful treatment option, particularly when there are concerns about bleeding risk or when the risk of VT is modest. The genetic risk for VT from F11 SNPs rs2036914 and rs2289252 exposes patients to a modest lifelong increase in risk for VT, and in this study of MEGA, the risk for VT in carriers of two alleles of the F11 variants was attenuated by statin use.


Thus, in conclusion, the association of each of F11 SNPs rs2036914 and rs2289252 with statin response for reducing VT risk in MEGA is shown in the FIGURE. The FIGURE shows risk of VT according to statin use for rs2289252, rs2036914, and Factor V Leiden genotypes. The odds ratios in the FIGURE (shown with 95% confidence intervals) were adjusted for sex and age.


As shown in the FIGURE, individuals who were T/T homozygotes or T/C heterozygotes at F11 SNP rs2289252 and who used statins had a reduced risk for VT relative to individuals of the same genotype who did not use statins (lower odds ratios of 1.06 for statin users vs. 1.83 for statin nonusers for T/T homozygous individuals, and lower odds ratio of 1.10 for statin users vs. 1.39 for statin nonusers for T/C heterozygous individuals).


The FIGURE also shows that individuals who were C/C homozygotes at F11 SNP rs2036914 and who used statins had a reduced risk for VT relative to individuals of the same genotype who did not use statins (lower odds ratio of 1.03 for statin users vs. 1.75 for statin nonusers for C/C homozygous individuals).


Factor XI Protein Levels


In addition to being associated with VT risk, F11 SNPs rs2036914 and rs2289252 are also associated with factor XI protein levels, and increased factor XI protein levels are associated with increased VT risk (although F11 SNPs rs2036914 and rs2289252 are associated with factor XI protein levels, both SNPs remain significantly associated with VT risk after adjustment for factor XI levels). Since increased factor XI protein levels are associated with increased VT risk, statin therapy may reduce VT risk by inhibiting factor XI levels associated with the risk alleles of F11 SNPs rs2036914 and rs2289252, or by inhibiting the mechanism by which elevated factor XI levels increase VT risk.


Accordingly, in certain exemplary embodiments, a genetic test that assays one or both of F11 SNPs rs2036914 or rs2289252 (or one or more other SNPs in high LD with either of these F11 SNP) is used in conjunction with a test that measures factor XI protein levels (e.g., in serum or plasma) to identify patients who will have a greater likelihood of VT event reduction (i.e., reduced VT risk) from statin therapy (i.e., increased statin benefit). In further embodiments, a test that measures factor XI protein levels can be used in combination with a genetic test that assays any of the SNPs disclosed herein for VT risk and/or response to statin treatment for reducing VT risk.


Example 3
Additional Analysis of SNPs Associated with Response to Statins for Reducing VT Risk

Table 7 provides the results from an additional analysis for SNPs associated with response to statins for reducing risk of VT. Table 7 provides SNPs that were significantly associated with response to statins for reducing risk of VT in the MEGA substudy of statin users.


In this Example, the MEGA study was analyzed to determine whether certain genotypes of SNPs were at increased risk for VT among statin users and also among statin nonusers. The MEGA study is described above in Examples 1 and 2. In the additional analysis described here in Example 3, the results of which are provided in Table 7, a subset of controls were randomly selected rather that using all controls (all cases were used) from MEGA, since controls greatly outnumbered cases in MEGA.


Description of Statin Substudy of MEGA


DNA was available for 9803 participants. Because active cancer is a strong risk factor for VT that might mask other associations, participants with a known malignancy or missing malignancy status were excluded from the current analysis (n=708); participants without medication use information were also excluded (n=204); thus, 3698 cases with VT and 4473 controls with no history of VT were investigated in the current study. Of the 3698 cases with VT, 125 cases were self-reported statin users and, of the 4473 controls, 257 were self-reported statin users. Because only 384 (5%) of the total cohort were statin users, 539 cases and 607 controls were randomly selected from among the statin nonusers to genotype and use in the analysis. Logistic regression models that adjusted for age and sex were used to assess association between genotype and VT in statin users and nonusers separately using SAS software (section of Table 7 labeled “Statin response by genotype group”). The association between genotype and VT was assessed in statin users (section of Table 7 labeled “Risk of VT in statin use group”) and nonusers (section of Table 7 labeled “Risk of VT in no statin use group”) separately using regression models that adjusted for age and sex using SAS software (version 9.1) (SAS Institute Inc., Cary, N.C., USA).


Example 4
SNPs Associated with Risk for VT, Particularly Recurrent VT

An analysis was carried out to identify SNPs associated with VT, particularly recurrent VT. These SNPs are provided in Table 8. Specifically, Table 8 provides 33 SNPs associated with VT risk in a MEGA case-control study and also with recurrent VT risk in a MEGA recurrent VT prospective study. The MEGA study/sample set is described above in Examples 1 and 2.


Study Design


Recurrent VT Study


The effect of genetic variants on the risk of recurrent VT in MEGA was assessed. Patients that had a primary VT (either DVT of the leg, PE, or both) were included in the current study; patients with DVT of the arm only were excluded from the study (Flinterman et al., “Recurrent thrombosis and survival after a first venous thrombosis of the upper extremity”, Circulation. 2008; 118: 1366-72). Since active cancer is a risk factor for VT, participants were excluded who had malignancy or who had an unknown malignancy status at baseline of the original MEGA study (no information regarding cancer was available during the follow-up study of recurrent VT). 3,824 patients with a first VT from the MEGA study were followed for recurrent VT events over a mean of five years. Among these patients, 137 patients were lost to follow-up and excluded from the analysis. Of these 3,686 participants included in the current study, 565 had a recurrent VT (Table 10).


Primary VT Study


The MEGA primary VT study included 3824 cases and 4672 controls (Table 10). Individuals with a history of malignant disorders were excluded.









TABLE 10







Characteristics of cases and controls in MEGA















Primary


Recurrent



Character-

VT


VT


istic
Case
Control
p Value
Event
No Event
p Value





Number of
3824
4672

565
3121



patients


Men
1734
2203
0.11
366
1293
<0.0001


Mean age
48 (13)
48 (12)
0.98
50 (13)
47 (13)
<0.0001


(SD) in yrs









Examination and Laboratory Measures


Data collection methods for the recurrent VT study are described in Flinterman et al. (“Recurrent thrombosis and survival after a first venous thrombosis of the upper extremity”, Circulation. 2008; 118: 1366-72). Briefly, in 2006, an inquiry form was sent to those patients who had a primary VT and who had initially agreed to participate in a follow-up study. The patients were asked if they had had another VT event in any location since their primary VT event and were asked to answer a follow-up questionnaire. Recurrences were included when confirmed by ultrasound, contrast venography, or computed tomography according to the discharge letters (Flinterman et al., “Recurrent thrombosis and survival after a first venous thrombosis of the upper extremity”, Circulation. 2008; 118: 1366-72). Information on patients with active cancer at the time of first VT was obtained from the baseline questionnaire and from the discharge letters of the first VT (Blom et al., “Malignancies, prothrombotic mutations, and the risk of venous thrombosis”, JAMA. 2005; 293: 715-22).


Genetic Analysis


Blood samples were taken at least three months after discontinuation of vitamin K antagonist treatment for the first thrombotic event. DNA was collected with buccal swabs from patients who were unable to give a blood sample and from all patients who were included beginning in June 2002 (Blom et al., “Malignancies, prothrombotic mutations, and the risk of venous thrombosis”, JAMA. 2005; 293: 715-22). SNP genotypes were determined by allele-specific real-time PCR (Germer et al., “High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR”, Genome Res. 2000; 10: 258-66) in a core laboratory; genotype distributions did not deviate from Hardy Weinberg expectations among controls (Pexact>0.01) (Weir, Genetic Data Analysis II. Sunderland: Sinauer Associates Inc., 1996).


Statistical Analysis


Recurrent VT analysis


Cumulative incidence was estimated by the Kaplan-Meier technique. Incidence rates were the number of new VT events over the total number of person-years. Person-years were calculated from date of first VT event and from discontinuation of the initial vitamin K antagonist treatment until recurrent VT event, death, or end of study, whichever came first. Participants who died during follow-up of a cause other than VT were censored at the date of death. Patients who were not able to complete the inquiry form were censored at their last contact and considered study withdrawals. The end-of-study date was Oct. 1, 2006. Hazard ratios (HRs) were estimated with a Cox proportional-hazards model after patients had discontinued vitamin K antagonist treatment. Adjustments were made for age and sex. No adjustment was made for race because the follow-up study included 95% whites. False discovery rate estimates were used to control for false-positive associations among the group of SNPs in the recurrent VT study (Benjamini et al., Journal of the Royal Statistical Society. 1995; Serials B: 1289-300). Analyses were done using SAS version 9 (SAS Institute Inc, Cary, N.C.) and SPSS for Windows, 14.0.2 (SPSS Inc, Chicago, Ill.). False discovery rates were estimated using the 2-sided, unadjusted P value from the additive model.


Primary VT analysis


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 VT and to adjust for age and sex. For each SNP, the OR per genotype was calculated relative to noncarriers of the risk allele. For SNPs on the X chromosome, the analysis was conducted separately in men and women. Analyses were done using SAS version 9 (SAS Institute Inc, Cary, N.C.) and SPSS for Windows, 14.0.2 (SPSS Inc, Chicago, Ill.).


Results


The SNPs identified as being associated with VT, particularly recurrent VT, are provided in Table 8.


Example 5
SNPs Associated with Risk for VT

Table 9 provides 10 SNPs that were associated with VT risk in the MEGA-1 subset of the MEGA study. These SNPs were specifically associated with primary VT risk in MEGA-1, and are also useful for determining risk for recurrent VT.


The MEGA study, including the MEGA-1 subset, is described in Blom et al., JAMA 2005; 293(6):715-722 (incorporated herein by reference in its entirety), as well as in Examples 1 and 2 above.


Example 6
Four-Marker Panel for Determining Risk of VT, Particularly Recurrent VT

Four of the SNPs identified herein as being associated with recurrent VT, as well as primary VT, were combined into a panel for determining VT risk, particularly recurrent VT risk. The panel (referred to herein as the “four-marker panel”, or “GRS” in Tables 11-12) comprised the following four SNPs (genes): rs6025 (F5), rs2066865 (FGG), rs8176719 (ABO), and rs2036914 (F11).


Risk genotypes for each of these four SNPs are AG+AA for rs6025 (F5), GT+GG for rs8176719 (ABO), AG+AA for rs2066865 (FGG), and CT+CC for rs2036914 (F11).


Equally weighting these four SNPs, it was found that the individuals in the top quartile (>90th percentile) had a two-fold increase (HR=2.04) in risk for recurrent VT compared with the bottom quartile group (<35th percentile) (see Table 11).









TABLE 11







Association of four-marker panel with recurrent VT












GRS







Percentile
Events
Total
HR
95% CI
P value















>=90
81
361
2.04
1.56-2.67
<0.0001


>35 and <90
326
1998
1.42
1.18-1.72
0.0003


<=35
158
1327
Ref







Percentile >=90: Above 90th percentile (based on number of risk allele carriers)






Further, using the four-marker panel in combination with an individual's gender, it was found that individuals in the top quartile (>84th percentile) had a three-fold increase (HR=3.1) in risk for recurrent VT compared with the bottom quartile group (<43th percentile) (see Table 12).









TABLE 12







Association of four-marker panel, in


combination with gender, with recurrent VT












GRS







Percentile
Events
Total
HR
95% CI
P value















>=84
155
575
3.1
2.47-3.91
<0.0001


>43 and <84
267
1523
2.05
2.05-1.67
<0.0001


<=43
143
1588
Ref











Thus, this four-marker panel is particularly useful for determining an individual's risk for developing VT, particularly recurrent VT (as well as primary VT).


In further exemplary embodiments of the four-marker panel, additional markers are assayed in combination with the four markers (particularly additional markers selected from those disclosed herein). In further exemplary embodiments of the four-marker panel, any one, two, or three of the four markers (F5 SNP rs6025, FGG SNP rs2066865, ABO rs8176719, and F11 SNP rs2036914) are assayed, optionally in combination with additional markers (particularly additional markers selected from those disclosed herein). For example, other markers can be substituted for any one or more markers of the four-marker panel. In certain exemplary embodiments, one or more other SNPs in the F11 gene (such as SNP rs2289252) are substituted for F11 SNP rs2036914 (or assayed in addition to rs2036914). In certain embodiments, PTPN21 SNP rs2274736 (disclosed herein) is added to the four-marker panel or substituted in place of one of the markers of the four-marker panel. Additionally, in certain embodiments, F2 SNP rs 1799963 is added to the four-marker panel or substituted in place of one of the markers of the four-marker panel.


In additional embodiments, one or more protein biomarkers can be assayed in combination with the four-marker panel, or a subset of the four-marker panel (and/or any of the other SNPs disclosed herein). For example, measurement of factor XI protein levels can be assayed in combination with the four-marker panel, or can be substituted in place of assaying F11 SNP rs2036914 (or F11 SNP rs2289252), or can be measured in conjunction with any of the other SNPs disclosed herein.


Similarly, measurement of factor VIII protein levels can be assayed in combination with the four-marker panel or can be substituted in place of assaying ABO SNP rs8176719 (or can be measured in conjunction with any of the other SNPs disclosed herein). ABO SNP rs8176719 is associated with factor VIII protein levels, and factor VIII protein levels are associated with VT risk.


Fibrinogen gamma and/or fibrinogen gamma primer protein levels can also be measured in conjunction with the four-marker panel or a subset thereof (or can be measured in conjunction with any of the other SNPs disclosed herein).


Example 7
LD SNPs Associated with VT Risk and Statin Response

Another investigation was conducted to identify additional SNPs that are calculated to be in linkage disequilibrium (LD) with certain “interrogated SNPs” that have been found to be associated with VT risk and/or response to statin treatment (particularly for reducing the risk of VT), as described herein and shown in the tables. The interrogated SNPs are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 3. The methodology is described earlier in the instant application. To summarize briefly, the power threshold (7) was set at an appropriate level, such as 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) above). The threshold rT2 value 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. Several exemplary LD SNPs for the interrogated SNPs are listed in Table 3; each LD SNP is associated with its respective interrogated SNP. Also shown are the public SNP IDs (rs numbers) for the interrogated and LD SNPs, when available, and the threshold r2 value and the power used to determine this, and the r2 value of linkage disequilibrium between the interrogated SNP and its corresponding LD SNP. As an example in Table 3, the interrogated SNP rs2066865 (hCV11503414) was calculated to be in LD with rs2066864 (hCV11503416) at an r2 value of 1, based on a 51% power calculation, thus establishing the latter SNP as a marker associated with statin response 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 response to statin treatment. 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) 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





Interrogated SNP
Interrogated rs
LD SNP
LD SNP rs
Power
Threshold r2
r2





















hCV11503414
rs2066865
hCV11281035
rs4583739
0.51
0.048174697
0.0695


hCV11503414
rs2066865
hCV11503378
rs1490655
0.51
0.048174697
0.0612


hCV11503414
rs2066865
hCV11503379
rs1490654
0.51
0.048174697
0.0677


hCV11503414
rs2066865
hCV11503382
rs1873369
0.51
0.048174697
0.257


hCV11503414
rs2066865
hCV11503416
rs2066864
0.51
0.048174697
1


hCV11503414
rs2066865
hCV11503431
rs2066861
0.51
0.048174697
1


hCV11503414
rs2066865
hCV11503469
rs2066854
0.51
0.048174697
0.9559


hCV11503414
rs2066865
hCV11503470
rs1800788
0.51
0.048174697
0.4341


hCV11503414
rs2066865
hCV11852898
rs6819508
0.51
0.048174697
0.0566


hCV11503414
rs2066865
hCV11853353
rs9995943
0.51
0.048174697
0.0864


hCV11503414
rs2066865
hCV11853354
rs10030235
0.51
0.048174697
0.0832


hCV11503414
rs2066865
hCV11853357
rs10033383
0.51
0.048174697
0.1091


hCV11503414
rs2066865
hCV11853358
rs10000511
0.51
0.048174697
0.0909


hCV11503414
rs2066865
hCV11853362
rs4696572
0.51
0.048174697
0.1012


hCV11503414
rs2066865
hCV11853363
rs4696573
0.51
0.048174697
0.0905


hCV11503414
rs2066865
hCV11853373
rs1907155
0.51
0.048174697
0.0947


hCV11503414
rs2066865
hCV11853378
rs1907154
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV11853384
rs12646456
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV11853387
rs1490683
0.51
0.048174697
0.217


hCV11503414
rs2066865
hCV11853415
rs1490653
0.51
0.048174697
0.0593


hCV11503414
rs2066865
hCV11853416
rs4346631
0.51
0.048174697
0.0664


hCV11503414
rs2066865
hCV11853418
rs12501998
0.51
0.048174697
0.0542


hCV11503414
rs2066865
hCV11853419
rs13151559
0.51
0.048174697
0.0542


hCV11503414
rs2066865
hCV11853423
rs3857093
0.51
0.048174697
0.0542


hCV11503414
rs2066865
hCV11853424
rs871541
0.51
0.048174697
0.0542


hCV11503414
rs2066865
hCV11853483
rs12644950
0.51
0.048174697
1


hCV11503414
rs2066865
hCV11853489
rs7681423
0.51
0.048174697
1


hCV11503414
rs2066865
hCV11853496
rs7654093
0.51
0.048174697
1


hCV11503414
rs2066865
hCV11853631
rs12651106
0.51
0.048174697
0.1612


hCV11503414
rs2066865
hCV11853650
rs9307922
0.51
0.048174697
0.1074


hCV11503414
rs2066865
hCV1190562
rs1490684
0.51
0.048174697
0.0947


hCV11503414
rs2066865
hCV1190563
rs4696565
0.51
0.048174697
0.114


hCV11503414
rs2066865
hCV1190567
rs4696210
0.51
0.048174697
0.114


hCV11503414
rs2066865
hCV1190572
rs1032335
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV1190580
rs9998926
0.51
0.048174697
0.0874


hCV11503414
rs2066865
hCV1190581
rs6856249
0.51
0.048174697
0.114


hCV11503414
rs2066865
hCV1190582
rs10013533
0.51
0.048174697
0.114


hCV11503414
rs2066865
hCV15860433
rs2070006
0.51
0.048174697
0.4534


hCV11503414
rs2066865
hCV176753
rs2404478
0.51
0.048174697
0.0542


hCV11503414
rs2066865
hCV21680
rs7666020
0.51
0.048174697
0.153


hCV11503414
rs2066865
hCV21681
rs6536018
0.51
0.048174697
0.3185


hCV11503414
rs2066865
hCV22273499
rs7668014
0.51
0.048174697
0.0903


hCV11503414
rs2066865
hCV22274180
rs11935584
0.51
0.048174697
0.1032


hCV11503414
rs2066865
hCV229029
rs13103792
0.51
0.048174697
0.0486


hCV11503414
rs2066865
hCV2407252
rs149225
0.51
0.048174697
0.1


hCV11503414
rs2066865
hCV2407354
rs276166
0.51
0.048174697
0.0534


hCV11503414
rs2066865
hCV24834
rs4235247
0.51
0.048174697
0.4263


hCV11503414
rs2066865
hCV25610762
rs7668818
0.51
0.048174697
0.0707


hCV11503414
rs2066865
hCV26019871
rs4547780
0.51
0.048174697
0.3146


hCV11503414
rs2066865
hCV26024202
rs11731813
0.51
0.048174697
0.2237


hCV11503414
rs2066865
hCV26024285
rs11726919
0.51
0.048174697
0.1063


hCV11503414
rs2066865
hCV26024286
rs11726850
0.51
0.048174697
0.1063


hCV11503414
rs2066865
hCV26024287
rs7666541
0.51
0.048174697
0.1357


hCV11503414
rs2066865
hCV26024294
rs11731663
0.51
0.048174697
0.1063


hCV11503414
rs2066865
hCV265748
rs12500118
0.51
0.048174697
0.1669


hCV11503414
rs2066865
hCV27020269
rs7659613
0.51
0.048174697
0.5249


hCV11503414
rs2066865
hCV27020277
rs6825454
0.51
0.048174697
0.8713


hCV11503414
rs2066865
hCV27020280
rs4463047
0.51
0.048174697
0.2252


hCV11503414
rs2066865
hCV27020304
rs13101534
0.51
0.048174697
0.1091


hCV11503414
rs2066865
hCV27313130
rs4634202
0.51
0.048174697
0.103


hCV11503414
rs2066865
hCV27479909
rs3775785
0.51
0.048174697
0.1072


hCV11503414
rs2066865
hCV27905214
rs4323084
0.51
0.048174697
0.2956


hCV11503414
rs2066865
hCV27907560
rs4696576
0.51
0.048174697
0.135


hCV11503414
rs2066865
hCV27937396
rs4634201
0.51
0.048174697
0.4298


hCV11503414
rs2066865
hCV286004
rs1118824
0.51
0.048174697
0.1213


hCV11503414
rs2066865
hCV2891425
rs1948714
0.51
0.048174697
0.1065


hCV11503414
rs2066865
hCV2891532
rs13110294
0.51
0.048174697
0.1006


hCV11503414
rs2066865
hCV2892850
rs10050268
0.51
0.048174697
0.0552


hCV11503414
rs2066865
hCV2892855
rs6536024
0.51
0.048174697
0.2222


hCV11503414
rs2066865
hCV2892858
rs12648395
0.51
0.048174697
0.1213


hCV11503414
rs2066865
hCV2892859
rs13130318
0.51
0.048174697
0.859


hCV11503414
rs2066865
hCV2892863
rs1049636
0.51
0.048174697
0.1213


hCV11503414
rs2066865
hCV2892869
rs13109457
0.51
0.048174697
0.955


hCV11503414
rs2066865
hCV2892870
rs2070011
0.51
0.048174697
0.439


hCV11503414
rs2066865
hCV2892876
rs2070018
0.51
0.048174697
0.0566


hCV11503414
rs2066865
hCV2892877
rs6050
0.51
0.048174697
0.873


hCV11503414
rs2066865
hCV2892893
rs12648258
0.51
0.048174697
0.4009


hCV11503414
rs2066865
hCV2892895
rs12641958
0.51
0.048174697
0.0903


hCV11503414
rs2066865
hCV2892896
rs11940724
0.51
0.048174697
0.0903


hCV11503414
rs2066865
hCV2892899
rs7680155
0.51
0.048174697
0.1032


hCV11503414
rs2066865
hCV2892905
rs12642770
0.51
0.048174697
0.3619


hCV11503414
rs2066865
hCV2892918
rs12511469
0.51
0.048174697
0.3888


hCV11503414
rs2066865
hCV2892923
rs13435192
0.51
0.048174697
0.1113


hCV11503414
rs2066865
hCV2892924
rs13435101
0.51
0.048174697
0.1105


hCV11503414
rs2066865
hCV2892925
rs7689945
0.51
0.048174697
0.1063


hCV11503414
rs2066865
hCV2892926
rs7662567
0.51
0.048174697
0.3986


hCV11503414
rs2066865
hCV2892927
rs13123551
0.51
0.048174697
0.1327


hCV11503414
rs2066865
hCV2892928
rs13147579
0.51
0.048174697
0.4128


hCV11503414
rs2066865
hCV28953838
rs7690851
0.51
0.048174697
0.3221


hCV11503414
rs2066865
hCV28953840
rs6536017
0.51
0.048174697
0.1155


hCV11503414
rs2066865
hCV28954780
rs7656522
0.51
0.048174697
0.0537


hCV11503414
rs2066865
hCV28966638
rs7676857
0.51
0.048174697
0.1625


hCV11503414
rs2066865
hCV29317506
rs7686002
0.51
0.048174697
0.0551


hCV11503414
rs2066865
hCV29420822
rs4642230
0.51
0.048174697
0.4837


hCV11503414
rs2066865
hCV29420827
rs7654425
0.51
0.048174697
0.0903


hCV11503414
rs2066865
hCV29420828
rs7660120
0.51
0.048174697
0.0796


hCV11503414
rs2066865
hCV29570696
rs9997519
0.51
0.048174697
0.0523


hCV11503414
rs2066865
hCV29582612
rs4550901
0.51
0.048174697
0.0566


hCV11503414
rs2066865
hCV29751345
rs6811271
0.51
0.048174697
0.108


hCV11503414
rs2066865
hCV29983641
rs10008078
0.51
0.048174697
0.461


hCV11503414
rs2066865
hCV30004073
rs6832957
0.51
0.048174697
0.049


hCV11503414
rs2066865
hCV30562176
rs9284660
0.51
0.048174697
0.1006


hCV11503414
rs2066865
hCV30679139
rs13139082
0.51
0.048174697
0.0593


hCV11503414
rs2066865
hCV30679140
rs13112066
0.51
0.048174697
0.0499


hCV11503414
rs2066865
hCV30679141
rs13111621
0.51
0.048174697
0.0629


hCV11503414
rs2066865
hCV30679164
rs12649437
0.51
0.048174697
0.1051


hCV11503414
rs2066865
hCV30679170
rs13148992
0.51
0.048174697
0.2324


hCV11503414
rs2066865
hCV30679242
rs4235243
0.51
0.048174697
0.1248


hCV11503414
rs2066865
hCV30679244
rs4575978
0.51
0.048174697
0.1063


hCV11503414
rs2066865
hCV30679245
rs4386583
0.51
0.048174697
0.1063


hCV11503414
rs2066865
hCV30711231
rs12642469
0.51
0.048174697
0.461


hCV11503414
rs2066865
hCV31863942
rs13101382
0.51
0.048174697
0.1052


hCV11503414
rs2066865
hCV31863979
rs12186294
0.51
0.048174697
0.2778


hCV11503414
rs2066865
hCV31863982
rs7659024
0.51
0.048174697
1


hCV11503414
rs2066865
hCV31863989
rs4308349
0.51
0.048174697
0.0513


hCV11503414
rs2066865
hCV31863993
rs7673587
0.51
0.048174697
0.1032


hCV11503414
rs2066865
hCV32212659
rs4622984
0.51
0.048174697
0.1879


hCV11503414
rs2066865
hCV32212662
rs11099958
0.51
0.048174697
0.0527


hCV11503414
rs2066865
hCV32212663
rs7670827
0.51
0.048174697
0.0974


hCV11503414
rs2066865
hCV32212664
rs12642646
0.51
0.048174697
0.0491


hCV11503414
rs2066865
hCV32212669
rs12649647
0.51
0.048174697
0.0577


hCV11503414
rs2066865
hCV354895
rs11737226
0.51
0.048174697
0.2322


hCV11503414
rs2066865
hCV354896
rs7690972
0.51
0.048174697
0.2322


hCV11503414
rs2066865
hCV36809
rs10517590
0.51
0.048174697
0.133


hCV11503414
rs2066865
hCV400532
rs11099956
0.51
0.048174697
0.1095


hCV11503414
rs2066865
hCV426162
rs10857275
0.51
0.048174697
0.1132


hCV11503414
rs2066865
hCV426165
rs990185
0.51
0.048174697
0.1074


hCV11503414
rs2066865
hCV426167
rs1388087
0.51
0.048174697
0.0905


hCV11503414
rs2066865
hCV426168
rs1388088
0.51
0.048174697
0.114


hCV11503414
rs2066865
hCV426169
rs1388066
0.51
0.048174697
0.1336


hCV11503414
rs2066865
hCV426170
rs1388067
0.51
0.048174697
0.114


hCV11503414
rs2066865
hCV426172
rs7670027
0.51
0.048174697
0.1443


hCV11503414
rs2066865
hCV426173
rs12504201
0.51
0.048174697
0.2207


hCV11503414
rs2066865
hCV426175
rs9884952
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV426176
rs9884775
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV426178
rs9884570
0.51
0.048174697
0.1519


hCV11503414
rs2066865
hCV426181
rs11099955
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV426182
rs10014536
0.51
0.048174697
0.1769


hCV11503414
rs2066865
hCV426183
rs10014635
0.51
0.048174697
0.1772


hCV11503414
rs2066865
hCV426184
rs1032336
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV437164
rs7685964
0.51
0.048174697
0.1071


hCV11503414
rs2066865
hCV470979
rs1490672
0.51
0.048174697
0.2211


hCV11503414
rs2066865
hCV501682
rs4403033
0.51
0.048174697
0.1063


hCV11503414
rs2066865
hCV501683
rs4312742
0.51
0.048174697
0.1248


hCV11503414
rs2066865
hCV501686
rs4327464
0.51
0.048174697
0.1026


hCV11503414
rs2066865
hCV7429674
rs871540
0.51
0.048174697
0.0542


hCV11503414
rs2066865
hCV7429780
rs1800792
0.51
0.048174697
0.2745


hCV11503414
rs2066865
hCV7429782
rs1118823
0.51
0.048174697
0.1185


hCV11503414
rs2066865
hCV7429783
rs1044291
0.51
0.048174697
0.0903


hCV11503414
rs2066865
hCV7429793
rs1025154
0.51
0.048174697
0.461


hCV11503414
rs2066865
hCV7430148
rs1490685
0.51
0.048174697
0.163


hCV11503414
rs2066865
hCV7430149
rs1490649
0.51
0.048174697
0.1131


hCV11503414
rs2066865
hCV7430150
rs1490648
0.51
0.048174697
0.1182


hCV11503414
rs2066865
hCV7430152
rs1490656
0.51
0.048174697
0.1029


hCV11503414
rs2066865
hCV7430153
rs1388077
0.51
0.048174697
0.114


hCV11503414
rs2066865
hCV7430158
rs1466662
0.51
0.048174697
0.1669


hCV11503414
rs2066865
hCV8938834
rs1500372
0.51
0.048174697
0.076


hCV11503414
rs2066865
hCV8938838
rs1392546
0.51
0.048174697
0.076


hCV11503414
rs2066865
hCV9317142
rs12186175
0.51
0.048174697
0.1052


hCV11503414
rs2066865
hCV99436
rs10015747
0.51
0.048174697
0.1308


hCV11503414
rs2066865
hDV70934991
rs17301943
0.51
0.048174697
0.0542


hCV11503414
rs2066865
hDV70945235
rs17373860
0.51
0.048174697
0.16


hCV11503414
rs2066865
hDV77232287
rs7666918
0.51
0.048174697
0.0903


hCV11503414
rs2066865
hDV96226316
rs6834312
0.51
0.048174697
0.1334


hCV11503469
rs2066854
hCV11281035
rs4583739
0.51
0.048166678
0.094


hCV11503469
rs2066854
hCV11503378
rs1490655
0.51
0.048166678
0.068


hCV11503469
rs2066854
hCV11503379
rs1490654
0.51
0.048166678
0.0512


hCV11503469
rs2066854
hCV11503382
rs1873369
0.51
0.048166678
0.1718


hCV11503469
rs2066854
hCV11503414
rs2066865
0.51
0.048166678
0.9559


hCV11503469
rs2066854
hCV11503416
rs2066864
0.51
0.048166678
0.9579


hCV11503469
rs2066854
hCV11503431
rs2066861
0.51
0.048166678
0.9559


hCV11503469
rs2066854
hCV11503470
rs1800788
0.51
0.048166678
0.3765


hCV11503469
rs2066854
hCV11853342
rs7660343
0.51
0.048166678
0.0674


hCV11503469
rs2066854
hCV11853353
rs9995943
0.51
0.048166678
0.0981


hCV11503469
rs2066854
hCV11853354
rs10030235
0.51
0.048166678
0.0868


hCV11503469
rs2066854
hCV11853357
rs10033383
0.51
0.048166678
0.0595


hCV11503469
rs2066854
hCV11853362
rs4696572
0.51
0.048166678
0.1483


hCV11503469
rs2066854
hCV11853363
rs4696573
0.51
0.048166678
0.0981


hCV11503469
rs2066854
hCV11853373
rs1907155
0.51
0.048166678
0.1398


hCV11503469
rs2066854
hCV11853378
rs1907154
0.51
0.048166678
0.0869


hCV11503469
rs2066854
hCV11853384
rs12646456
0.51
0.048166678
0.0869


hCV11503469
rs2066854
hCV11853387
rs1490683
0.51
0.048166678
0.1451


hCV11503469
rs2066854
hCV11853416
rs4346631
0.51
0.048166678
0.05


hCV11503469
rs2066854
hCV11853418
rs12501998
0.51
0.048166678
0.0786


hCV11503469
rs2066854
hCV11853419
rs13151559
0.51
0.048166678
0.0786


hCV11503469
rs2066854
hCV11853423
rs3857093
0.51
0.048166678
0.0786


hCV11503469
rs2066854
hCV11853424
rs871541
0.51
0.048166678
0.0786


hCV11503469
rs2066854
hCV11853483
rs12644950
0.51
0.048166678
0.9545


hCV11503469
rs2066854
hCV11853489
rs7681423
0.51
0.048166678
0.9579


hCV11503469
rs2066854
hCV11853496
rs7654093
0.51
0.048166678
0.9559


hCV11503469
rs2066854
hCV11853631
rs12651106
0.51
0.048166678
0.1768


hCV11503469
rs2066854
hCV1190562
rs1490684
0.51
0.048166678
0.1398


hCV11503469
rs2066854
hCV1190563
rs4696565
0.51
0.048166678
0.063


hCV11503469
rs2066854
hCV1190567
rs4696210
0.51
0.048166678
0.063


hCV11503469
rs2066854
hCV1190572
rs1032335
0.51
0.048166678
0.0869


hCV11503469
rs2066854
hCV1190580
rs9998926
0.51
0.048166678
0.0915


hCV11503469
rs2066854
hCV1190581
rs6856249
0.51
0.048166678
0.063


hCV11503469
rs2066854
hCV1190582
rs10013533
0.51
0.048166678
0.063


hCV11503469
rs2066854
hCV15860433
rs2070006
0.51
0.048166678
0.5293


hCV11503469
rs2066854
hCV15971616
rs2227421
0.51
0.048166678
0.1143


hCV11503469
rs2066854
hCV176753
rs2404478
0.51
0.048166678
0.0786


hCV11503469
rs2066854
hCV21680
rs7666020
0.51
0.048166678
0.1247


hCV11503469
rs2066854
hCV21681
rs6536018
0.51
0.048166678
0.2928


hCV11503469
rs2066854
hCV22273499
rs7668014
0.51
0.048166678
0.1071


hCV11503469
rs2066854
hCV22274180
rs11935584
0.51
0.048166678
0.1125


hCV11503469
rs2066854
hCV229029
rs13103792
0.51
0.048166678
0.062


hCV11503469
rs2066854
hCV2407223
rs156502
0.51
0.048166678
0.0621


hCV11503469
rs2066854
hCV2407232
rs156550
0.51
0.048166678
0.0563


hCV11503469
rs2066854
hCV2407238
rs156543
0.51
0.048166678
0.0615


hCV11503469
rs2066854
hCV2407252
rs149225
0.51
0.048166678
0.105


hCV11503469
rs2066854
hCV24834
rs4235247
0.51
0.048166678
0.4128


hCV11503469
rs2066854
hCV25610762
rs7668818
0.51
0.048166678
0.0634


hCV11503469
rs2066854
hCV26019871
rs4547780
0.51
0.048166678
0.3094


hCV11503469
rs2066854
hCV26024202
rs11731813
0.51
0.048166678
0.225


hCV11503469
rs2066854
hCV26024287
rs7666541
0.51
0.048166678
0.1353


hCV11503469
rs2066854
hCV26024295
rs12643125
0.51
0.048166678
0.1125


hCV11503469
rs2066854
hCV265748
rs12500118
0.51
0.048166678
0.1103


hCV11503469
rs2066854
hCV27020184
rs47379
0.51
0.048166678
0.0776


hCV11503469
rs2066854
hCV27020269
rs7659613
0.51
0.048166678
0.5455


hCV11503469
rs2066854
hCV27020277
rs6825454
0.51
0.048166678
0.8694


hCV11503469
rs2066854
hCV27020280
rs4463047
0.51
0.048166678
0.2409


hCV11503469
rs2066854
hCV27020284
rs1846707
0.51
0.048166678
0.1139


hCV11503469
rs2066854
hCV27313130
rs4634202
0.51
0.048166678
0.1555


hCV11503469
rs2066854
hCV27479909
rs3775785
0.51
0.048166678
0.0578


hCV11503469
rs2066854
hCV27905214
rs4323084
0.51
0.048166678
0.325


hCV11503469
rs2066854
hCV27907560
rs4696576
0.51
0.048166678
0.0999


hCV11503469
rs2066854
hCV27937396
rs4634201
0.51
0.048166678
0.4472


hCV11503469
rs2066854
hCV286004
rs1118824
0.51
0.048166678
0.1531


hCV11503469
rs2066854
hCV2891496
rs156584
0.51
0.048166678
0.0621


hCV11503469
rs2066854
hCV2891515
rs11940892
0.51
0.048166678
0.0615


hCV11503469
rs2066854
hCV2891530
rs7662464
0.51
0.048166678
0.0615


hCV11503469
rs2066854
hCV2891532
rs13110294
0.51
0.048166678
0.0626


hCV11503469
rs2066854
hCV2891552
rs1876031
0.51
0.048166678
0.1011


hCV11503469
rs2066854
hCV2891554
rs12501328
0.51
0.048166678
0.059


hCV11503469
rs2066854
hCV2892850
rs10050268
0.51
0.048166678
0.0638


hCV11503469
rs2066854
hCV2892855
rs6536024
0.51
0.048166678
0.2667


hCV11503469
rs2066854
hCV2892858
rs12648395
0.51
0.048166678
0.1531


hCV11503469
rs2066854
hCV2892859
rs13130318
0.51
0.048166678
0.8253


hCV11503469
rs2066854
hCV2892863
rs1049636
0.51
0.048166678
0.1531


hCV11503469
rs2066854
hCV2892869
rs13109457
0.51
0.048166678
0.9149


hCV11503469
rs2066854
hCV2892870
rs2070011
0.51
0.048166678
0.5068


hCV11503469
rs2066854
hCV2892877
rs6050
0.51
0.048166678
0.8287


hCV11503469
rs2066854
hCV2892878
rs2070022
0.51
0.048166678
0.0592


hCV11503469
rs2066854
hCV2892889
rs2227412
0.51
0.048166678
0.0547


hCV11503469
rs2066854
hCV2892893
rs12648258
0.51
0.048166678
0.4044


hCV11503469
rs2066854
hCV2892895
rs12641958
0.51
0.048166678
0.1071


hCV11503469
rs2066854
hCV2892896
rs11940724
0.51
0.048166678
0.1071


hCV11503469
rs2066854
hCV2892899
rs7680155
0.51
0.048166678
0.1125


hCV11503469
rs2066854
hCV2892905
rs12642770
0.51
0.048166678
0.3381


hCV11503469
rs2066854
hCV2892918
rs12511469
0.51
0.048166678
0.3613


hCV11503469
rs2066854
hCV2892923
rs13435192
0.51
0.048166678
0.1375


hCV11503469
rs2066854
hCV2892924
rs13435101
0.51
0.048166678
0.1375


hCV11503469
rs2066854
hCV2892925
rs7689945
0.51
0.048166678
0.1375


hCV11503469
rs2066854
hCV2892926
rs7662567
0.51
0.048166678
0.3671


hCV11503469
rs2066854
hCV2892927
rs13123551
0.51
0.048166678
0.1434


hCV11503469
rs2066854
hCV2892928
rs13147579
0.51
0.048166678
0.3836


hCV11503469
rs2066854
hCV28953838
rs7690851
0.51
0.048166678
0.3242


hCV11503469
rs2066854
hCV28953840
rs6536017
0.51
0.048166678
0.1025


hCV11503469
rs2066854
hCV28954780
rs7656522
0.51
0.048166678
0.0782


hCV11503469
rs2066854
hCV28954790
rs7662783
0.51
0.048166678
0.0496


hCV11503469
rs2066854
hCV28954801
rs4447837
0.51
0.048166678
0.062


hCV11503469
rs2066854
hCV28966638
rs7676857
0.51
0.048166678
0.1179


hCV11503469
rs2066854
hCV29420822
rs4642230
0.51
0.048166678
0.4022


hCV11503469
rs2066854
hCV29420827
rs7654425
0.51
0.048166678
0.1071


hCV11503469
rs2066854
hCV29420828
rs7660120
0.51
0.048166678
0.0906


hCV11503469
rs2066854
hCV29570696
rs9997519
0.51
0.048166678
0.0519


hCV11503469
rs2066854
hCV29636755
rs10517602
0.51
0.048166678
0.0706


hCV11503469
rs2066854
hCV29751345
rs6811271
0.51
0.048166678
0.1681


hCV11503469
rs2066854
hCV29983641
rs10008078
0.51
0.048166678
0.3893


hCV11503469
rs2066854
hCV30562176
rs9284660
0.51
0.048166678
0.0785


hCV11503469
rs2066854
hCV30679139
rs13139082
0.51
0.048166678
0.0616


hCV11503469
rs2066854
hCV30679140
rs13112066
0.51
0.048166678
0.0674


hCV11503469
rs2066854
hCV30679164
rs12649437
0.51
0.048166678
0.0849


hCV11503469
rs2066854
hCV30679170
rs13148992
0.51
0.048166678
0.2399


hCV11503469
rs2066854
hCV30711231
rs12642469
0.51
0.048166678
0.3893


hCV11503469
rs2066854
hCV31863937
rs12507608
0.51
0.048166678
0.0706


hCV11503469
rs2066854
hCV31863979
rs12186294
0.51
0.048166678
0.3086


hCV11503469
rs2066854
hCV31863982
rs7659024
0.51
0.048166678
0.9559


hCV11503469
rs2066854
hCV31863993
rs7673587
0.51
0.048166678
0.1125


hCV11503469
rs2066854
hCV32212658
rs11099959
0.51
0.048166678
0.0536


hCV11503469
rs2066854
hCV32212659
rs4622984
0.51
0.048166678
0.195


hCV11503469
rs2066854
hCV32212663
rs7670827
0.51
0.048166678
0.1002


hCV11503469
rs2066854
hCV32212664
rs12642646
0.51
0.048166678
0.0849


hCV11503469
rs2066854
hCV32287640
rs4367156
0.51
0.048166678
0.062


hCV11503469
rs2066854
hCV354895
rs11737226
0.51
0.048166678
0.2251


hCV11503469
rs2066854
hCV354896
rs7690972
0.51
0.048166678
0.2251


hCV11503469
rs2066854
hCV37878
rs4235241
0.51
0.048166678
0.1157


hCV11503469
rs2066854
hCV400532
rs11099956
0.51
0.048166678
0.0951


hCV11503469
rs2066854
hCV426167
rs1388087
0.51
0.048166678
0.0981


hCV11503469
rs2066854
hCV426168
rs1388088
0.51
0.048166678
0.063


hCV11503469
rs2066854
hCV426169
rs1388066
0.51
0.048166678
0.0794


hCV11503469
rs2066854
hCV426170
rs1388067
0.51
0.048166678
0.063


hCV11503469
rs2066854
hCV426172
rs7670027
0.51
0.048166678
0.083


hCV11503469
rs2066854
hCV426173
rs12504201
0.51
0.048166678
0.1597


hCV11503469
rs2066854
hCV426175
rs9884952
0.51
0.048166678
0.0816


hCV11503469
rs2066854
hCV426176
rs9884775
0.51
0.048166678
0.0869


hCV11503469
rs2066854
hCV426178
rs9884570
0.51
0.048166678
0.078


hCV11503469
rs2066854
hCV426181
rs11099955
0.51
0.048166678
0.0869


hCV11503469
rs2066854
hCV426182
rs10014536
0.51
0.048166678
0.1101


hCV11503469
rs2066854
hCV426183
rs10014635
0.51
0.048166678
0.0914


hCV11503469
rs2066854
hCV426184
rs1032336
0.51
0.048166678
0.0869


hCV11503469
rs2066854
hCV437164
rs7685964
0.51
0.048166678
0.0537


hCV11503469
rs2066854
hCV470979
rs1490672
0.51
0.048166678
0.2217


hCV11503469
rs2066854
hCV489970
rs11734901
0.51
0.048166678
0.1235


hCV11503469
rs2066854
hCV501681
rs4076040
0.51
0.048166678
0.1157


hCV11503469
rs2066854
hCV7429674
rs871540
0.51
0.048166678
0.0786


hCV11503469
rs2066854
hCV7429780
rs1800792
0.51
0.048166678
0.3086


hCV11503469
rs2066854
hCV7429782
rs1118823
0.51
0.048166678
0.1531


hCV11503469
rs2066854
hCV7429783
rs1044291
0.51
0.048166678
0.1141


hCV11503469
rs2066854
hCV7429793
rs1025154
0.51
0.048166678
0.3893


hCV11503469
rs2066854
hCV7430148
rs1490685
0.51
0.048166678
0.0869


hCV11503469
rs2066854
hCV7430149
rs1490649
0.51
0.048166678
0.0623


hCV11503469
rs2066854
hCV7430150
rs1490648
0.51
0.048166678
0.0661


hCV11503469
rs2066854
hCV7430152
rs1490656
0.51
0.048166678
0.0539


hCV11503469
rs2066854
hCV7430153
rs1388077
0.51
0.048166678
0.063


hCV11503469
rs2066854
hCV7430158
rs1466662
0.51
0.048166678
0.1103


hCV11503469
rs2066854
hDV70817639
rs17031739
0.51
0.048166678
0.0603


hCV11503469
rs2066854
hDV70817640
rs17031740
0.51
0.048166678
0.062


hCV11503469
rs2066854
hDV70817803
rs17031951
0.51
0.048166678
0.0706


hCV11503469
rs2066854
hDV70817805
rs17031954
0.51
0.048166678
0.0706


hCV11503469
rs2066854
hDV70817844
rs17032000
0.51
0.048166678
0.0706


hCV11503469
rs2066854
hDV70934991
rs17301943
0.51
0.048166678
0.0786


hCV11503469
rs2066854
hDV70945235
rs17373860
0.51
0.048166678
0.129


hCV11503469
rs2066854
hDV72277158
rs28673871
0.51
0.048166678
0.0592


hCV11503469
rs2066854
hDV77232287
rs7666918
0.51
0.048166678
0.1071


hCV11503469
rs2066854
hDV96226316
rs6834312
0.51
0.048166678
0.0607


hCV11503470
rs1800788
hCV11503382
rs1873369
0.51
0.150481176
0.5598


hCV11503470
rs1800788
hCV11503414
rs2066865
0.51
0.150481176
0.4341


hCV11503470
rs1800788
hCV11503416
rs2066864
0.51
0.150481176
0.4007


hCV11503470
rs1800788
hCV11503431
rs2066861
0.51
0.150481176
0.4356


hCV11503470
rs1800788
hCV11503469
rs2066854
0.51
0.150481176
0.3765


hCV11503470
rs1800788
hCV11853483
rs12644950
0.51
0.150481176
0.3743


hCV11503470
rs1800788
hCV11853489
rs7681423
0.51
0.150481176
0.4007


hCV11503470
rs1800788
hCV11853496
rs7654093
0.51
0.150481176
0.4356


hCV11503470
rs1800788
hCV15860433
rs2070006
0.51
0.150481176
0.2862


hCV11503470
rs1800788
hCV21680
rs7666020
0.51
0.150481176
0.168


hCV11503470
rs1800788
hCV21681
rs6536018
0.51
0.150481176
0.2707


hCV11503470
rs1800788
hCV24834
rs4235247
0.51
0.150481176
0.6801


hCV11503470
rs1800788
hCV26019871
rs4547780
0.51
0.150481176
0.2046


hCV11503470
rs1800788
hCV26024202
rs11731813
0.51
0.150481176
0.4748


hCV11503470
rs1800788
hCV27020269
rs7659613
0.51
0.150481176
0.3134


hCV11503470
rs1800788
hCV27020277
rs6825454
0.51
0.150481176
0.4968


hCV11503470
rs1800788
hCV27020280
rs4463047
0.51
0.150481176
0.4485


hCV11503470
rs1800788
hCV27313130
rs4634202
0.51
0.150481176
0.3826


hCV11503470
rs1800788
hCV27905214
rs4323084
0.51
0.150481176
0.5288


hCV11503470
rs1800788
hCV27907560
rs4696576
0.51
0.150481176
0.2691


hCV11503470
rs1800788
hCV27937396
rs4634201
0.51
0.150481176
0.6797


hCV11503470
rs1800788
hCV2892859
rs13130318
0.51
0.150481176
0.2782


hCV11503470
rs1800788
hCV2892869
rs13109457
0.51
0.150481176
0.4255


hCV11503470
rs1800788
hCV2892870
rs2070011
0.51
0.150481176
0.3019


hCV11503470
rs1800788
hCV2892877
rs6050
0.51
0.150481176
0.5042


hCV11503470
rs1800788
hCV2892893
rs12648258
0.51
0.150481176
1


hCV11503470
rs1800788
hCV2892905
rs12642770
0.51
0.150481176
0.8219


hCV11503470
rs1800788
hCV2892918
rs12511469
0.51
0.150481176
1


hCV11503470
rs1800788
hCV2892923
rs13435192
0.51
0.150481176
0.2139


hCV11503470
rs1800788
hCV2892924
rs13435101
0.51
0.150481176
0.2119


hCV11503470
rs1800788
hCV2892925
rs7689945
0.51
0.150481176
0.2079


hCV11503470
rs1800788
hCV2892926
rs7662567
0.51
0.150481176
1


hCV11503470
rs1800788
hCV2892927
rs13123551
0.51
0.150481176
0.2674


hCV11503470
rs1800788
hCV2892928
rs13147579
0.51
0.150481176
1


hCV11503470
rs1800788
hCV28953838
rs7690851
0.51
0.150481176
0.211


hCV11503470
rs1800788
hCV28953840
rs6536017
0.51
0.150481176
0.1546


hCV11503470
rs1800788
hCV29420822
rs4642230
0.51
0.150481176
0.9


hCV11503470
rs1800788
hCV29983641
rs10008078
0.51
0.150481176
0.9719


hCV11503470
rs1800788
hCV30679170
rs13148992
0.51
0.150481176
0.4826


hCV11503470
rs1800788
hCV30711231
rs12642469
0.51
0.150481176
0.9719


hCV11503470
rs1800788
hCV31863979
rs12186294
0.51
0.150481176
0.1637


hCV11503470
rs1800788
hCV31863982
rs7659024
0.51
0.150481176
0.4356


hCV11503470
rs1800788
hCV32212658
rs11099959
0.51
0.150481176
0.163


hCV11503470
rs1800788
hCV32212659
rs4622984
0.51
0.150481176
0.4821


hCV11503470
rs1800788
hCV32212664
rs12642646
0.51
0.150481176
0.2273


hCV11503470
rs1800788
hCV32212669
rs12649647
0.51
0.150481176
0.1508


hCV11503470
rs1800788
hCV354895
rs11737226
0.51
0.150481176
0.5659


hCV11503470
rs1800788
hCV354896
rs7690972
0.51
0.150481176
0.5659


hCV11503470
rs1800788
hCV470979
rs1490672
0.51
0.150481176
0.4671


hCV11503470
rs1800788
hCV7429793
rs1025154
0.51
0.150481176
0.9719


hCV11503470
rs1800788
hDV70945235
rs17373860
0.51
0.150481176
0.2419


hCV11541681
rs2001490
hCV112099
rs12052539
0.51
0.847343426
0.9243


hCV11541681
rs2001490
hCV112100
rs17350125
0.51
0.847343426
0.9268


hCV11541681
rs2001490
hCV11537012
rs12992607
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV11537013
rs12713793
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV11541694
rs12619258
0.51
0.847343426
1


hCV11541681
rs2001490
hCV11541701
rs6748233
0.51
0.847343426
0.9268


hCV11541681
rs2001490
hCV11541702
rs4852978
0.51
0.847343426
0.9268


hCV11541681
rs2001490
hCV11541712
rs12713791
0.51
0.847343426
0.8856


hCV11541681
rs2001490
hCV11541719
rs12615807
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV11541721
rs2006997
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV11941453
rs2001436
0.51
0.847343426
1


hCV11541681
rs2001490
hCV133926
rs12053242
0.51
0.847343426
0.9268


hCV11541681
rs2001490
hCV133927
rs7599453
0.51
0.847343426
0.9237


hCV11541681
rs2001490
hCV133928
rs4852977
0.51
0.847343426
0.9268


hCV11541681
rs2001490
hCV133930
rs1815028
0.51
0.847343426
0.9268


hCV11541681
rs2001490
hCV15804221
rs2421674
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV15804228
rs2421675
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV180709
rs7591112
0.51
0.847343426
0.8898


hCV11541681
rs2001490
hCV180710
rs11891140
0.51
0.847343426
0.8898


hCV11541681
rs2001490
hCV1835582
rs12713789
0.51
0.847343426
0.8874


hCV11541681
rs2001490
hCV1835584
rs6749841
0.51
0.847343426
0.8856


hCV11541681
rs2001490
hCV2050088
rs2272178
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV2050091
rs35791379
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV2050092
rs12624267
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV2050096
rs2116367
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV25924555
rs13003035
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV26996655
rs12713790
0.51
0.847343426
0.8889


hCV11541681
rs2001490
hCV26996656
rs1806683
0.51
0.847343426
0.9243


hCV11541681
rs2001490
hCV26996674
rs13006448
0.51
0.847343426
1


hCV11541681
rs2001490
hCV26996679
rs6732812
0.51
0.847343426
1


hCV11541681
rs2001490
hCV26996688
rs13015885
0.51
0.847343426
1


hCV11541681
rs2001490
hCV26996689
rs13014700
0.51
0.847343426
1


hCV11541681
rs2001490
hCV26996690
rs2421575
0.51
0.847343426
1


hCV11541681
rs2001490
hCV26996697
rs12611487
0.51
0.847343426
1


hCV11541681
rs2001490
hCV26996701
rs7608328
0.51
0.847343426
0.8545


hCV11541681
rs2001490
hCV26996705
rs12997018
0.51
0.847343426
0.9547


hCV11541681
rs2001490
hCV29307907
rs4852316
0.51
0.847343426
0.9243


hCV11541681
rs2001490
hCV303807
rs17350188
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV31840120
rs12713798
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV31840129
rs11126417
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV31840132
rs2421676
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV31840134
rs11894953
0.51
0.847343426
0.849


hCV11541681
rs2001490
hCV31840136
rs12713795
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV31840146
rs11126415
0.51
0.847343426
0.9268


hCV11541681
rs2001490
hCV31840149
rs12233112
0.51
0.847343426
1


hCV11541681
rs2001490
hCV31840152
rs12998980
0.51
0.847343426
1


hCV11541681
rs2001490
hCV31840159
rs13013228
0.51
0.847343426
1


hCV11541681
rs2001490
hCV31840166
rs4513320
0.51
0.847343426
1


hCV11541681
rs2001490
hCV505733
rs11126416
0.51
0.847343426
0.8544


hCV11541681
rs2001490
hCV512569
rs6755500
0.51
0.847343426
0.9236


hCV11541681
rs2001490
hCV95670
rs4852975
0.51
0.847343426
1


hCV11541681
rs2001490
hCV95671
rs11126414
0.51
0.847343426
1


hCV11541681
rs2001490
hCV95672
rs6750515
0.51
0.847343426
0.8515


hCV11541681
rs2001490
hDV68778390
rs10188074
0.51
0.847343426
0.9596


hCV11541681
rs2001490
hDV69785784
rs13000788
0.51
0.847343426
1


hCV11541681
rs2001490
hDV70942181
rs17350056
0.51
0.847343426
1


hCV11541681
rs2001490
hDV70953030
rs17434634
0.51
0.847343426
1


hCV11541681
rs2001490
hDV70953035
rs17434655
0.51
0.847343426
1


hCV11541681
rs2001490
hDV77051911
rs4852972
0.51
0.847343426
1


hCV11541681
rs2001490
hDV77051912
rs4852976
0.51
0.847343426
0.9243


hCV11786258
rs4253303
hCV11786147
rs4862662
0.51
0.09882857
0.6957


hCV11786258
rs4253303
hCV11786203
rs4253251
0.51
0.09882857
0.1395


hCV11786258
rs4253303
hCV11786235
rs4253287
0.51
0.09882857
0.116


hCV11786258
rs4253303
hCV11786259
rs4253304
0.51
0.09882857
0.8944


hCV11786258
rs4253303
hCV12066106
rs1914926
0.51
0.09882857
0.1036


hCV11786258
rs4253303
hCV12066118
rs2048
0.51
0.09882857
0.5556


hCV11786258
rs4253303
hCV12066119
rs1912826
0.51
0.09882857
0.4905


hCV11786258
rs4253303
hCV12066124
rs2036914
0.51
0.09882857
0.3227


hCV11786258
rs4253303
hCV15968025
rs2292425
0.51
0.09882857
0.3145


hCV11786258
rs4253303
hCV15968026
rs2292426
0.51
0.09882857
0.2823


hCV11786258
rs4253303
hCV15968034
rs2292428
0.51
0.09882857
0.337


hCV11786258
rs4253303
hCV15968043
rs2292423
0.51
0.09882857
0.8913


hCV11786258
rs4253303
hCV15975109
rs2304596
0.51
0.09882857
0.1395


hCV11786258
rs4253303
hCV2103343
rs4241824
0.51
0.09882857
0.255


hCV11786258
rs4253303
hCV2103348
rs11931515
0.51
0.09882857
0.116


hCV11786258
rs4253303
hCV2103391
rs1008728
0.51
0.09882857
0.1419


hCV11786258
rs4253303
hCV2103392
rs12500826
0.51
0.09882857
0.1267


hCV11786258
rs4253303
hCV22271609
rs4253326
0.51
0.09882857
0.1138


hCV11786258
rs4253303
hCV22272267
rs3733402
0.51
0.09882857
0.5632


hCV11786258
rs4253303
hCV25474413
rs3822057
0.51
0.09882857
0.2622


hCV11786258
rs4253303
hCV25474414
rs4253399
0.51
0.09882857
0.2697


hCV11786258
rs4253303
hCV25634781
rs4253299
0.51
0.09882857
0.1325


hCV11786258
rs4253303
hCV25989001
hCV25989001
0.51
0.09882857
0.1474


hCV11786258
rs4253303
hCV25990131
rs13146272
0.51
0.09882857
0.3213


hCV11786258
rs4253303
hCV26038139
rs4253405
0.51
0.09882857
0.1069


hCV11786258
rs4253303
hCV26265197
rs10014399
0.51
0.09882857
0.1412


hCV11786258
rs4253303
hCV26265199
rs2221843
0.51
0.09882857
0.1325


hCV11786258
rs4253303
hCV26265231
rs7684025
0.51
0.09882857
0.5918


hCV11786258
rs4253303
hCV27474895
rs3756011
0.51
0.09882857
0.1518


hCV11786258
rs4253303
hCV27477533
rs3756008
0.51
0.09882857
0.315


hCV11786258
rs4253303
hCV27482765
rs3775301
0.51
0.09882857
0.1395


hCV11786258
rs4253303
hCV27506149
rs3822055
0.51
0.09882857
0.1325


hCV11786258
rs4253303
hCV27902808
rs4253236
0.51
0.09882857
0.366


hCV11786258
rs4253303
hCV28960679
rs6844764
0.51
0.09882857
0.3907


hCV11786258
rs4253303
hCV29053260
rs4861707
0.51
0.09882857
0.1962


hCV11786258
rs4253303
hCV29053264
rs7667777
0.51
0.09882857
0.7578


hCV11786258
rs4253303
hCV29053265
rs4253244
0.51
0.09882857
0.3533


hCV11786258
rs4253303
hCV29718000
rs4253238
0.51
0.09882857
0.5569


hCV11786258
rs4253303
hCV29877725
rs4253295
0.51
0.09882857
1


hCV11786258
rs4253303
hCV30983927
rs6552962
0.51
0.09882857
0.1072


hCV11786258
rs4253303
hCV32209636
rs11132387
0.51
0.09882857
0.2106


hCV11786258
rs4253303
hCV32209638
rs12507040
0.51
0.09882857
0.1024


hCV11786258
rs4253303
hCV32291217
rs4253323
0.51
0.09882857
0.1395


hCV11786258
rs4253303
hCV32291269
rs4253417
0.51
0.09882857
0.2035


hCV11786258
rs4253303
hCV32291295
rs4253292
0.51
0.09882857
0.1404


hCV11786258
rs4253303
hCV32291301
rs4253302
0.51
0.09882857
0.1385


hCV11786258
rs4253303
hCV32295028
rs4253260
0.51
0.09882857
0.1395


hCV11786258
rs4253303
hCV3229991
rs4241815
0.51
0.09882857
0.5632


hCV11786258
rs4253303
hCV3229992
rs3775298
0.51
0.09882857
0.5632


hCV11786258
rs4253303
hCV3229995
rs11132382
0.51
0.09882857
0.5569


hCV11786258
rs4253303
hCV3230000
rs4253294
0.51
0.09882857
0.2479


hCV11786258
rs4253303
hCV3230002
rs4253297
0.51
0.09882857
1


hCV11786258
rs4253303
hCV3230003
rs2304595
0.51
0.09882857
0.8848


hCV11786258
rs4253303
hCV3230006
rs4253308
0.51
0.09882857
1


hCV11786258
rs4253303
hCV3230007
rs4253311
0.51
0.09882857
0.5632


hCV11786258
rs4253303
hCV3230011
rs4253320
0.51
0.09882857
1


hCV11786258
rs4253303
hCV3230012
rs4241821
0.51
0.09882857
0.1325


hCV11786258
rs4253303
hCV3230013
rs3775303
0.51
0.09882857
0.8944


hCV11786258
rs4253303
hCV3230014
rs4861709
0.51
0.09882857
0.2479


hCV11786258
rs4253303
hCV3230017
rs4253327
0.51
0.09882857
0.2534


hCV11786258
rs4253303
hCV3230018
rs925453
0.51
0.09882857
0.2319


hCV11786258
rs4253303
hCV3230019
rs4253332
0.51
0.09882857
0.2319


hCV11786258
rs4253303
hCV3230022
rs11132383
0.51
0.09882857
0.1658


hCV11786258
rs4253303
hCV3230025
rs3756009
0.51
0.09882857
0.2464


hCV11786258
rs4253303
hCV3230038
rs2289252
0.51
0.09882857
0.1956


hCV11786258
rs4253303
hCV3230083
rs10013653
0.51
0.09882857
0.4797


hCV11786258
rs4253303
hCV3230084
rs7682918
0.51
0.09882857
0.5961


hCV11786258
rs4253303
hCV3230094
rs7687818
0.51
0.09882857
0.6447


hCV11786258
rs4253303
hCV3230096
rs3817184
0.51
0.09882857
0.7346


hCV11786258
rs4253303
hCV3230097
rs3736455
0.51
0.09882857
0.2761


hCV11786258
rs4253303
hCV3230101
rs6835839
0.51
0.09882857
0.3578


hCV11786258
rs4253303
hCV3230106
rs1473597
0.51
0.09882857
0.3534


hCV11786258
rs4253303
hCV3230110
rs2276917
0.51
0.09882857
0.337


hCV11786258
rs4253303
hCV3230113
rs1053094
0.51
0.09882857
0.491


hCV11786258
rs4253303
hCV3230125
rs11938564
0.51
0.09882857
0.1367


hCV11786258
rs4253303
hCV3230131
rs13136269
0.51
0.09882857
0.1024


hCV11786258
rs4253303
hCV3230133
rs12511874
0.51
0.09882857
0.1024


hCV11786258
rs4253303
hCV3230134
rs12500151
0.51
0.09882857
0.1024


hCV11786258
rs4253303
hCV3230136
rs13116273
0.51
0.09882857
0.1243


hCV11786258
rs4253303
hCV32313006
rs4253248
0.51
0.09882857
0.5569


hCV11786258
rs4253303
hCV32313024
rs4253239
0.51
0.09882857
0.1404


hCV11786258
rs4253303
hCV32358975
rs4253255
0.51
0.09882857
0.5556


hCV11786258
rs4253303
hCV32358984
rs4253256
0.51
0.09882857
0.3667


hCV11786258
rs4253303
hCV8241630
rs925451
0.51
0.09882857
0.2889


hCV11786258
rs4253303
hCV8241631
rs1511802
0.51
0.09882857
1


hCV11786258
rs4253303
hCV8241632
rs1511801
0.51
0.09882857
0.5625


hCV11786258
rs4253303
hDV71222711
rs4253252
0.51
0.09882857
0.5569


hCV11786258
rs4253303
hDV76175111
rs35079309
0.51
0.09882857
0.1206


hCV11975250
rs6025
hCV11341861
rs10800436
0.51
0.015514847
0.1922


hCV11975250
rs6025
hCV11341869
rs2176473
0.51
0.015514847
0.0375


hCV11975250
rs6025
hCV11341876
rs1980198
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV11341878
rs4656670
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV11341882
rs12024897
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV11341898
rs12563090
0.51
0.015514847
0.0332


hCV11975250
rs6025
hCV11342138
rs2142760
0.51
0.015514847
0.0175


hCV11975250
rs6025
hCV11975194
rs2038024
0.51
0.015514847
0.0613


hCV11975250
rs6025
hCV11975195
rs1894692
0.51
0.015514847
1


hCV11975250
rs6025
hCV11975285
rs6127
0.51
0.015514847
0.026


hCV11975250
rs6025
hCV11975296
rs6131
0.51
0.015514847
0.0848


hCV11975250
rs6025
hCV11975318
rs1883228
0.51
0.015514847
0.0768


hCV11975250
rs6025
hCV11975322
rs5357
0.51
0.015514847
0.0827


hCV11975250
rs6025
hCV11975325
rs5367
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV11975329
rs5363
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV11975331
rs5362
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV11975332
rs5361
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV11975488
rs2057249
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV15802103
rs2420370
0.51
0.015514847
0.117


hCV11975250
rs6025
hCV15802110
rs2420371
0.51
0.015514847
0.3415


hCV11975250
rs6025
hCV15858911
rs2806392
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV15868017
rs2223303
0.51
0.015514847
0.0183


hCV11975250
rs6025
hCV15878582
rs2275299
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV15962928
rs2285211
0.51
0.015514847
0.0303


hCV11975250
rs6025
hCV16161169
rs2205847
0.51
0.015514847
0.0872


hCV11975250
rs6025
hCV16177404
rs2272920
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV221700
rs6677410
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV2217923
rs2014878
0.51
0.015514847
0.159


hCV11975250
rs6025
hCV2456693
rs6672589
0.51
0.015514847
0.0169


hCV11975250
rs6025
hCV2456695
rs10919173
0.51
0.015514847
0.0169


hCV11975250
rs6025
hCV2456708
rs1517745
0.51
0.015514847
0.0544


hCV11975250
rs6025
hCV2456730
rs961404
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV2456733
rs12021580
0.51
0.015514847
0.0168


hCV11975250
rs6025
hCV2456741
rs6696810
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV2456747
rs3820059
0.51
0.015514847
0.0423


hCV11975250
rs6025
hCV2456768
rs6427186
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV2459402
rs12045330
0.51
0.015514847
0.0369


hCV11975250
rs6025
hCV2459404
rs6663862
0.51
0.015514847
0.0763


hCV11975250
rs6025
hCV2459408
rs7531806
0.51
0.015514847
0.0171


hCV11975250
rs6025
hCV2459420
rs4987351
0.51
0.015514847
0.0246


hCV11975250
rs6025
hCV2459428
rs4987285
0.51
0.015514847
0.0804


hCV11975250
rs6025
hCV2459446
rs4786
0.51
0.015514847
0.0799


hCV11975250
rs6025
hCV2459453
rs3917419
0.51
0.015514847
0.0192


hCV11975250
rs6025
hCV2459459
rs932307
0.51
0.015514847
0.0872


hCV11975250
rs6025
hCV2459460
rs5353
0.51
0.015514847
0.0839


hCV11975250
rs6025
hCV2480400
rs1569474
0.51
0.015514847
0.0436


hCV11975250
rs6025
hCV2480404
rs7551819
0.51
0.015514847
0.0183


hCV11975250
rs6025
hCV2480416
rs732314
0.51
0.015514847
0.0196


hCV11975250
rs6025
hCV2480424
rs2244529
0.51
0.015514847
0.0523


hCV11975250
rs6025
hCV2480428
rs3917740
0.51
0.015514847
0.0725


hCV11975250
rs6025
hCV2481727
rs6670407
0.51
0.015514847
0.0281


hCV11975250
rs6025
hCV2481731
rs9332640
0.51
0.015514847
0.0271


hCV11975250
rs6025
hCV2481732
rs12131397
0.51
0.015514847
0.0273


hCV11975250
rs6025
hCV25616192
rs10919168
0.51
0.015514847
0.0534


hCV11975250
rs6025
hCV25617131
rs3917410
0.51
0.015514847
0.1718


hCV11975250
rs6025
hCV25617143
rs3917425
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV25619707
rs4987308
0.51
0.015514847
0.0827


hCV11975250
rs6025
hCV25921520
rs12132173
0.51
0.015514847
0.1726


hCV11975250
rs6025
hCV25922175
rs12120229
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV27242639
rs7544221
0.51
0.015514847
0.0413


hCV11975250
rs6025
hCV27242706
rs7524348
0.51
0.015514847
0.0169


hCV11975250
rs6025
hCV27242742
rs12408451
0.51
0.015514847
0.0278


hCV11975250
rs6025
hCV27243253
rs2420505
0.51
0.015514847
0.1007


hCV11975250
rs6025
hCV27478380
rs3766141
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV27480806
rs3766129
0.51
0.015514847
0.0347


hCV11975250
rs6025
hCV27497504
rs3917683
0.51
0.015514847
0.0162


hCV11975250
rs6025
hCV27523232
rs3917681
0.51
0.015514847
0.0583


hCV11975250
rs6025
hCV27886241
rs4656690
0.51
0.015514847
0.0449


hCV11975250
rs6025
hCV27886249
rs3917406
0.51
0.015514847
0.0349


hCV11975250
rs6025
hCV279320
rs10800441
0.51
0.015514847
0.0327


hCV11975250
rs6025
hCV27936996
rs4656697
0.51
0.015514847
0.033


hCV11975250
rs6025
hCV28023624
rs4656704
0.51
0.015514847
0.0804


hCV11975250
rs6025
hCV29397237
rs6427185
0.51
0.015514847
0.0423


hCV11975250
rs6025
hCV29397245
rs6656822
0.51
0.015514847
0.0571


hCV11975250
rs6025
hCV29397247
rs6427194
0.51
0.015514847
0.1171


hCV11975250
rs6025
hCV29397248
rs6427195
0.51
0.015514847
0.2959


hCV11975250
rs6025
hCV29397252
rs6427197
0.51
0.015514847
0.2959


hCV11975250
rs6025
hCV29397255
rs6427202
0.51
0.015514847
0.0281


hCV11975250
rs6025
hCV29397262
rs3917786
0.51
0.015514847
0.0276


hCV11975250
rs6025
hCV29397289
rs4656198
0.51
0.015514847
0.1007


hCV11975250
rs6025
hCV29585595
rs10489173
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV29748285
rs6687813
0.51
0.015514847
0.3169


hCV11975250
rs6025
hCV29820280
rs6696217
0.51
0.015514847
0.2454


hCV11975250
rs6025
hCV30036721
rs3917449
0.51
0.015514847
0.0183


hCV11975250
rs6025
hCV30126935
rs6692451
0.51
0.015514847
0.1071


hCV11975250
rs6025
hCV30324835
rs10489183
0.51
0.015514847
0.0751


hCV11975250
rs6025
hCV30631277
rs10489182
0.51
0.015514847
0.0439


hCV11975250
rs6025
hCV32141371
rs10800447
0.51
0.015514847
0.0534


hCV11975250
rs6025
hCV32141374
rs10919174
0.51
0.015514847
0.0183


hCV11975250
rs6025
hCV32141406
rs10737547
0.51
0.015514847
0.1348


hCV11975250
rs6025
hCV32141457
rs6678795
0.51
0.015514847
0.0226


hCV11975250
rs6025
hCV32141484
rs3917768
0.51
0.015514847
0.0159


hCV11975250
rs6025
hCV32141485
rs3917744
0.51
0.015514847
0.0407


hCV11975250
rs6025
hCV32141499
rs3917862
0.51
0.015514847
0.1954


hCV11975250
rs6025
hCV32141505
rs3917657
0.51
0.015514847
0.1023


hCV11975250
rs6025
hCV32141519
rs12131631
0.51
0.015514847
0.1222


hCV11975250
rs6025
hCV32141520
rs12123695
0.51
0.015514847
0.0578


hCV11975250
rs6025
hCV32141521
rs10800462
0.51
0.015514847
0.0178


hCV11975250
rs6025
hCV32141522
rs12126695
0.51
0.015514847
0.0631


hCV11975250
rs6025
hCV32141523
rs10919204
0.51
0.015514847
0.0631


hCV11975250
rs6025
hCV32141527
rs10919207
0.51
0.015514847
0.0631


hCV11975250
rs6025
hCV32141586
rs12137905
0.51
0.015514847
0.0827


hCV11975250
rs6025
hCV32141621
rs12133642
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV32141622
rs12133666
0.51
0.015514847
0.1011


hCV11975250
rs6025
hCV32141631
rs3917436
0.51
0.015514847
0.0801


hCV11975250
rs6025
hCV32141639
rs3917411
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV32141645
rs3917452
0.51
0.015514847
0.1726


hCV11975250
rs6025
hCV32141663
rs12142587
0.51
0.015514847
0.0826


hCV11975250
rs6025
hCV32141665
rs10800470
0.51
0.015514847
0.0462


hCV11975250
rs6025
hCV32141669
rs10800472
0.51
0.015514847
0.0467


hCV11975250
rs6025
hCV32141741
rs12135361
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141779
rs12122767
0.51
0.015514847
0.14


hCV11975250
rs6025
hCV32141799
rs12133074
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141820
rs12132384
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141821
rs12135726
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141828
rs12136425
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141844
rs12142093
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141847
rs12143057
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141873
rs12131357
0.51
0.015514847
0.1803


hCV11975250
rs6025
hCV32141874
rs12121045
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141888
rs12124561
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141892
rs12125595
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141893
rs12125679
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141894
rs12128308
0.51
0.015514847
0.1587


hCV11975250
rs6025
hCV32141903
rs12131192
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV32141968
rs12124907
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV32141971
rs12118305
0.51
0.015514847
0.1018


hCV11975250
rs6025
hCV32398748
rs3917417
0.51
0.015514847
0.1167


hCV11975250
rs6025
hCV32398763
rs3917392
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV325211
rs3753305
0.51
0.015514847
0.0251


hCV11975250
rs6025
hCV325253
rs2236868
0.51
0.015514847
0.0246


hCV11975250
rs6025
hCV337817
rs9332586
0.51
0.015514847
0.0178


hCV11975250
rs6025
hCV474695
rs10800463
0.51
0.015514847
0.0244


hCV11975250
rs6025
hCV574681
rs575147
0.51
0.015514847
0.1072


hCV11975250
rs6025
hCV574682
rs590181
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV574683
rs544008
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV574693
rs601355
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV574707
rs565397
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV574726
rs664962
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV574743
rs545963
0.51
0.015514847
0.1724


hCV11975250
rs6025
hCV574757
rs654664
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV574764
rs638486
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV574785
rs511609
0.51
0.015514847
0.1583


hCV11975250
rs6025
hCV574788
rs629408
0.51
0.015514847
0.1726


hCV11975250
rs6025
hCV574789
rs629421
0.51
0.015514847
0.1726


hCV11975250
rs6025
hCV8688930
rs3905328
0.51
0.015514847
0.043


hCV11975250
rs6025
hCV8690976
rs1124843
0.51
0.015514847
0.0423


hCV11975250
rs6025
hCV8697031
rs1400836
0.51
0.015514847
0.0423


hCV11975250
rs6025
hCV8697043
rs1517747
0.51
0.015514847
0.0183


hCV11975250
rs6025
hCV8697049
rs1517744
0.51
0.015514847
0.0559


hCV11975250
rs6025
hCV8697055
rs1208134
0.51
0.015514847
0.1939


hCV11975250
rs6025
hCV8697995
rs4519
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV8698056
rs488488
0.51
0.015514847
0.117


hCV11975250
rs6025
hCV8698071
rs673789
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV8919425
rs970740
0.51
0.015514847
0.1171


hCV11975250
rs6025
hCV8919431
rs6009
0.51
0.015514847
0.2959


hCV11975250
rs6025
hCV8919452
rs1018827
0.51
0.015514847
0.2769


hCV11975250
rs6025
hCV8919485
rs1800808
0.51
0.015514847
0.0583


hCV11975250
rs6025
hCV8919492
rs1569476
0.51
0.015514847
0.0303


hCV11975250
rs6025
hCV8919494
rs1011267
0.51
0.015514847
0.0194


hCV11975250
rs6025
hCV8919500
rs1011266
0.51
0.015514847
0.131


hCV11975250
rs6025
hCV8919501
rs909628
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV8919509
rs1051091
0.51
0.015514847
0.0872


hCV11975250
rs6025
hCV8919515
rs1569457
0.51
0.015514847
0.0827


hCV11975250
rs6025
hCV8919527
rs1800016
0.51
0.015514847
0.1655


hCV11975250
rs6025
hCV8919528
rs1800015
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV8919530
rs1805193
0.51
0.015514847
0.1728


hCV11975250
rs6025
hCV9945935
rs3917750
0.51
0.015514847
0.0183


hCV11975250
rs6025
hDV70670007
rs16828222
0.51
0.015514847
0.1655


hCV11975250
rs6025
hDV70694593
rs16861990
0.51
0.015514847
0.1939


hCV11975250
rs6025
hDV70695296
rs16862919
0.51
0.015514847
0.189


hCV11975250
rs6025
hDV70695328
rs16862956
0.51
0.015514847
0.116


hCV11975250
rs6025
hDV70695338
rs16862968
0.51
0.015514847
0.1728


hCV11975250
rs6025
hDV70965007
rs17529304
0.51
0.015514847
0.1655


hCV11975250
rs6025
hDV70966798
rs17543370
0.51
0.015514847
0.1651


hCV11975250
rs6025
hDV70966830
rs17543611
0.51
0.015514847
0.1655


hCV11975250
rs6025
hDV70974851
rs17601631
0.51
0.015514847
0.1655


hCV11975250
rs6025
hDV70975002
rs17602701
0.51
0.015514847
0.1651


hCV11975250
rs6025
hDV70975134
rs17603666
0.51
0.015514847
0.1655


hCV11975250
rs6025
hDV71028805
rs4987299
0.51
0.015514847
0.1728


hCV11975250
rs6025
hDV71028807
rs4987302
0.51
0.015514847
0.0827


hCV11975250
rs6025
hDV71028808
rs4987304
0.51
0.015514847
0.0827


hCV11975250
rs6025
hDV71028809
rs4987307
0.51
0.015514847
0.0827


hCV11975250
rs6025
hDV71028811
rs4987318
0.51
0.015514847
0.033


hCV11975250
rs6025
hDV71028814
rs4987323
0.51
0.015514847
0.1728


hCV11975250
rs6025
hDV71028815
rs4987324
0.51
0.015514847
0.1728


hCV11975250
rs6025
hDV71028816
rs4987325
0.51
0.015514847
0.0827


hCV11975250
rs6025
hDV71028819
rs4987340
0.51
0.015514847
0.0827


hCV11975250
rs6025
hDV71028821
rs4987343
0.51
0.015514847
0.0827


hCV11975250
rs6025
hDV71028822
rs4987345
0.51
0.015514847
0.0826


hCV11975250
rs6025
hDV71028828
rs4987395
0.51
0.015514847
0.0827


hCV11975250
rs6025
hDV71070471
rs4987363
0.51
0.015514847
0.1728


hCV11975250
rs6025
hDV76908547
rs3917400
0.51
0.015514847
0.103


hCV11975250
rs6025
hDV76908557
rs3917427
0.51
0.015514847
0.1728


hCV11975250
rs6025
hDV76908563
rs3917441
0.51
0.015514847
0.103


hCV11975250
rs6025
hDV76908571
rs3917454
0.51
0.015514847
0.25


hCV11975250
rs6025
hDV76908576
rs3917461
0.51
0.015514847
0.1592


hCV11975250
rs6025
hDV76908651
rs3917729
0.51
0.015514847
0.0583


hCV11975250
rs6025
hDV77030725
rs4656701
0.51
0.015514847
0.0804


hCV11975250
rs6025
hDV77030727
rs4656703
0.51
0.015514847
0.0804


hCV12066124
rs2036914
hCV11786147
rs4862662
0.51
0.050680687
0.2824


hCV12066124
rs2036914
hCV11786203
rs4253251
0.51
0.050680687
0.0507


hCV12066124
rs2036914
hCV11786235
rs4253287
0.51
0.050680687
0.0572


hCV12066124
rs2036914
hCV11786258
rs4253303
0.51
0.050680687
0.3227


hCV12066124
rs2036914
hCV11786259
rs4253304
0.51
0.050680687
0.3572


hCV12066124
rs2036914
hCV11786295
rs4253421
0.51
0.050680687
0.1004


hCV12066124
rs2036914
hCV11786307
rs1062547
0.51
0.050680687
0.4099


hCV12066124
rs2036914
hCV11786327
rs13133050
0.51
0.050680687
0.1901


hCV12066124
rs2036914
hCV12066116
rs1877320
0.51
0.050680687
0.1385


hCV12066124
rs2036914
hCV12066118
rs2048
0.51
0.050680687
0.3579


hCV12066124
rs2036914
hCV12066119
rs1912826
0.51
0.050680687
0.3713


hCV12066124
rs2036914
hCV12066129
rs1593
0.51
0.050680687
0.1505


hCV12066124
rs2036914
hCV12086148
rs1877321
0.51
0.050680687
0.0621


hCV12066124
rs2036914
hCV15793897
rs3087505
0.51
0.050680687
0.1103


hCV12066124
rs2036914
hCV15811716
rs2102575
0.51
0.050680687
0.1039


hCV12066124
rs2036914
hCV15968025
rs2292425
0.51
0.050680687
0.175


hCV12066124
rs2036914
hCV15968026
rs2292426
0.51
0.050680687
0.2128


hCV12066124
rs2036914
hCV15968034
rs2292428
0.51
0.050680687
0.181


hCV12066124
rs2036914
hCV15968043
rs2292423
0.51
0.050680687
0.3742


hCV12066124
rs2036914
hCV15975109
rs2304596
0.51
0.050680687
0.0738


hCV12066124
rs2036914
hCV16172925
rs2241818
0.51
0.050680687
0.0795


hCV12066124
rs2036914
hCV16172935
rs2241817
0.51
0.050680687
0.4102


hCV12066124
rs2036914
hCV2103337
rs13102931
0.51
0.050680687
0.0611


hCV12066124
rs2036914
hCV2103343
rs4241824
0.51
0.050680687
0.9265


hCV12066124
rs2036914
hCV2103375
rs12502630
0.51
0.050680687
0.0643


hCV12066124
rs2036914
hCV2103388
rs4613610
0.51
0.050680687
0.0917


hCV12066124
rs2036914
hCV2103391
rs1008728
0.51
0.050680687
0.2419


hCV12066124
rs2036914
hCV2103392
rs12500826
0.51
0.050680687
0.3937


hCV12066124
rs2036914
hCV2103401
rs7687352
0.51
0.050680687
0.0531


hCV12066124
rs2036914
hCV2103402
rs9993749
0.51
0.050680687
0.0695


hCV12066124
rs2036914
hCV22272267
rs3733402
0.51
0.050680687
0.3605


hCV12066124
rs2036914
hCV25474413
rs3822057
0.51
0.050680687
0.9449


hCV12066124
rs2036914
hCV25474414
rs4253399
0.51
0.050680687
0.5632


hCV12066124
rs2036914
hCV25634763
rs4253241
0.51
0.050680687
0.0841


hCV12066124
rs2036914
hCV25988221
rs9995366
0.51
0.050680687
0.0931


hCV12066124
rs2036914
hCV25989001
hCV25989001
0.51
0.050680687
0.0578


hCV12066124
rs2036914
hCV25990131
rs13146272
0.51
0.050680687
0.1776


hCV12066124
rs2036914
hCV26038139
rs4253405
0.51
0.050680687
0.5831


hCV12066124
rs2036914
hCV26265197
rs10014399
0.51
0.050680687
0.0507


hCV12066124
rs2036914
hCV26265231
rs7684025
0.51
0.050680687
0.3217


hCV12066124
rs2036914
hCV27309991
rs4572916
0.51
0.050680687
0.1646


hCV12066124
rs2036914
hCV27473099
rs3733403
0.51
0.050680687
0.1015


hCV12066124
rs2036914
hCV27474895
rs3756011
0.51
0.050680687
0.4851


hCV12066124
rs2036914
hCV27477533
rs3756008
0.51
0.050680687
0.5443


hCV12066124
rs2036914
hCV27482765
rs3775301
0.51
0.050680687
0.0738


hCV12066124
rs2036914
hCV27490984
rs3822058
0.51
0.050680687
0.4255


hCV12066124
rs2036914
hCV27521729
rs3822056
0.51
0.050680687
0.1148


hCV12066124
rs2036914
hCV27902803
rs4862665
0.51
0.050680687
0.0931


hCV12066124
rs2036914
hCV27902808
rs4253236
0.51
0.050680687
0.1725


hCV12066124
rs2036914
hCV28960679
rs6844764
0.51
0.050680687
0.1096


hCV12066124
rs2036914
hCV29053261
rs6842047
0.51
0.050680687
0.1103


hCV12066124
rs2036914
hCV29053264
rs7667777
0.51
0.050680687
0.2682


hCV12066124
rs2036914
hCV29053265
rs4253244
0.51
0.050680687
0.1619


hCV12066124
rs2036914
hCV29419315
rs6841024
0.51
0.050680687
0.1051


hCV12066124
rs2036914
hCV29640635
rs10029715
0.51
0.050680687
0.099


hCV12066124
rs2036914
hCV29718000
rs4253238
0.51
0.050680687
0.4135


hCV12066124
rs2036914
hCV29826351
rs10025990
0.51
0.050680687
0.1626


hCV12066124
rs2036914
hCV29877725
rs4253295
0.51
0.050680687
0.3398


hCV12066124
rs2036914
hCV30307525
rs10025152
0.51
0.050680687
0.099


hCV12066124
rs2036914
hCV30492573
rs10471184
0.51
0.050680687
0.1103


hCV12066124
rs2036914
hCV30562347
rs4253418
0.51
0.050680687
0.0632


hCV12066124
rs2036914
hCV30983902
rs4862668
0.51
0.050680687
0.1385


hCV12066124
rs2036914
hCV30983907
rs4253246
0.51
0.050680687
0.0841


hCV12066124
rs2036914
hCV30983927
rs6552962
0.51
0.050680687
0.0526


hCV12066124
rs2036914
hCV32209629
rs12715865
0.51
0.050680687
0.1168


hCV12066124
rs2036914
hCV32209636
rs11132387
0.51
0.050680687
0.4117


hCV12066124
rs2036914
hCV32209637
rs13143773
0.51
0.050680687
0.3327


hCV12066124
rs2036914
hCV32209638
rs12507040
0.51
0.050680687
0.387


hCV12066124
rs2036914
hCV32291217
rs4253323
0.51
0.050680687
0.0738


hCV12066124
rs2036914
hCV32291256
rs4253406
0.51
0.050680687
0.0631


hCV12066124
rs2036914
hCV32291269
rs4253417
0.51
0.050680687
0.389


hCV12066124
rs2036914
hCV32291286
rs4253422
0.51
0.050680687
0.2525


hCV12066124
rs2036914
hCV32291287
rs4253423
0.51
0.050680687
0.2525


hCV12066124
rs2036914
hCV32291295
rs4253292
0.51
0.050680687
0.1224


hCV12066124
rs2036914
hCV32291301
rs4253302
0.51
0.050680687
0.0694


hCV12066124
rs2036914
hCV32295028
rs4253260
0.51
0.050680687
0.0738


hCV12066124
rs2036914
hCV3229991
rs4241815
0.51
0.050680687
0.3605


hCV12066124
rs2036914
hCV3229992
rs3775298
0.51
0.050680687
0.3605


hCV12066124
rs2036914
hCV3229995
rs11132382
0.51
0.050680687
0.3958


hCV12066124
rs2036914
hCV3230000
rs4253294
0.51
0.050680687
0.1496


hCV12066124
rs2036914
hCV3230001
rs4253296
0.51
0.050680687
0.0841


hCV12066124
rs2036914
hCV3230002
rs4253297
0.51
0.050680687
0.3058


hCV12066124
rs2036914
hCV3230003
rs2304595
0.51
0.050680687
0.4092


hCV12066124
rs2036914
hCV3230004
rs4253301
0.51
0.050680687
0.1069


hCV12066124
rs2036914
hCV3230006
rs4253308
0.51
0.050680687
0.3398


hCV12066124
rs2036914
hCV3230007
rs4253311
0.51
0.050680687
0.3605


hCV12066124
rs2036914
hCV3230011
rs4253320
0.51
0.050680687
0.3058


hCV12066124
rs2036914
hCV3230013
rs3775303
0.51
0.050680687
0.3572


hCV12066124
rs2036914
hCV3230014
rs4861709
0.51
0.050680687
0.1496


hCV12066124
rs2036914
hCV3230017
rs4253327
0.51
0.050680687
0.0613


hCV12066124
rs2036914
hCV3230018
rs925453
0.51
0.050680687
0.1526


hCV12066124
rs2036914
hCV3230019
rs4253332
0.51
0.050680687
0.1452


hCV12066124
rs2036914
hCV3230021
rs13135645
0.51
0.050680687
0.154


hCV12066124
rs2036914
hCV3230022
rs11132383
0.51
0.050680687
0.1678


hCV12066124
rs2036914
hCV3230025
rs3756009
0.51
0.050680687
0.5789


hCV12066124
rs2036914
hCV3230030
rs4253408
0.51
0.050680687
0.0667


hCV12066124
rs2036914
hCV3230031
rs4253419
0.51
0.050680687
0.2525


hCV12066124
rs2036914
hCV3230038
rs2289252
0.51
0.050680687
0.3834


hCV12066124
rs2036914
hCV3230083
rs10013653
0.51
0.050680687
0.3086


hCV12066124
rs2036914
hCV3230084
rs7682918
0.51
0.050680687
0.2285


hCV12066124
rs2036914
hCV3230094
rs7687818
0.51
0.050680687
0.3495


hCV12066124
rs2036914
hCV3230096
rs3817184
0.51
0.050680687
0.2824


hCV12066124
rs2036914
hCV3230097
rs3736455
0.51
0.050680687
0.2379


hCV12066124
rs2036914
hCV3230101
rs6835839
0.51
0.050680687
0.1143


hCV12066124
rs2036914
hCV3230106
rs1473597
0.51
0.050680687
0.1783


hCV12066124
rs2036914
hCV3230110
rs2276917
0.51
0.050680687
0.1882


hCV12066124
rs2036914
hCV3230113
rs1053094
0.51
0.050680687
0.3142


hCV12066124
rs2036914
hCV3230118
rs4253429
0.51
0.050680687
0.2525


hCV12066124
rs2036914
hCV3230119
rs4253430
0.51
0.050680687
0.4139


hCV12066124
rs2036914
hCV3230125
rs11938564
0.51
0.050680687
0.3091


hCV12066124
rs2036914
hCV3230131
rs13136269
0.51
0.050680687
0.387


hCV12066124
rs2036914
hCV3230133
rs12511874
0.51
0.050680687
0.3354


hCV12066124
rs2036914
hCV3230134
rs12500151
0.51
0.050680687
0.3713


hCV12066124
rs2036914
hCV3230136
rs13116273
0.51
0.050680687
0.3869


hCV12066124
rs2036914
hCV32313006
rs4253248
0.51
0.050680687
0.4015


hCV12066124
rs2036914
hCV32313007
rs4862666
0.51
0.050680687
0.0931


hCV12066124
rs2036914
hCV32313024
rs4253239
0.51
0.050680687
0.1224


hCV12066124
rs2036914
hCV32358975
rs4253255
0.51
0.050680687
0.3463


hCV12066124
rs2036914
hCV32358984
rs4253256
0.51
0.050680687
0.1734


hCV12066124
rs2036914
hCV8241628
rs907439
0.51
0.050680687
0.1646


hCV12066124
rs2036914
hCV8241630
rs925451
0.51
0.050680687
0.5632


hCV12066124
rs2036914
hCV8241631
rs1511802
0.51
0.050680687
0.3604


hCV12066124
rs2036914
hCV8241632
rs1511801
0.51
0.050680687
0.3736


hCV12066124
rs2036914
hCV8241633
rs1511800
0.51
0.050680687
0.0931


hCV12066124
rs2036914
hDV71222711
rs4253252
0.51
0.050680687
0.4015


hCV1376266
rs1654413
hCV11977629
rs1654459
0.51
0.544795666
0.7222


hCV1376266
rs1654413
hCV1376257
rs10416380
0.51
0.544795666
0.9433


hCV1376266
rs1654413
hCV1376262
rs1671150
0.51
0.544795666
1


hCV1376266
rs1654413
hCV1376264
rs1671151
0.51
0.544795666
1


hCV1376266
rs1654413
hCV1376265
rs1671152
0.51
0.544795666
0.8286


hCV1376266
rs1654413
hCV1376342
rs1654416
0.51
0.544795666
1


hCV1376266
rs1654413
hCV1376359
rs2886412
0.51
0.544795666
1


hCV1376266
rs1654413
hCV15973734
rs2304167
0.51
0.544795666
1


hCV1376266
rs1654413
hCV16044361
rs2569513
0.51
0.544795666
0.7222


hCV1376266
rs1654413
hCV26895244
rs1671153
0.51
0.544795666
1


hCV1376266
rs1654413
hCV26895257
rs2886415
0.51
0.544795666
1


hCV1376266
rs1654413
hCV29271569
rs1626971
0.51
0.544795666
0.7269


hCV1376266
rs1654413
hCV31722831
rs11671922
0.51
0.544795666
1


hCV1376266
rs1654413
hCV31722832
rs11084381
0.51
0.544795666
1


hCV1376266
rs1654413
hCV31722834
rs11084382
0.51
0.544795666
0.8448


hCV1376266
rs1654413
hCV31722835
rs11668169
0.51
0.544795666
1


hCV1376266
rs1654413
hCV31722836
rs11672026
0.51
0.544795666
1


hCV1376266
rs1654413
hCV7841075
rs1671196
0.51
0.544795666
1


hCV1376266
rs1654413
hCV8703249
rs1654444
0.51
0.544795666
0.7222


hCV1376266
rs1654413
hCV8704962
rs775893
0.51
0.544795666
0.5627


hCV1376266
rs1654413
hCV8717752
rs1671217
0.51
0.544795666
0.7269


hCV1376266
rs1654413
hCV8717761
rs1654439
0.51
0.544795666
0.675


hCV1376266
rs1654413
hCV8717793
rs1654433
0.51
0.544795666
0.7222


hCV1376266
rs1654413
hCV8717794
rs1654432
0.51
0.544795666
0.7222


hCV1376266
rs1654413
hCV8717845
rs892090
0.51
0.544795666
0.8292


hCV1376266
rs1654413
hCV8717846
rs892089
0.51
0.544795666
1


hCV1376266
rs1654413
hCV8717871
rs1654421
0.51
0.544795666
1


hCV1376266
rs1654413
hCV8717873
rs1613662
0.51
0.544795666
0.8292


hCV1376266
rs1654413
hCV8717881
rs1654420
0.51
0.544795666
1


hCV1376266
rs1654413
hCV8717893
rs1671192
0.51
0.544795666
1


hCV1376266
rs1654413
hCV8718961
rs1654451
0.51
0.544795666
0.7211


hCV1376266
rs1654413
hCV8718972
rs1654447
0.51
0.544795666
0.7222


hCV1376266
rs1654413
hCV9490926
rs1654419
0.51
0.544795666
1


hCV1376342
rs1654416
hCV11977629
rs1654459
0.51
0.409514099
0.5842


hCV1376342
rs1654416
hCV1376257
rs10416380
0.51
0.409514099
0.9457


hCV1376342
rs1654416
hCV1376262
rs1671150
0.51
0.409514099
0.9724


hCV1376342
rs1654416
hCV1376264
rs1671151
0.51
0.409514099
0.9724


hCV1376342
rs1654416
hCV1376265
rs1671152
0.51
0.409514099
0.7822


hCV1376342
rs1654416
hCV1376266
rs1654413
0.51
0.409514099
1


hCV1376342
rs1654416
hCV1376359
rs2886412
0.51
0.409514099
1


hCV1376342
rs1654416
hCV15973734
rs2304167
0.51
0.409514099
0.9724


hCV1376342
rs1654416
hCV16044361
rs2569513
0.51
0.409514099
0.6123


hCV1376342
rs1654416
hCV26895244
rs1671153
0.51
0.409514099
0.9724


hCV1376342
rs1654416
hCV26895257
rs2886415
0.51
0.409514099
1


hCV1376342
rs1654416
hCV29271569
rs1626971
0.51
0.409514099
0.7325


hCV1376342
rs1654416
hCV31722831
rs11671922
0.51
0.409514099
1


hCV1376342
rs1654416
hCV31722832
rs11084381
0.51
0.409514099
0.9207


hCV1376342
rs1654416
hCV31722834
rs11084382
0.51
0.409514099
0.8079


hCV1376342
rs1654416
hCV31722835
rs11668169
0.51
0.409514099
0.9205


hCV1376342
rs1654416
hCV31722836
rs11672026
0.51
0.409514099
0.9163


hCV1376342
rs1654416
hCV7841075
rs1671196
0.51
0.409514099
0.9207


hCV1376342
rs1654416
hCV8703249
rs1654444
0.51
0.409514099
0.633


hCV1376342
rs1654416
hCV8704962
rs775893
0.51
0.409514099
0.4637


hCV1376342
rs1654416
hCV8717752
rs1671217
0.51
0.409514099
0.7325


hCV1376342
rs1654416
hCV8717761
rs1654439
0.51
0.409514099
0.5468


hCV1376342
rs1654416
hCV8717793
rs1654433
0.51
0.409514099
0.6123


hCV1376342
rs1654416
hCV8717794
rs1654432
0.51
0.409514099
0.6123


hCV1376342
rs1654416
hCV8717845
rs892090
0.51
0.409514099
0.7313


hCV1376342
rs1654416
hCV8717846
rs892089
0.51
0.409514099
1


hCV1376342
rs1654416
hCV8717871
rs1654421
0.51
0.409514099
0.7784


hCV1376342
rs1654416
hCV8717873
rs1613662
0.51
0.409514099
0.7313


hCV1376342
rs1654416
hCV8717881
rs1654420
0.51
0.409514099
0.9205


hCV1376342
rs1654416
hCV8717893
rs1671192
0.51
0.409514099
1


hCV1376342
rs1654416
hCV8718961
rs1654451
0.51
0.409514099
0.5824


hCV1376342
rs1654416
hCV8718972
rs1654447
0.51
0.409514099
0.6338


hCV1376342
rs1654416
hCV9490926
rs1654419
0.51
0.409514099
0.9205


hCV15793897
rs3087505
hCV11786203
rs4253251
0.51
0.201010916
0.4643


hCV15793897
rs3087505
hCV11786295
rs4253421
0.51
0.201010916
0.6968


hCV15793897
rs3087505
hCV12066116
rs1877320
0.51
0.201010916
0.8216


hCV15793897
rs3087505
hCV12066129
rs1593
0.51
0.201010916
0.7273


hCV15793897
rs3087505
hCV15811716
rs2102575
0.51
0.201010916
0.9425


hCV15793897
rs3087505
hCV15968026
rs2292426
0.51
0.201010916
0.2078


hCV15793897
rs3087505
hCV2103388
rs4613610
0.51
0.201010916
0.4687


hCV15793897
rs3087505
hCV22271609
rs4253326
0.51
0.201010916
0.4122


hCV15793897
rs3087505
hCV25634781
rs4253299
0.51
0.201010916
0.4656


hCV15793897
rs3087505
hCV25988221
rs9995366
0.51
0.201010916
0.838


hCV15793897
rs3087505
hCV26265197
rs10014399
0.51
0.201010916
0.4643


hCV15793897
rs3087505
hCV26265199
rs2221843
0.51
0.201010916
0.4656


hCV15793897
rs3087505
hCV27309991
rs4572916
0.51
0.201010916
0.4643


hCV15793897
rs3087505
hCV27506149
rs3822055
0.51
0.201010916
0.4656


hCV15793897
rs3087505
hCV27902803
rs4862665
0.51
0.201010916
0.838


hCV15793897
rs3087505
hCV29053261
rs6842047
0.51
0.201010916
0.8875


hCV15793897
rs3087505
hCV29053266
rs7687961
0.51
0.201010916
0.4508


hCV15793897
rs3087505
hCV29640635
rs10029715
0.51
0.201010916
0.362


hCV15793897
rs3087505
hCV29826351
rs10025990
0.51
0.201010916
0.9133


hCV15793897
rs3087505
hCV30307525
rs10025152
0.51
0.201010916
0.362


hCV15793897
rs3087505
hCV30492573
rs10471184
0.51
0.201010916
0.8875


hCV15793897
rs3087505
hCV30562347
rs4253418
0.51
0.201010916
0.2672


hCV15793897
rs3087505
hCV30983902
rs4862668
0.51
0.201010916
0.8216


hCV15793897
rs3087505
hCV30983927
rs6552962
0.51
0.201010916
0.4909


hCV15793897
rs3087505
hCV32209629
rs12715865
0.51
0.201010916
0.4136


hCV15793897
rs3087505
hCV32209635
rs6848311
0.51
0.201010916
0.2855


hCV15793897
rs3087505
hCV32291246
rs4253403
0.51
0.201010916
0.2073


hCV15793897
rs3087505
hCV3230000
rs4253294
0.51
0.201010916
0.2753


hCV15793897
rs3087505
hCV3230012
rs4241821
0.51
0.201010916
0.4656


hCV15793897
rs3087505
hCV3230014
rs4861709
0.51
0.201010916
0.2753


hCV15793897
rs3087505
hCV3230017
rs4253327
0.51
0.201010916
0.2509


hCV15793897
rs3087505
hCV3230018
rs925453
0.51
0.201010916
0.2553


hCV15793897
rs3087505
hCV3230019
rs4253332
0.51
0.201010916
0.2614


hCV15793897
rs3087505
hCV32313007
rs4862666
0.51
0.201010916
0.838


hCV15793897
rs3087505
hCV8241628
rs907439
0.51
0.201010916
0.4643


hCV15793897
rs3087505
hCV8241633
rs1511800
0.51
0.201010916
0.838


hCV15860433
rs2070006
hCV11503382
rs1873369
0.51
0.09197249
0.2934


hCV15860433
rs2070006
hCV11503414
rs2066865
0.51
0.09197249
0.4534


hCV15860433
rs2070006
hCV11503416
rs2066864
0.51
0.09197249
0.506


hCV15860433
rs2070006
hCV11503431
rs2066861
0.51
0.09197249
0.446


hCV15860433
rs2070006
hCV11503469
rs2066854
0.51
0.09197249
0.5293


hCV15860433
rs2070006
hCV11503470
rs1800788
0.51
0.09197249
0.2862


hCV15860433
rs2070006
hCV11852898
rs6819508
0.51
0.09197249
0.1131


hCV15860433
rs2070006
hCV11853387
rs1490683
0.51
0.09197249
0.0995


hCV15860433
rs2070006
hCV11853483
rs12644950
0.51
0.09197249
0.4932


hCV15860433
rs2070006
hCV11853489
rs7681423
0.51
0.09197249
0.506


hCV15860433
rs2070006
hCV11853496
rs7654093
0.51
0.09197249
0.446


hCV15860433
rs2070006
hCV21680
rs7666020
0.51
0.09197249
0.1304


hCV15860433
rs2070006
hCV21681
rs6536018
0.51
0.09197249
0.1435


hCV15860433
rs2070006
hCV22273499
rs7668014
0.51
0.09197249
0.2505


hCV15860433
rs2070006
hCV22274180
rs11935584
0.51
0.09197249
0.2386


hCV15860433
rs2070006
hCV2407354
rs276166
0.51
0.09197249
0.1025


hCV15860433
rs2070006
hCV24834
rs4235247
0.51
0.09197249
0.2186


hCV15860433
rs2070006
hCV25610762
rs7668818
0.51
0.09197249
0.1508


hCV15860433
rs2070006
hCV26019871
rs4547780
0.51
0.09197249
0.174


hCV15860433
rs2070006
hCV26024202
rs11731813
0.51
0.09197249
0.2684


hCV15860433
rs2070006
hCV27020269
rs7659613
0.51
0.09197249
0.9639


hCV15860433
rs2070006
hCV27020277
rs6825454
0.51
0.09197249
0.4782


hCV15860433
rs2070006
hCV27020280
rs4463047
0.51
0.09197249
0.1824


hCV15860433
rs2070006
hCV27313130
rs4634202
0.51
0.09197249
0.443


hCV15860433
rs2070006
hCV27313137
rs12645631
0.51
0.09197249
0.1049


hCV15860433
rs2070006
hCV27905214
rs4323084
0.51
0.09197249
0.3386


hCV15860433
rs2070006
hCV27907560
rs4696576
0.51
0.09197249
0.1561


hCV15860433
rs2070006
hCV27937396
rs4634201
0.51
0.09197249
0.239


hCV15860433
rs2070006
hCV2892859
rs13130318
0.51
0.09197249
0.4434


hCV15860433
rs2070006
hCV2892869
rs13109457
0.51
0.09197249
0.5189


hCV15860433
rs2070006
hCV2892870
rs2070011
0.51
0.09197249
0.9612


hCV15860433
rs2070006
hCV2892876
rs2070018
0.51
0.09197249
0.2139


hCV15860433
rs2070006
hCV2892877
rs6050
0.51
0.09197249
0.4576


hCV15860433
rs2070006
hCV2892878
rs2070022
0.51
0.09197249
0.104


hCV15860433
rs2070006
hCV2892893
rs12648258
0.51
0.09197249
0.2624


hCV15860433
rs2070006
hCV2892895
rs12641958
0.51
0.09197249
0.2505


hCV15860433
rs2070006
hCV2892896
rs11940724
0.51
0.09197249
0.2505


hCV15860433
rs2070006
hCV2892899
rs7680155
0.51
0.09197249
0.2386


hCV15860433
rs2070006
hCV2892905
rs12642770
0.51
0.09197249
0.3701


hCV15860433
rs2070006
hCV2892918
rs12511469
0.51
0.09197249
0.2997


hCV15860433
rs2070006
hCV2892926
rs7662567
0.51
0.09197249
0.2596


hCV15860433
rs2070006
hCV2892928
rs13147579
0.51
0.09197249
0.2712


hCV15860433
rs2070006
hCV28953838
rs7690851
0.51
0.09197249
0.1824


hCV15860433
rs2070006
hCV28953840
rs6536017
0.51
0.09197249
0.1839


hCV15860433
rs2070006
hCV28966638
rs7676857
0.51
0.09197249
0.1018


hCV15860433
rs2070006
hCV29420822
rs4642230
0.51
0.09197249
0.2828


hCV15860433
rs2070006
hCV29420827
rs7654425
0.51
0.09197249
0.2505


hCV15860433
rs2070006
hCV29420828
rs7660120
0.51
0.09197249
0.2053


hCV15860433
rs2070006
hCV29570696
rs9997519
0.51
0.09197249
0.1033


hCV15860433
rs2070006
hCV29582612
rs4550901
0.51
0.09197249
0.2139


hCV15860433
rs2070006
hCV29983641
rs10008078
0.51
0.09197249
0.2893


hCV15860433
rs2070006
hCV30285831
rs10013914
0.51
0.09197249
0.1353


hCV15860433
rs2070006
hCV30679170
rs13148992
0.51
0.09197249
0.2746


hCV15860433
rs2070006
hCV30711231
rs12642469
0.51
0.09197249
0.2893


hCV15860433
rs2070006
hCV31863979
rs12186294
0.51
0.09197249
0.5331


hCV15860433
rs2070006
hCV31863982
rs7659024
0.51
0.09197249
0.446


hCV15860433
rs2070006
hCV31863989
rs4308349
0.51
0.09197249
0.2709


hCV15860433
rs2070006
hCV31863993
rs7673587
0.51
0.09197249
0.2386


hCV15860433
rs2070006
hCV32212659
rs4622984
0.51
0.09197249
0.385


hCV15860433
rs2070006
hCV32212662
rs11099958
0.51
0.09197249
0.1092


hCV15860433
rs2070006
hCV32212663
rs7670827
0.51
0.09197249
0.1457


hCV15860433
rs2070006
hCV32212669
rs12649647
0.51
0.09197249
0.1198


hCV15860433
rs2070006
hCV354895
rs11737226
0.51
0.09197249
0.2725


hCV15860433
rs2070006
hCV354896
rs7690972
0.51
0.09197249
0.2725


hCV15860433
rs2070006
hCV36809
rs10517590
0.51
0.09197249
0.1026


hCV15860433
rs2070006
hCV426173
rs12504201
0.51
0.09197249
0.1421


hCV15860433
rs2070006
hCV470979
rs1490672
0.51
0.09197249
0.2591


hCV15860433
rs2070006
hCV7428370
rs1456450
0.51
0.09197249
0.1012


hCV15860433
rs2070006
hCV7429780
rs1800792
0.51
0.09197249
0.5074


hCV15860433
rs2070006
hCV7429783
rs1044291
0.51
0.09197249
0.2505


hCV15860433
rs2070006
hCV7429793
rs1025154
0.51
0.09197249
0.2893


hCV15860433
rs2070006
hCV9317206
rs2070008
0.51
0.09197249
0.252


hCV15860433
rs2070006
hDV70945235
rs17373860
0.51
0.09197249
0.1588


hCV15860433
rs2070006
hDV72277158
rs28673871
0.51
0.09197249
0.1082


hCV15860433
rs2070006
hDV77232287
rs7666918
0.51
0.09197249
0.2505


hCV15949414
rs2234628
hCV11327199
rs12637760
0.51
0.263389785
1


hCV15949414
rs2234628
hCV15961938
rs2284816
0.51
0.263389785
1


hCV15949414
rs2234628
hCV16189344
rs2298422
0.51
0.263389785
0.8478


hCV15949414
rs2234628
hCV1845321
rs12636358
0.51
0.263389785
1


hCV15949414
rs2234628
hCV27512998
rs3762790
0.51
0.263389785
1


hCV15949414
rs2234628
hCV30700451
rs12631864
0.51
0.263389785
1


hCV15949414
rs2234628
hCV30700457
rs12635900
0.51
0.263389785
0.9045


hCV15949414
rs2234628
hCV3083980
rs12637034
0.51
0.263389785
1


hCV15949414
rs2234628
hCV32001449
rs12636077
0.51
0.263389785
1


hCV15949414
rs2234628
hDV70822211
rs17037809
0.51
0.263389785
1


hCV15949414
rs2234628
hDV70822215
rs17037814
0.51
0.263389785
1


hCV15949414
rs2234628
hDV70822219
rs17037819
0.51
0.263389785
1


hCV15949414
rs2234628
hDV71601922
rs17037775
0.51
0.263389785
1


hCV15949414
rs2234628
hDV76880100
rs3749388
0.51
0.263389785
1


hCV15968043
rs2292423
hCV11786147
rs4862662
0.51
0.095896459
0.6131


hCV15968043
rs2292423
hCV11786203
rs4253251
0.51
0.095896459
0.1841


hCV15968043
rs2292423
hCV11786235
rs4253287
0.51
0.095896459
0.1251


hCV15968043
rs2292423
hCV11786258
rs4253303
0.51
0.095896459
0.8913


hCV15968043
rs2292423
hCV11786259
rs4253304
0.51
0.095896459
1


hCV15968043
rs2292423
hCV11786327
rs13133050
0.51
0.095896459
0.1279


hCV15968043
rs2292423
hCV12066118
rs2048
0.51
0.095896459
0.6531


hCV15968043
rs2292423
hCV12066119
rs1912826
0.51
0.095896459
0.594


hCV15968043
rs2292423
hCV12066124
rs2036914
0.51
0.095896459
0.3742


hCV15968043
rs2292423
hCV1474481
rs7693361
0.51
0.095896459
0.1013


hCV15968043
rs2292423
hCV15968025
rs2292425
0.51
0.095896459
0.2221


hCV15968043
rs2292423
hCV15968026
rs2292426
0.51
0.095896459
0.3124


hCV15968043
rs2292423
hCV15968034
rs2292428
0.51
0.095896459
0.3976


hCV15968043
rs2292423
hCV15975109
rs2304596
0.51
0.095896459
0.1471


hCV15968043
rs2292423
hCV2103343
rs4241824
0.51
0.095896459
0.3048


hCV15968043
rs2292423
hCV2103391
rs1008728
0.51
0.095896459
0.2022


hCV15968043
rs2292423
hCV2103392
rs12500826
0.51
0.095896459
0.179


hCV15968043
rs2292423
hCV2103401
rs7687352
0.51
0.095896459
0.1006


hCV15968043
rs2292423
hCV2103402
rs9993749
0.51
0.095896459
0.1071


hCV15968043
rs2292423
hCV22271609
rs4253326
0.51
0.095896459
0.1576


hCV15968043
rs2292423
hCV22272267
rs3733402
0.51
0.095896459
0.6588


hCV15968043
rs2292423
hCV25474413
rs3822057
0.51
0.095896459
0.313


hCV15968043
rs2292423
hCV25474414
rs4253399
0.51
0.095896459
0.338


hCV15968043
rs2292423
hCV25634781
rs4253299
0.51
0.095896459
0.179


hCV15968043
rs2292423
hCV25989001
hCV25989001
0.51
0.095896459
0.156


hCV15968043
rs2292423
hCV25990131
rs13146272
0.51
0.095896459
0.2261


hCV15968043
rs2292423
hCV26038139
rs4253405
0.51
0.095896459
0.1127


hCV15968043
rs2292423
hCV26265197
rs10014399
0.51
0.095896459
0.1871


hCV15968043
rs2292423
hCV26265199
rs2221843
0.51
0.095896459
0.179


hCV15968043
rs2292423
hCV26265231
rs7684025
0.51
0.095896459
0.6916


hCV15968043
rs2292423
hCV27309991
rs4572916
0.51
0.095896459
0.1062


hCV15968043
rs2292423
hCV27474895
rs3756011
0.51
0.095896459
0.1967


hCV15968043
rs2292423
hCV27477533
rs3756008
0.51
0.095896459
0.3624


hCV15968043
rs2292423
hCV27482765
rs3775301
0.51
0.095896459
0.1471


hCV15968043
rs2292423
hCV27506149
rs3822055
0.51
0.095896459
0.179


hCV15968043
rs2292423
hCV27902808
rs4253236
0.51
0.095896459
0.4376


hCV15968043
rs2292423
hCV28960679
rs6844764
0.51
0.095896459
0.2857


hCV15968043
rs2292423
hCV29053260
rs4861707
0.51
0.095896459
0.1391


hCV15968043
rs2292423
hCV29053264
rs7667777
0.51
0.095896459
0.6735


hCV15968043
rs2292423
hCV29053265
rs4253244
0.51
0.095896459
0.4158


hCV15968043
rs2292423
hCV29640635
rs10029715
0.51
0.095896459
0.1031


hCV15968043
rs2292423
hCV29718000
rs4253238
0.51
0.095896459
0.6615


hCV15968043
rs2292423
hCV29826351
rs10025990
0.51
0.095896459
0.0963


hCV15968043
rs2292423
hCV29877725
rs4253295
0.51
0.095896459
0.8892


hCV15968043
rs2292423
hCV30307525
rs10025152
0.51
0.095896459
0.1031


hCV15968043
rs2292423
hCV32209636
rs11132387
0.51
0.095896459
0.2244


hCV15968043
rs2292423
hCV32209638
rs12507040
0.51
0.095896459
0.108


hCV15968043
rs2292423
hCV32291217
rs4253323
0.51
0.095896459
0.1471


hCV15968043
rs2292423
hCV32291269
rs4253417
0.51
0.095896459
0.2504


hCV15968043
rs2292423
hCV32291286
rs4253422
0.51
0.095896459
0.0995


hCV15968043
rs2292423
hCV32291287
rs4253423
0.51
0.095896459
0.0995


hCV15968043
rs2292423
hCV32291295
rs4253292
0.51
0.095896459
0.1503


hCV15968043
rs2292423
hCV32291301
rs4253302
0.51
0.095896459
0.1455


hCV15968043
rs2292423
hCV32295028
rs4253260
0.51
0.095896459
0.1471


hCV15968043
rs2292423
hCV3229991
rs4241815
0.51
0.095896459
0.6588


hCV15968043
rs2292423
hCV3229992
rs3775298
0.51
0.095896459
0.6588


hCV15968043
rs2292423
hCV3229995
rs11132382
0.51
0.095896459
0.6615


hCV15968043
rs2292423
hCV3230000
rs4253294
0.51
0.095896459
0.3176


hCV15968043
rs2292423
hCV3230002
rs4253297
0.51
0.095896459
0.8979


hCV15968043
rs2292423
hCV3230003
rs2304595
0.51
0.095896459
1


hCV15968043
rs2292423
hCV3230006
rs4253308
0.51
0.095896459
0.8892


hCV15968043
rs2292423
hCV3230007
rs4253311
0.51
0.095896459
0.6588


hCV15968043
rs2292423
hCV3230011
rs4253320
0.51
0.095896459
0.8979


hCV15968043
rs2292423
hCV3230012
rs4241821
0.51
0.095896459
0.179


hCV15968043
rs2292423
hCV3230013
rs3775303
0.51
0.095896459
1


hCV15968043
rs2292423
hCV3230014
rs4861709
0.51
0.095896459
0.3176


hCV15968043
rs2292423
hCV3230017
rs4253327
0.51
0.095896459
0.3086


hCV15968043
rs2292423
hCV3230018
rs925453
0.51
0.095896459
0.304


hCV15968043
rs2292423
hCV3230019
rs4253332
0.51
0.095896459
0.304


hCV15968043
rs2292423
hCV3230021
rs13135645
0.51
0.095896459
0.1067


hCV15968043
rs2292423
hCV3230022
rs11132383
0.51
0.095896459
0.2177


hCV15968043
rs2292423
hCV3230025
rs3756009
0.51
0.095896459
0.3012


hCV15968043
rs2292423
hCV3230031
rs4253419
0.51
0.095896459
0.0995


hCV15968043
rs2292423
hCV3230038
rs2289252
0.51
0.095896459
0.2462


hCV15968043
rs2292423
hCV3230083
rs10013653
0.51
0.095896459
0.5543


hCV15968043
rs2292423
hCV3230084
rs7682918
0.51
0.095896459
0.5227


hCV15968043
rs2292423
hCV3230094
rs7687818
0.51
0.095896459
0.7508


hCV15968043
rs2292423
hCV3230096
rs3817184
0.51
0.095896459
0.6453


hCV15968043
rs2292423
hCV3230097
rs3736455
0.51
0.095896459
0.3107


hCV15968043
rs2292423
hCV3230101
rs6835839
0.51
0.095896459
0.4126


hCV15968043
rs2292423
hCV3230106
rs1473597
0.51
0.095896459
0.4173


hCV15968043
rs2292423
hCV3230110
rs2276917
0.51
0.095896459
0.3976


hCV15968043
rs2292423
hCV3230113
rs1053094
0.51
0.095896459
0.59


hCV15968043
rs2292423
hCV3230118
rs4253429
0.51
0.095896459
0.0995


hCV15968043
rs2292423
hCV3230125
rs11938564
0.51
0.095896459
0.163


hCV15968043
rs2292423
hCV3230131
rs13136269
0.51
0.095896459
0.108


hCV15968043
rs2292423
hCV3230133
rs12511874
0.51
0.095896459
0.108


hCV15968043
rs2292423
hCV3230134
rs12500151
0.51
0.095896459
0.108


hCV15968043
rs2292423
hCV3230136
rs13116273
0.51
0.095896459
0.129


hCV15968043
rs2292423
hCV32313006
rs4253248
0.51
0.095896459
0.6615


hCV15968043
rs2292423
hCV32313024
rs4253239
0.51
0.095896459
0.1503


hCV15968043
rs2292423
hCV32358975
rs4253255
0.51
0.095896459
0.6531


hCV15968043
rs2292423
hCV32358984
rs4253256
0.51
0.095896459
0.4314


hCV15968043
rs2292423
hCV8241628
rs907439
0.51
0.095896459
0.1062


hCV15968043
rs2292423
hCV8241630
rs925451
0.51
0.095896459
0.338


hCV15968043
rs2292423
hCV8241631
rs1511802
0.51
0.095896459
0.8892


hCV15968043
rs2292423
hCV8241632
rs1511801
0.51
0.095896459
0.6519


hCV15968043
rs2292423
hDV71222711
rs4253252
0.51
0.095896459
0.6615


hCV15968043
rs2292423
hDV76175111
rs35079309
0.51
0.095896459
0.1621


hCV15990789
rs2355466
hCV25743768
rs4757548
0.51
0.951959625
0.9603


hCV16177220
rs2266911
hCV2451164
rs2357252
0.51
0.395362464
0.7006


hCV16177220
rs2266911
hCV2451180
rs2072886
0.51
0.395362464
0.4412


hCV16177220
rs2266911
hCV29241293
rs7061257
0.51
0.395362464
0.7143


hCV16177220
rs2266911
hCV32361087
rs4825898
0.51
0.395362464
0.893


hCV16180170
rs2227589
hCV11342529
rs1951627
0.51
0.229511448
0.3108


hCV16180170
rs2227589
hCV11975630
rs2065170
0.51
0.229511448
1


hCV16180170
rs2227589
hCV15864094
rs2068871
0.51
0.229511448
0.9425


hCV16180170
rs2227589
hCV15956059
rs2227592
0.51
0.229511448
1


hCV16180170
rs2227589
hCV16135173
rs2146372
0.51
0.229511448
1


hCV16180170
rs2227589
hCV16290208
rs2759328
0.51
0.229511448
1


hCV16180170
rs2227589
hCV1681325
rs898657
0.51
0.229511448
0.288


hCV16180170
rs2227589
hCV1681328
rs10912647
0.51
0.229511448
0.2457


hCV16180170
rs2227589
hCV25600635
rs7539322
0.51
0.229511448
0.8856


hCV16180170
rs2227589
hCV25932979
rs16846809
0.51
0.229511448
0.5549


hCV16180170
rs2227589
hCV27483572
rs3791022
0.51
0.229511448
1


hCV16180170
rs2227589
hCV28998001
rs6425251
0.51
0.229511448
0.2457


hCV16180170
rs2227589
hCV29517287
rs2901747
0.51
0.229511448
0.2436


hCV16180170
rs2227589
hCV29989899
rs6685043
0.51
0.229511448
0.6095


hCV16180170
rs2227589
hCV30205817
rs10489254
0.51
0.229511448
0.5549


hCV16180170
rs2227589
hCV30404194
rs6691053
0.51
0.229511448
0.3572


hCV16180170
rs2227589
hCV30472885
rs7520441
0.51
0.229511448
0.315


hCV16180170
rs2227589
hCV30804119
rs10912651
0.51
0.229511448
0.2376


hCV16180170
rs2227589
hCV30804135
rs12078293
0.51
0.229511448
0.2457


hCV16180170
rs2227589
hCV30804139
rs12089930
0.51
0.229511448
0.245


hCV16180170
rs2227589
hCV8911729
rs941987
0.51
0.229511448
0.8292


hCV16180170
rs2227589
hCV8911768
rs941988
0.51
0.229511448
1


hCV16180170
rs2227589
hCV9575253
rs1031751
0.51
0.229511448
0.3146


hCV16180170
rs2227589
hCV9575263
rs898658
0.51
0.229511448
0.2457


hCV16180170
rs2227589
hDV70683090
rs16846433
0.51
0.229511448
0.9425


hCV16180170
rs2227589
hDV70683162
rs16846526
0.51
0.229511448
1


hCV16180170
rs2227589
hDV70683177
rs16846546
0.51
0.229511448
1


hCV16180170
rs2227589
hDV70683187
rs16846561
0.51
0.229511448
1


hCV16180170
rs2227589
hDV70683212
rs16846593
0.51
0.229511448
0.5549


hCV16180170
rs2227589
hDV70683382
rs16846815
0.51
0.229511448
0.5078


hCV16180170
rs2227589
hDV70934851
rs17301125
0.51
0.229511448
0.2534


hCV16182835
rs2274736
hCV11295871
rs17203789
0.51
0.445188644
0.6809


hCV16182835
rs2274736
hCV11295918
rs12586348
0.51
0.445188644
0.6574


hCV16182835
rs2274736
hCV11454301
rs11159868
0.51
0.445188644
0.6481


hCV16182835
rs2274736
hCV11454302
rs7157149
0.51
0.445188644
0.6481


hCV16182835
rs2274736
hCV11474667
rs10150311
0.51
0.445188644
0.9163


hCV16182835
rs2274736
hCV11474668
rs10138002
0.51
0.445188644
0.9163


hCV16182835
rs2274736
hCV11474679
rs2778936
0.51
0.445188644
0.9591


hCV16182835
rs2274736
hCV11657898
rs1956406
0.51
0.445188644
0.5421


hCV16182835
rs2274736
hCV11657912
rs1950806
0.51
0.445188644
0.6481


hCV16182835
rs2274736
hCV11666712
rs1864747
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV11666713
rs1864746
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV11666722
rs1864748
0.51
0.445188644
0.6812


hCV16182835
rs2274736
hCV11666724
rs1864744
0.51
0.445188644
1


hCV16182835
rs2274736
hCV11666737
rs1955600
0.51
0.445188644
0.6562


hCV16182835
rs2274736
hCV1262727
rs12587200
0.51
0.445188644
0.6574


hCV16182835
rs2274736
hCV1262753
rs12436982
0.51
0.445188644
0.6322


hCV16182835
rs2274736
hCV15870067
rs2224333
0.51
0.445188644
0.6651


hCV16182835
rs2274736
hCV16185886
rs2297129
0.51
0.445188644
1


hCV16182835
rs2274736
hCV16189259
rs2295135
0.51
0.445188644
0.6601


hCV16182835
rs2274736
hCV211940
rs12587386
0.51
0.445188644
0.6583


hCV16182835
rs2274736
hCV2231821
rs453112
0.51
0.445188644
0.9596


hCV16182835
rs2274736
hCV2485030
rs12589467
0.51
0.445188644
0.6583


hCV16182835
rs2274736
hCV2485038
rs865285
0.51
0.445188644
0.8835


hCV16182835
rs2274736
hCV2485039
rs3179969
0.51
0.445188644
0.9793


hCV16182835
rs2274736
hCV25933483
rs10143744
0.51
0.445188644
0.879


hCV16182835
rs2274736
hCV25935678
rs4904452
0.51
0.445188644
0.9573


hCV16182835
rs2274736
hCV25942539
rs2401751
0.51
0.445188644
1


hCV16182835
rs2274736
hCV27202496
rs1099698
0.51
0.445188644
0.9558


hCV16182835
rs2274736
hCV27202497
rs12589480
0.51
0.445188644
0.6692


hCV16182835
rs2274736
hCV27202543
rs7146241
0.51
0.445188644
0.9591


hCV16182835
rs2274736
hCV27202682
rs10142228
0.51
0.445188644
0.4551


hCV16182835
rs2274736
hCV27520559
rs3814855
0.51
0.445188644
0.6697


hCV16182835
rs2274736
hCV2796701
rs9323834
0.51
0.445188644
0.4697


hCV16182835
rs2274736
hCV2796704
rs10134036
0.51
0.445188644
0.4645


hCV16182835
rs2274736
hCV2796706
rs9671813
0.51
0.445188644
0.4777


hCV16182835
rs2274736
hCV29385782
rs7141608
0.51
0.445188644
0.9591


hCV16182835
rs2274736
hCV29385806
rs8020072
0.51
0.445188644
0.6704


hCV16182835
rs2274736
hCV29549024
rs10137225
0.51
0.445188644
0.4489


hCV16182835
rs2274736
hCV29567112
rs10484010
0.51
0.445188644
0.4622


hCV16182835
rs2274736
hCV29729918
rs10143767
0.51
0.445188644
0.6878


hCV16182835
rs2274736
hCV29910416
rs10139817
0.51
0.445188644
0.4677


hCV16182835
rs2274736
hCV30414828
rs7144432
0.51
0.445188644
0.9596


hCV16182835
rs2274736
hCV30414829
rs10134008
0.51
0.445188644
0.6988


hCV16182835
rs2274736
hCV30468559
rs10132509
0.51
0.445188644
0.496


hCV16182835
rs2274736
hCV32095372
rs12586714
0.51
0.445188644
0.881


hCV16182835
rs2274736
hCV32095396
rs11845147
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV32095401
rs11847417
0.51
0.445188644
0.9163


hCV16182835
rs2274736
hCV32095402
rs11159857
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV32095403
rs4390529
0.51
0.445188644
0.917


hCV16182835
rs2274736
hCV32095404
rs4301952
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV32095415
rs12050316
0.51
0.445188644
0.8616


hCV16182835
rs2274736
hCV32095422
rs2033418
0.51
0.445188644
0.9135


hCV16182835
rs2274736
hCV32095429
rs12436642
0.51
0.445188644
0.9381


hCV16182835
rs2274736
hCV32095430
rs11159859
0.51
0.445188644
0.8539


hCV16182835
rs2274736
hCV32095431
rs11629164
0.51
0.445188644
0.8395


hCV16182835
rs2274736
hCV32095460
rs12434935
0.51
0.445188644
0.6651


hCV16182835
rs2274736
hCV32095525
rs12590826
0.51
0.445188644
0.6121


hCV16182835
rs2274736
hCV32095533
rs12588535
0.51
0.445188644
0.6651


hCV16182835
rs2274736
hCV3211521
rs12431548
0.51
0.445188644
0.6512


hCV16182835
rs2274736
hCV3211539
rs1998670
0.51
0.445188644
0.6891


hCV16182835
rs2274736
hCV3211540
rs2274735
0.51
0.445188644
0.9793


hCV16182835
rs2274736
hCV3211544
rs9323830
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV3211545
rs7160647
0.51
0.445188644
0.9163


hCV16182835
rs2274736
hCV3211546
rs7143642
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV3211548
rs7151164
0.51
0.445188644
0.919


hCV16182835
rs2274736
hCV3211549
rs12433026
0.51
0.445188644
0.8973


hCV16182835
rs2274736
hCV3211559
rs2004329
0.51
0.445188644
0.6919


hCV16182835
rs2274736
hCV3211560
rs12436326
0.51
0.445188644
0.6988


hCV16182835
rs2274736
hCV3211561
rs8017811
0.51
0.445188644
0.9581


hCV16182835
rs2274736
hCV3211562
rs4904454
0.51
0.445188644
0.9596


hCV16182835
rs2274736
hCV3211566
rs930181
0.51
0.445188644
0.9591


hCV16182835
rs2274736
hCV3211568
rs816075
0.51
0.445188644
1


hCV16182835
rs2274736
hCV342703
rs12433464
0.51
0.445188644
0.6601


hCV16182835
rs2274736
hCV342704
rs1955598
0.51
0.445188644
0.7953


hCV16182835
rs2274736
hCV7583060
rs1028455
0.51
0.445188644
0.8774


hCV16182835
rs2274736
hCV7583094
rs1048190
0.51
0.445188644
0.6083


hCV16182835
rs2274736
hCV9595812
rs845758
0.51
0.445188644
0.822


hCV16182835
rs2274736
hCV9595827
rs845757
0.51
0.445188644
0.9591


hCV16182835
rs2274736
hCV9595840
rs816072
0.51
0.445188644
1


hCV16182835
rs2274736
hCV9595849
rs1152376
0.51
0.445188644
0.9793


hCV16182835
rs2274736
hCV9595856
rs816069
0.51
0.445188644
0.9586


hCV16182835
rs2274736
hCV9595863
rs1344747
0.51
0.445188644
0.9596


hCV16182835
rs2274736
hCV9595868
rs891750
0.51
0.445188644
0.6812


hCV16182835
rs2274736
hCV9595869
rs891749
0.51
0.445188644
0.6812


hCV16182835
rs2274736
hCV9595897
rs1287825
0.51
0.445188644
0.4565


hCV16182835
rs2274736
hDV70886228
rs17124652
0.51
0.445188644
0.6583


hCV16182835
rs2274736
hDV70886264
rs17124700
0.51
0.445188644
0.6583


hCV16182835
rs2274736
hDV70918505
rs17188228
0.51
0.445188644
0.6141


hCV16182835
rs2274736
hDV70929207
rs17260380
0.51
0.445188644
0.6481


hCV16182835
rs2274736
hDV70929214
rs17260415
0.51
0.445188644
0.6571


hCV16182835
rs2274736
hDV70991668
rs17698817
0.51
0.445188644
0.6223


hCV16182835
rs2274736
hDV70991980
rs17700521
0.51
0.445188644
0.5853


hCV16182835
rs2274736
hDV71004484
rs17772064
0.51
0.445188644
0.6697


hCV16182835
rs2274736
hDV71004511
rs17772222
0.51
0.445188644
0.6697


hCV16182835
rs2274736
hDV71004521
rs17772288
0.51
0.445188644
0.65


hCV16182835
rs2274736
hDV71008979
rs17798341
0.51
0.445188644
0.6988


hCV16182835
rs2274736
hDV71605687
rs17188046
0.51
0.445188644
0.6571


hCV16182835
rs2274736
hDV77012938
rs4514599
0.51
0.445188644
0.8712


hCV16182835
rs2274736
hDV77027209
rs4635267
0.51
0.445188644
0.6646


hCV16182835
rs2274736
hDV77248933
rs8021690
0.51
0.445188644
0.6481


hCV1825046
rs2069952
hCV1064756
rs734111
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV11189130
rs2065979
0.51
0.131481735
1


hCV1825046
rs2069952
hCV11189159
rs6060270
0.51
0.131481735
0.2033


hCV1825046
rs2069952
hCV11189164
rs3746427
0.51
0.131481735
1


hCV1825046
rs2069952
hCV11189240
rs2038504
0.51
0.131481735
0.7662


hCV1825046
rs2069952
hCV11189318
rs7263251
0.51
0.131481735
0.1718


hCV1825046
rs2069952
hCV11189331
rs6087649
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV11189332
rs2273683
0.51
0.131481735
0.4987


hCV1825046
rs2069952
hCV11189369
rs6119535
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV11189450
rs6060048
0.51
0.131481735
0.3343


hCV1825046
rs2069952
hCV11656916
rs7004
0.51
0.131481735
0.1338


hCV1825046
rs2069952
hCV11656971
rs2050652
0.51
0.131481735
0.3132


hCV1825046
rs2069952
hCV11656979
rs2065108
0.51
0.131481735
0.4684


hCV1825046
rs2069952
hCV11656982
rs1885115
0.51
0.131481735
0.3304


hCV1825046
rs2069952
hCV11656983
rs1998233
0.51
0.131481735
0.2712


hCV1825046
rs2069952
hCV11656986
rs1885119
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV1207858
rs6141514
0.51
0.131481735
0.2888


hCV1825046
rs2069952
hCV1207862
rs6119524
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV1207879
rs2295354
0.51
0.131481735
0.2537


hCV1825046
rs2069952
hCV1207880
rs2295353
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV1207887
rs959829
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV1207889
rs1998028
0.51
0.131481735
0.3128


hCV1825046
rs2069952
hCV1207890
rs6087625
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV1207891
rs2378259
0.51
0.131481735
0.3343


hCV1825046
rs2069952
hCV1207893
rs6087624
0.51
0.131481735
0.3703


hCV1825046
rs2069952
hCV1207895
rs6120708
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV1207897
rs3787222
0.51
0.131481735
0.3012


hCV1825046
rs2069952
hCV1207898
rs1018503
0.51
0.131481735
0.3343


hCV1825046
rs2069952
hCV1207902
rs2295352
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV1207903
rs6087623
0.51
0.131481735
0.3128


hCV1825046
rs2069952
hCV1207909
rs6119512
0.51
0.131481735
0.3128


hCV1825046
rs2069952
hCV1207914
rs910870
0.51
0.131481735
0.3128


hCV1825046
rs2069952
hCV1207915
rs910869
0.51
0.131481735
0.2471


hCV1825046
rs2069952
hCV1265078
rs6088569
0.51
0.131481735
0.4047


hCV1825046
rs2069952
hCV1265079
rs6088570
0.51
0.131481735
0.4069


hCV1825046
rs2069952
hCV1265082
rs6088575
0.51
0.131481735
0.4069


hCV1825046
rs2069952
hCV1265086
rs2378251
0.51
0.131481735
0.4069


hCV1825046
rs2069952
hCV1265087
rs2889855
0.51
0.131481735
0.4069


hCV1825046
rs2069952
hCV1265092
rs6088578
0.51
0.131481735
0.4403


hCV1825046
rs2069952
hCV1265109
rs6058108
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV1271625
rs6060341
0.51
0.131481735
0.1454


hCV1825046
rs2069952
hCV1271649
rs6120880
0.51
0.131481735
0.3283


hCV1825046
rs2069952
hCV1271653
rs2425019
0.51
0.131481735
0.1786


hCV1825046
rs2069952
hCV1271661
rs6088765
0.51
0.131481735
0.2649


hCV1825046
rs2069952
hCV1271671
rs2093058
0.51
0.131481735
1


hCV1825046
rs2069952
hCV1271676
rs1577924
0.51
0.131481735
1


hCV1825046
rs2069952
hCV1271685
rs663550
0.51
0.131481735
0.9658


hCV1825046
rs2069952
hCV1271688
rs6058202
0.51
0.131481735
1


hCV1825046
rs2069952
hCV1347919
rs1058003
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV1347925
rs6120790
0.51
0.131481735
0.1339


hCV1825046
rs2069952
hCV1347930
rs3736802
0.51
0.131481735
0.4897


hCV1825046
rs2069952
hCV1347943
rs6060164
0.51
0.131481735
0.3948


hCV1825046
rs2069952
hCV1347944
rs6087660
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV1347963
rs13042358
0.51
0.131481735
0.7561


hCV1825046
rs2069952
hCV1348023
rs6087677
0.51
0.131481735
0.4741


hCV1825046
rs2069952
hCV1361222
rs3818273
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV1361223
rs3746450
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV15860322
rs2069948
0.51
0.131481735
1


hCV1825046
rs2069952
hCV15870054
rs2224320
0.51
0.131481735
0.429


hCV1825046
rs2069952
hCV15876219
rs2281626
0.51
0.131481735
0.2747


hCV1825046
rs2069952
hCV16003843
rs2378332
0.51
0.131481735
0.3948


hCV1825046
rs2069952
hCV16013546
rs2425012
0.51
0.131481735
0.7218


hCV1825046
rs2069952
hCV16013558
rs2425009
0.51
0.131481735
0.2569


hCV1825046
rs2069952
hCV16013570
rs2077574
0.51
0.131481735
0.2569


hCV1825046
rs2069952
hCV16013581
rs2253484
0.51
0.131481735
0.4987


hCV1825046
rs2069952
hCV16013593
rs2425001
0.51
0.131481735
0.3727


hCV1825046
rs2069952
hCV16013594
rs2424999
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV16013698
rs2425052
0.51
0.131481735
0.1551


hCV1825046
rs2069952
hCV16013724
rs2425044
0.51
0.131481735
0.158


hCV1825046
rs2069952
hCV16076405
rs2145557
0.51
0.131481735
0.4321


hCV1825046
rs2069952
hCV16179579
rs2273684
0.51
0.131481735
0.3893


hCV1825046
rs2069952
hCV16179908
rs2273805
0.51
0.131481735
0.4805


hCV1825046
rs2069952
hCV16190708
rs2295701
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV16191203
rs2295887
0.51
0.131481735
0.4684


hCV1825046
rs2069952
hCV16191204
rs2295886
0.51
0.131481735
0.3062


hCV1825046
rs2069952
hCV16191205
rs2295885
0.51
0.131481735
0.3062


hCV1825046
rs2069952
hCV1825004
rs1415771
0.51
0.131481735
0.7302


hCV1825046
rs2069952
hCV1825005
rs945959
0.51
0.131481735
0.7327


hCV1825046
rs2069952
hCV1825006
rs1124511
0.51
0.131481735
0.7327


hCV1825046
rs2069952
hCV1825018
rs11696967
0.51
0.131481735
0.2033


hCV1825046
rs2069952
hCV1825019
rs6088732
0.51
0.131481735
0.2033


hCV1825046
rs2069952
hCV1825021
rs6088733
0.51
0.131481735
0.2195


hCV1825046
rs2069952
hCV1825025
rs6088738
0.51
0.131481735
0.2033


hCV1825046
rs2069952
hCV1825040
rs6060278
0.51
0.131481735
0.2033


hCV1825046
rs2069952
hCV1825047
rs9574
0.51
0.131481735
1


hCV1825046
rs2069952
hCV1825056
rs6060285
0.51
0.131481735
0.9635


hCV1825046
rs2069952
hCV1825062
rs6087685
0.51
0.131481735
0.2311


hCV1825046
rs2069952
hCV2142560
rs4911449
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV2142561
rs4911450
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV2142562
rs4911451
0.51
0.131481735
0.5486


hCV1825046
rs2069952
hCV2142566
rs6088650
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV2142567
rs725521
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV2142575
rs2236270
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV2142576
rs2236271
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV2142578
rs6088655
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV2142584
rs3761144
0.51
0.131481735
0.6325


hCV1825046
rs2069952
hCV2142586
rs6060130
0.51
0.131481735
0.6325


hCV1825046
rs2069952
hCV2142587
rs6088664
0.51
0.131481735
0.6283


hCV1825046
rs2069952
hCV2142597
rs6120778
0.51
0.131481735
0.7561


hCV1825046
rs2069952
hCV2142599
rs6060140
0.51
0.131481735
0.7561


hCV1825046
rs2069952
hCV2142611
rs1885114
0.51
0.131481735
0.7561


hCV1825046
rs2069952
hCV2142616
rs3746438
0.51
0.131481735
0.6906


hCV1825046
rs2069952
hCV2521759
rs2076668
0.51
0.131481735
0.3128


hCV1825046
rs2069952
hCV2521760
rs6088624
0.51
0.131481735
0.3189


hCV1825046
rs2069952
hCV2521763
rs12625149
0.51
0.131481735
0.255


hCV1825046
rs2069952
hCV2521764
rs12626122
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV2521776
rs6087634
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV25619953
rs6060151
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV25619954
rs4911462
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV25619982
rs6120838
0.51
0.131481735
0.5278


hCV1825046
rs2069952
hCV25750225
rs4911163
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV27166951
rs6087663
0.51
0.131481735
0.2569


hCV1825046
rs2069952
hCV27166987
rs6119542
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV27166995
rs6088618
0.51
0.131481735
0.4255


hCV1825046
rs2069952
hCV27166997
rs6088615
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV27167007
rs2180276
0.51
0.131481735
0.3128


hCV1825046
rs2069952
hCV27167022
rs6060013
0.51
0.131481735
0.3242


hCV1825046
rs2069952
hCV27167045
rs2378252
0.51
0.131481735
0.2702


hCV1825046
rs2069952
hCV27167691
rs2378333
0.51
0.131481735
0.4684


hCV1825046
rs2069952
hCV27167696
rs6088716
0.51
0.131481735
0.4698


hCV1825046
rs2069952
hCV27472681
rs3746430
0.51
0.131481735
0.2569


hCV1825046
rs2069952
hCV27486123
rs3803937
0.51
0.131481735
0.4167


hCV1825046
rs2069952
hCV27503616
rs3803938
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV27833500
rs17092385
0.51
0.131481735
0.15


hCV1825046
rs2069952
hCV27893015
rs4911167
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV27893018
rs4911441
0.51
0.131481735
0.3592


hCV1825046
rs2069952
hCV27982387
rs4911460
0.51
0.131481735
0.3948


hCV1825046
rs2069952
hCV28004288
rs4911455
0.51
0.131481735
0.1718


hCV1825046
rs2069952
hCV29372788
rs6060163
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV29372800
rs6058149
0.51
0.131481735
0.1519


hCV1825046
rs2069952
hCV29372802
rs6579204
0.51
0.131481735
0.2141


hCV1825046
rs2069952
hCV29372803
rs6088659
0.51
0.131481735
0.1833


hCV1825046
rs2069952
hCV29372811
rs7266550
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV29372820
rs6120739
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV29372834
rs6060001
0.51
0.131481735
0.3893


hCV1825046
rs2069952
hCV29373050
rs6088722
0.51
0.131481735
0.3062


hCV1825046
rs2069952
hCV29373051
rs6142300
0.51
0.131481735
0.3062


hCV1825046
rs2069952
hCV29373055
rs6060196
0.51
0.131481735
0.2707


hCV1825046
rs2069952
hCV29530377
rs6088747
0.51
0.131481735
1


hCV1825046
rs2069952
hCV29530378
rs6058179
0.51
0.131481735
0.3062


hCV1825046
rs2069952
hCV29566578
rs6060172
0.51
0.131481735
0.3948


hCV1825046
rs2069952
hCV29584663
rs6060162
0.51
0.131481735
0.3948


hCV1825046
rs2069952
hCV29620866
rs6088724
0.51
0.131481735
0.4805


hCV1825046
rs2069952
hCV29638959
rs6060154
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV29674936
rs6087618
0.51
0.131481735
0.307


hCV1825046
rs2069952
hCV29674974
rs6058224
0.51
0.131481735
0.158


hCV1825046
rs2069952
hCV29674976
rs6060266
0.51
0.131481735
0.1983


hCV1825046
rs2069952
hCV2969302
rs6120730
0.51
0.131481735
0.3454


hCV1825046
rs2069952
hCV2969304
rs2424997
0.51
0.131481735
0.3343


hCV1825046
rs2069952
hCV2969305
rs6060052
0.51
0.131481735
0.323


hCV1825046
rs2069952
hCV29693115
rs6119534
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV29693120
rs6060003
0.51
0.131481735
0.3893


hCV1825046
rs2069952
hCV29693169
rs6058192
0.51
0.131481735
0.2935


hCV1825046
rs2069952
hCV29711231
rs6119536
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV29729418
rs6142294
0.51
0.131481735
0.8242


hCV1825046
rs2069952
hCV29747405
rs6088640
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV29747445
rs6060199
0.51
0.131481735
0.7956


hCV1825046
rs2069952
hCV29783257
rs6087619
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV29819450
rs4142034
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV29837701
rs6060045
0.51
0.131481735
0.3343


hCV1825046
rs2069952
hCV29837747
rs6088728
0.51
0.131481735
0.4684


hCV1825046
rs2069952
hCV29837748
rs6088721
0.51
0.131481735
0.4684


hCV1825046
rs2069952
hCV29855628
rs6058150
0.51
0.131481735
0.1718


hCV1825046
rs2069952
hCV29855681
rs6087683
0.51
0.131481735
1


hCV1825046
rs2069952
hCV29855684
rs6120816
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV2988252
rs2425005
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV2988253
rs6087632
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV2988254
rs6060064
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV29909897
rs6142324
0.51
0.131481735
1


hCV1825046
rs2069952
hCV29909901
rs6060205
0.51
0.131481735
0.4332


hCV1825046
rs2069952
hCV29945782
rs6087626
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV29963933
rs6088590
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV29982069
rs6060170
0.51
0.131481735
0.3857


hCV1825046
rs2069952
hCV29982073
rs6088580
0.51
0.131481735
0.4112


hCV1825046
rs2069952
hCV30000150
rs4911465
0.51
0.131481735
0.2707


hCV1825046
rs2069952
hCV30035910
rs6088692
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV30053848
rs6088687
0.51
0.131481735
0.3948


hCV1825046
rs2069952
hCV30053849
rs6088677
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV30053852
rs6088660
0.51
0.131481735
0.1575


hCV1825046
rs2069952
hCV30072029
rs6119516
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV30090036
rs6120747
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV3010271
rs2889861
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV30126097
rs6120827
0.51
0.131481735
0.2707


hCV1825046
rs2069952
hCV30144027
rs6119559
0.51
0.131481735
0.2569


hCV1825046
rs2069952
hCV30162176
rs6060127
0.51
0.131481735
0.1698


hCV1825046
rs2069952
hCV30162181
rs6120723
0.51
0.131481735
0.2714


hCV1825046
rs2069952
hCV30180146
rs6060216
0.51
0.131481735
0.4122


hCV1825046
rs2069952
hCV30198062
rs6088764
0.51
0.131481735
0.2291


hCV1825046
rs2069952
hCV30270039
rs6060301
0.51
0.131481735
0.4086


hCV1825046
rs2069952
hCV30323913
rs6060137
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV30323914
rs6087657
0.51
0.131481735
0.2569


hCV1825046
rs2069952
hCV30342005
rs6060133
0.51
0.131481735
0.198


hCV1825046
rs2069952
hCV30342055
rs6088727
0.51
0.131481735
0.4684


hCV1825046
rs2069952
hCV30360331
rs6088568
0.51
0.131481735
0.4069


hCV1825046
rs2069952
hCV30360384
rs6058194
0.51
0.131481735
0.2195


hCV1825046
rs2069952
hCV30378399
rs6141509
0.51
0.131481735
0.3343


hCV1825046
rs2069952
hCV30378437
rs6088713
0.51
0.131481735
0.3062


hCV1825046
rs2069952
hCV30396340
rs6120849
0.51
0.131481735
0.216


hCV1825046
rs2069952
hCV30450320
rs4911478
0.51
0.131481735
1


hCV1825046
rs2069952
hCV30450323
rs6058166
0.51
0.131481735
0.4122


hCV1825046
rs2069952
hCV30468101
rs6088735
0.51
0.131481735
0.2033


hCV1825046
rs2069952
hCV30485907
rs6087653
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV30503905
rs4911165
0.51
0.131481735
0.1823


hCV1825046
rs2069952
hCV30503911
rs4911161
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV30503955
rs6060194
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV30540259
rs6087664
0.51
0.131481735
0.4132


hCV1825046
rs2069952
hCV30558455
rs6088638
0.51
0.131481735
0.1462


hCV1825046
rs2069952
hCV30594383
rs6060038
0.51
0.131481735
0.3343


hCV1825046
rs2069952
hCV30612241
rs6060168
0.51
0.131481735
0.7561


hCV1825046
rs2069952
hCV30612290
rs6060250
0.51
0.131481735
0.3355


hCV1825046
rs2069952
hCV30630342
rs6141526
0.51
0.131481735
0.7713


hCV1825046
rs2069952
hCV30630345
rs4911456
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hCV32066111
rs10875492
0.51
0.131481735
0.3927


hCV1825046
rs2069952
hCV32066659
rs7272884
0.51
0.131481735
0.158


hCV1825046
rs2069952
hCV3249260
rs7263157
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249262
rs6120750
0.51
0.131481735
0.2537


hCV1825046
rs2069952
hCV3249263
rs6088635
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249264
rs6087641
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249268
rs6058137
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249269
rs8116657
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV3249271
rs4911164
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV3249272
rs6087644
0.51
0.131481735
0.5123


hCV1825046
rs2069952
hCV3249275
rs6088642
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249278
rs6120757
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249279
rs926734
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249280
rs6120758
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249282
rs2064454
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249286
rs6088646
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249289
rs2223881
0.51
0.131481735
0.5351


hCV1825046
rs2069952
hCV3249290
rs2076667
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV3249293
rs6058154
0.51
0.131481735
0.7561


hCV1825046
rs2069952
hCV599565
rs633198
0.51
0.131481735
1


hCV1825046
rs2069952
hCV624502
rs666210
0.51
0.131481735
0.2804


hCV1825046
rs2069952
hCV624503
rs633784
0.51
0.131481735
0.2804


hCV1825046
rs2069952
hCV7499886
rs1415774
0.51
0.131481735
1


hCV1825046
rs2069952
hCV7593276
rs1535466
0.51
0.131481735
0.3224


hCV1825046
rs2069952
hCV7593320
rs1060615
0.51
0.131481735
0.4769


hCV1825046
rs2069952
hCV7593321
rs1013677
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hCV7593328
rs1018447
0.51
0.131481735
0.5093


hCV1825046
rs2069952
hDV70862585
rs17092209
0.51
0.131481735
0.1405


hCV1825046
rs2069952
hDV70862720
rs17092378
0.51
0.131481735
0.3132


hCV1825046
rs2069952
hDV70936356
rs17310782
0.51
0.131481735
0.2554


hCV1825046
rs2069952
hDV71833331
rs6142280
0.51
0.131481735
0.7559


hCV1825046
rs2069952
hDV71898298
rs7361656
0.51
0.131481735
0.2982


hCV1825046
rs2069952
hDV72053898
rs8114671
0.51
0.131481735
1


hCV1841975
rs1799810
hCV11263777
rs11683986
0.51
0.254914511
0.4647


hCV1841975
rs1799810
hCV11263786
rs13408910
0.51
0.254914511
0.429


hCV1841975
rs1799810
hCV11266746
rs6753288
0.51
0.254914511
0.834


hCV1841975
rs1799810
hCV11266765
rs11679414
0.51
0.254914511
0.5751


hCV1841975
rs1799810
hCV11268771
rs4662718
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV12046224
rs10850
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV1441133
rs7568070
0.51
0.254914511
0.356


hCV1841975
rs1799810
hCV1441173
rs4536600
0.51
0.254914511
0.641


hCV1841975
rs1799810
hCV1441189
rs4150499
0.51
0.254914511
0.5379


hCV1841975
rs1799810
hCV1441196
rs4150474
0.51
0.254914511
0.5354


hCV1841975
rs1799810
hCV15860236
rs2069904
0.51
0.254914511
0.7263


hCV1841975
rs1799810
hCV169044
rs11691088
0.51
0.254914511
0.5832


hCV1841975
rs1799810
hCV1841983
rs5937
0.51
0.254914511
0.6119


hCV1841975
rs1799810
hCV25630050
rs3732209
0.51
0.254914511
0.5787


hCV1841975
rs1799810
hCV25960135
rs4150402
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV26980926
rs4150471
0.51
0.254914511
0.5379


hCV1841975
rs1799810
hCV273435
rs7607907
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV27907596
rs4321325
0.51
0.254914511
0.335


hCV1841975
rs1799810
hCV27964958
rs4662713
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV28026949
rs4662720
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV28952331
rs6755028
0.51
0.254914511
0.5319


hCV1841975
rs1799810
hCV28955091
rs7567389
0.51
0.254914511
0.3991


hCV1841975
rs1799810
hCV28955092
rs6430936
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV28966787
rs7585314
0.51
0.254914511
0.5343


hCV1841975
rs1799810
hCV29570359
rs6738690
0.51
0.254914511
0.5288


hCV1841975
rs1799810
hCV29636350
rs10496661
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV30166207
rs7590030
0.51
0.254914511
0.5787


hCV1841975
rs1799810
hCV30418053
rs6757492
0.51
0.254914511
0.545


hCV1841975
rs1799810
hCV30598525
rs7556675
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV30711743
rs11890243
0.51
0.254914511
0.4437


hCV1841975
rs1799810
hCV31814195
rs11680949
0.51
0.254914511
0.5659


hCV1841975
rs1799810
hCV31814218
rs6430938
0.51
0.254914511
0.6123


hCV1841975
rs1799810
hCV8806682
rs1011019
0.51
0.254914511
0.5598


hCV1841975
rs1799810
hCV8807983
rs1504136
0.51
0.254914511
0.5343


hCV1841975
rs1799810
hCV8807988
rs3893313
0.51
0.254914511
0.2563


hCV1841975
rs1799810
hCV8807993
rs1473623
0.51
0.254914511
0.5478


hCV1841975
rs1799810
hCV8810479
rs1604817
0.51
0.254914511
0.6417


hCV1841975
rs1799810
hCV8810750
rs1158867
0.51
0.254914511
1


hCV1841975
rs1799810
hCV9465822
rs11683427
0.51
0.254914511
0.3486


hCV1841975
rs1799810
hCV9468542
rs7599210
0.51
0.254914511
0.8322


hCV1841975
rs1799810
hDV75209985
rs2069898
0.51
0.254914511
0.7164


hCV1841983
rs5937
hCV1023645
rs334160
0.51
0.289879478
0.3788


hCV1841983
rs5937
hCV1023646
rs334159
0.51
0.289879478
0.3408


hCV1841983
rs5937
hCV1023653
rs334151
0.51
0.289879478
0.3788


hCV1841983
rs5937
hCV1023659
rs334146
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV1023661
rs334143
0.51
0.289879478
0.3543


hCV1841983
rs5937
hCV1023665
rs334138
0.51
0.289879478
0.3395


hCV1841983
rs5937
hCV1023666
rs334137
0.51
0.289879478
0.4012


hCV1841983
rs5937
hCV1023669
rs1075774
0.51
0.289879478
0.3374


hCV1841983
rs5937
hCV11263777
rs11683986
0.51
0.289879478
0.8536


hCV1841983
rs5937
hCV11263778
rs6749002
0.51
0.289879478
0.3378


hCV1841983
rs5937
hCV11263786
rs13408910
0.51
0.289879478
0.4521


hCV1841983
rs5937
hCV11266746
rs6753288
0.51
0.289879478
0.5815


hCV1841983
rs5937
hCV11266765
rs11679414
0.51
0.289879478
0.6966


hCV1841983
rs5937
hCV11268771
rs4662718
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV12046142
rs334152
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV12046143
rs334156
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV12046144
rs334158
0.51
0.289879478
0.3788


hCV1841983
rs5937
hCV12046224
rs10850
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV12047693
rs1864552
0.51
0.289879478
0.3779


hCV1841983
rs5937
hCV1441133
rs7568070
0.51
0.289879478
0.3758


hCV1841983
rs5937
hCV1441173
rs4536600
0.51
0.289879478
0.7198


hCV1841983
rs5937
hCV1441189
rs4150499
0.51
0.289879478
0.605


hCV1841983
rs5937
hCV1441196
rs4150474
0.51
0.289879478
0.6229


hCV1841983
rs5937
hCV15860236
rs2069904
0.51
0.289879478
0.9367


hCV1841983
rs5937
hCV15917574
rs2679409
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV16241157
rs2460106
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV169044
rs11691088
0.51
0.289879478
0.704


hCV1841983
rs5937
hCV1721256
rs2069910
0.51
0.289879478
0.3227


hCV1841983
rs5937
hCV1841975
rs1799810
0.51
0.289879478
0.6119


hCV1841983
rs5937
hCV25630050
rs3732209
0.51
0.289879478
0.7933


hCV1841983
rs5937
hCV25960135
rs4150402
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV25971425
rs4662741
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV25993019
rs11673952
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV26980926
rs4150471
0.51
0.289879478
0.6251


hCV1841983
rs5937
hCV27271075
rs2163348
0.51
0.289879478
0.3793


hCV1841983
rs5937
hCV273435
rs7607907
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV27964958
rs4662713
0.51
0.289879478
0.7178


hCV1841983
rs5937
hCV28026949
rs4662720
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV28952331
rs6755028
0.51
0.289879478
0.7962


hCV1841983
rs5937
hCV28952333
rs6754772
0.51
0.289879478
0.3767


hCV1841983
rs5937
hCV28955091
rs7567389
0.51
0.289879478
0.4991


hCV1841983
rs5937
hCV28955092
rs6430936
0.51
0.289879478
0.7189


hCV1841983
rs5937
hCV28966787
rs7585314
0.51
0.289879478
0.5885


hCV1841983
rs5937
hCV29404615
rs6709113
0.51
0.289879478
0.3311


hCV1841983
rs5937
hCV29404616
rs6706077
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV29404621
rs7600934
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV29404688
rs7582598
0.51
0.289879478
0.365


hCV1841983
rs5937
hCV29570359
rs6738690
0.51
0.289879478
0.6251


hCV1841983
rs5937
hCV29636350
rs10496661
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV30166207
rs7590030
0.51
0.289879478
0.7933


hCV1841983
rs5937
hCV30418053
rs6757492
0.51
0.289879478
0.6961


hCV1841983
rs5937
hCV30598525
rs7556675
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV30711743
rs11890243
0.51
0.289879478
0.5169


hCV1841983
rs5937
hCV31814195
rs11680949
0.51
0.289879478
0.6251


hCV1841983
rs5937
hCV31814218
rs6430938
0.51
0.289879478
0.8723


hCV1841983
rs5937
hCV3212726
rs12621149
0.51
0.289879478
0.292


hCV1841983
rs5937
hCV822512
rs334144
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV8806682
rs1011019
0.51
0.289879478
0.7374


hCV1841983
rs5937
hCV8807983
rs1504136
0.51
0.289879478
0.6258


hCV1841983
rs5937
hCV8807993
rs1473623
0.51
0.289879478
0.7761


hCV1841983
rs5937
hCV8808000
rs891514
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV8810479
rs1604817
0.51
0.289879478
0.6728


hCV1841983
rs5937
hCV8810750
rs1158867
0.51
0.289879478
0.6851


hCV1841983
rs5937
hCV8836422
rs777554
0.51
0.289879478
0.3932


hCV1841983
rs5937
hCV8837013
rs1019842
0.51
0.289879478
0.3723


hCV1841983
rs5937
hCV8837014
rs777569
0.51
0.289879478
0.3564


hCV1841983
rs5937
hCV9465822
rs11683427
0.51
0.289879478
0.4044


hCV1841983
rs5937
hCV9468542
rs7599210
0.51
0.289879478
0.5771


hCV1841983
rs5937
hDV70929450
rs17261845
0.51
0.289879478
0.2956


hCV1841983
rs5937
hDV70929452
rs17261859
0.51
0.289879478
0.2956


hCV1841983
rs5937
hDV75209985
rs2069898
0.51
0.289879478
0.8713


hCV1859855
rs2291260
hCV12052839
rs8021
0.51
0.469041298
0.5002


hCV1859855
rs2291260
hCV16089184
rs2873193
0.51
0.469041298
0.6229


hCV1859855
rs2291260
hCV16174004
rs2242291
0.51
0.469041298
0.6816


hCV1859855
rs2291260
hCV1859872
rs4758905
0.51
0.469041298
0.6816


hCV1859855
rs2291260
hCV1859912
rs12303977
0.51
0.469041298
0.6816


hCV1859855
rs2291260
hCV1859941
rs2306541
0.51
0.469041298
0.637


hCV1859855
rs2291260
hCV1859948
rs7297261
0.51
0.469041298
0.5354


hCV1859855
rs2291260
hCV1859956
rs7969859
0.51
0.469041298
0.6554


hCV1859855
rs2291260
hCV1859996
rs12815354
0.51
0.469041298
0.5246


hCV1859855
rs2291260
hCV1859997
rs12815207
0.51
0.469041298
0.5308


hCV1859855
rs2291260
hCV25761477
rs3741490
0.51
0.469041298
0.637


hCV1859855
rs2291260
hCV27522090
rs3825109
0.51
0.469041298
0.6918


hCV1859855
rs2291260
hCV27964264
rs4758939
0.51
0.469041298
0.6816


hCV1859855
rs2291260
hCV30960162
rs11147095
0.51
0.469041298
0.6816


hCV1859855
rs2291260
hCV31631014
rs12811327
0.51
0.469041298
0.5728


hCV1952126
rs7223784
hCV11626701
rs1032070
0.51
0.792412162
0.9128


hCV1952126
rs7223784
hCV27485323
rs3785897
0.51
0.792412162
0.8875


hCV1952126
rs7223784
hCV2769165
rs2071046
0.51
0.792412162
0.9129


hCV1952126
rs7223784
hCV2977462
rs4793099
0.51
0.792412162
0.9128


hCV1952126
rs7223784
hCV3140239
rs36023314
0.51
0.792412162
0.8867


hCV1952126
rs7223784
hCV3140264
rs6503704
0.51
0.792412162
1


hCV1952126
rs7223784
hCV31652022
rs12948909
0.51
0.792412162
1


hCV1952126
rs7223784
hCV31652026
rs11871801
0.51
0.792412162
1


hCV1952126
rs7223784
hCV587962
rs647397
0.51
0.792412162
0.8421


hCV22272267
rs3733402
hCV11786147
rs4862662
0.51
0.093086244
0.352


hCV22272267
rs3733402
hCV11786203
rs4253251
0.51
0.093086244
0.2672


hCV22272267
rs3733402
hCV11786258
rs4253303
0.51
0.093086244
0.5632


hCV22272267
rs3733402
hCV11786259
rs4253304
0.51
0.093086244
0.6456


hCV22272267
rs3733402
hCV11786295
rs4253421
0.51
0.093086244
0.1162


hCV22272267
rs3733402
hCV11786327
rs13133050
0.51
0.093086244
0.2482


hCV22272267
rs3733402
hCV12066118
rs2048
0.51
0.093086244
1


hCV22272267
rs3733402
hCV12066119
rs1912826
0.51
0.093086244
0.9284


hCV22272267
rs3733402
hCV12066124
rs2036914
0.51
0.093086244
0.3605


hCV22272267
rs3733402
hCV12066129
rs1593
0.51
0.093086244
0.1325


hCV22272267
rs3733402
hCV1332991
rs11723770
0.51
0.093086244
0.1232


hCV22272267
rs3733402
hCV1332992
rs12506228
0.51
0.093086244
0.1088


hCV22272267
rs3733402
hCV15793897
rs3087505
0.51
0.093086244
0.12


hCV22272267
rs3733402
hCV15811716
rs2102575
0.51
0.093086244
0.1089


hCV22272267
rs3733402
hCV15968025
rs2292425
0.51
0.093086244
0.18


hCV22272267
rs3733402
hCV15968026
rs2292426
0.51
0.093086244
0.2195


hCV22272267
rs3733402
hCV15968034
rs2292428
0.51
0.093086244
0.3058


hCV22272267
rs3733402
hCV15968043
rs2292423
0.51
0.093086244
0.6588


hCV22272267
rs3733402
hCV15975109
rs2304596
0.51
0.093086244
0.24


hCV22272267
rs3733402
hCV2103337
rs13102931
0.51
0.093086244
0.1025


hCV22272267
rs3733402
hCV2103343
rs4241824
0.51
0.093086244
0.3019


hCV22272267
rs3733402
hCV2103391
rs1008728
0.51
0.093086244
0.2065


hCV22272267
rs3733402
hCV2103392
rs12500826
0.51
0.093086244
0.1775


hCV22272267
rs3733402
hCV22271609
rs4253326
0.51
0.093086244
0.2299


hCV22272267
rs3733402
hCV25474413
rs3822057
0.51
0.093086244
0.312


hCV22272267
rs3733402
hCV25474414
rs4253399
0.51
0.093086244
0.1628


hCV22272267
rs3733402
hCV25634763
rs4253241
0.51
0.093086244
0.1188


hCV22272267
rs3733402
hCV25634781
rs4253299
0.51
0.093086244
0.2584


hCV22272267
rs3733402
hCV25989001
hCV25989001
0.51
0.093086244
0.2535


hCV22272267
rs3733402
hCV25990131
rs13146272
0.51
0.093086244
0.1915


hCV22272267
rs3733402
hCV26265197
rs10014399
0.51
0.093086244
0.2641


hCV22272267
rs3733402
hCV26265199
rs2221843
0.51
0.093086244
0.2584


hCV22272267
rs3733402
hCV26265231
rs7684025
0.51
0.093086244
0.3837


hCV22272267
rs3733402
hCV27473099
rs3733403
0.51
0.093086244
0.1386


hCV22272267
rs3733402
hCV27477533
rs3756008
0.51
0.093086244
0.1577


hCV22272267
rs3733402
hCV27482765
rs3775301
0.51
0.093086244
0.24


hCV22272267
rs3733402
hCV27482766
rs3775302
0.51
0.093086244
0.1546


hCV22272267
rs3733402
hCV27506149
rs3822055
0.51
0.093086244
0.2584


hCV22272267
rs3733402
hCV27521729
rs3822056
0.51
0.093086244
0.1313


hCV22272267
rs3733402
hCV27902808
rs4253236
0.51
0.093086244
0.6716


hCV22272267
rs3733402
hCV29053264
rs7667777
0.51
0.093086244
0.3951


hCV22272267
rs3733402
hCV29053265
rs4253244
0.51
0.093086244
0.6414


hCV22272267
rs3733402
hCV29718000
rs4253238
0.51
0.093086244
1


hCV22272267
rs3733402
hCV29826351
rs10025990
0.51
0.093086244
0.1333


hCV22272267
rs3733402
hCV29877725
rs4253295
0.51
0.093086244
0.5775


hCV22272267
rs3733402
hCV30983907
rs4253246
0.51
0.093086244
0.1188


hCV22272267
rs3733402
hCV32209636
rs11132387
0.51
0.093086244
0.1446


hCV22272267
rs3733402
hCV32291217
rs4253323
0.51
0.093086244
0.24


hCV22272267
rs3733402
hCV32291269
rs4253417
0.51
0.093086244
0.1165


hCV22272267
rs3733402
hCV32291286
rs4253422
0.51
0.093086244
0.168


hCV22272267
rs3733402
hCV32291287
rs4253423
0.51
0.093086244
0.168


hCV22272267
rs3733402
hCV32291295
rs4253292
0.51
0.093086244
0.2444


hCV22272267
rs3733402
hCV32291301
rs4253302
0.51
0.093086244
0.2397


hCV22272267
rs3733402
hCV32295028
rs4253260
0.51
0.093086244
0.24


hCV22272267
rs3733402
hCV3229991
rs4241815
0.51
0.093086244
1


hCV22272267
rs3733402
hCV3229992
rs3775298
0.51
0.093086244
1


hCV22272267
rs3733402
hCV3229995
rs11132382
0.51
0.093086244
1


hCV22272267
rs3733402
hCV3230000
rs4253294
0.51
0.093086244
0.4581


hCV22272267
rs3733402
hCV3230001
rs4253296
0.51
0.093086244
0.1188


hCV22272267
rs3733402
hCV3230002
rs4253297
0.51
0.093086244
0.5815


hCV22272267
rs3733402
hCV3230003
rs2304595
0.51
0.093086244
0.6471


hCV22272267
rs3733402
hCV3230004
rs4253301
0.51
0.093086244
0.1089


hCV22272267
rs3733402
hCV3230006
rs4253308
0.51
0.093086244
0.5775


hCV22272267
rs3733402
hCV3230007
rs4253311
0.51
0.093086244
1


hCV22272267
rs3733402
hCV3230010
rs4253315
0.51
0.093086244
0.1137


hCV22272267
rs3733402
hCV3230011
rs4253320
0.51
0.093086244
0.5815


hCV22272267
rs3733402
hCV3230012
rs4241821
0.51
0.093086244
0.2584


hCV22272267
rs3733402
hCV3230013
rs3775303
0.51
0.093086244
0.6456


hCV22272267
rs3733402
hCV3230014
rs4861709
0.51
0.093086244
0.4581


hCV22272267
rs3733402
hCV3230016
rs4253325
0.51
0.093086244
0.112


hCV22272267
rs3733402
hCV3230017
rs4253327
0.51
0.093086244
0.1008


hCV22272267
rs3733402
hCV3230018
rs925453
0.51
0.093086244
0.4359


hCV22272267
rs3733402
hCV3230019
rs4253332
0.51
0.093086244
0.4359


hCV22272267
rs3733402
hCV3230025
rs3756009
0.51
0.093086244
0.149


hCV22272267
rs3733402
hCV3230031
rs4253419
0.51
0.093086244
0.168


hCV22272267
rs3733402
hCV3230038
rs2289252
0.51
0.093086244
0.1192


hCV22272267
rs3733402
hCV3230083
rs10013653
0.51
0.093086244
0.3018


hCV22272267
rs3733402
hCV3230084
rs7682918
0.51
0.093086244
0.2829


hCV22272267
rs3733402
hCV3230094
rs7687818
0.51
0.093086244
0.4367


hCV22272267
rs3733402
hCV3230096
rs3817184
0.51
0.093086244
0.3722


hCV22272267
rs3733402
hCV3230097
rs3736455
0.51
0.093086244
0.2406


hCV22272267
rs3733402
hCV3230101
rs6835839
0.51
0.093086244
0.3515


hCV22272267
rs3733402
hCV3230106
rs1473597
0.51
0.093086244
0.318


hCV22272267
rs3733402
hCV3230110
rs2276917
0.51
0.093086244
0.3058


hCV22272267
rs3733402
hCV3230113
rs1053094
0.51
0.093086244
0.5831


hCV22272267
rs3733402
hCV3230118
rs4253429
0.51
0.093086244
0.168


hCV22272267
rs3733402
hCV3230125
rs11938564
0.51
0.093086244
0.1034


hCV22272267
rs3733402
hCV3230136
rs13116273
0.51
0.093086244
0.0947


hCV22272267
rs3733402
hCV32313006
rs4253248
0.51
0.093086244
1


hCV22272267
rs3733402
hCV32313024
rs4253239
0.51
0.093086244
0.2444


hCV22272267
rs3733402
hCV32358975
rs4253255
0.51
0.093086244
1


hCV22272267
rs3733402
hCV32358984
rs4253256
0.51
0.093086244
0.6645


hCV22272267
rs3733402
hCV7750713
rs4862596
0.51
0.093086244
0.1067


hCV22272267
rs3733402
hCV7750737
rs13140248
0.51
0.093086244
0.1031


hCV22272267
rs3733402
hCV8241630
rs925451
0.51
0.093086244
0.1476


hCV22272267
rs3733402
hCV8241631
rs1511802
0.51
0.093086244
0.5775


hCV22272267
rs3733402
hCV8241632
rs1511801
0.51
0.093086244
1


hCV22272267
rs3733402
hDV68550952
rs4253289
0.51
0.093086244
0.102


hCV22272267
rs3733402
hDV71222711
rs4253252
0.51
0.093086244
1


hCV22273419
rs2304167
hCV11977629
rs1654459
0.51
0.488273752
0.5665


hCV22273419
rs2304167
hCV1376257
rs10416380
0.51
0.488273752
0.9727


hCV22273419
rs2304167
hCV1376262
rs1671150
0.51
0.488273752
1


hCV22273419
rs2304167
hCV1376264
rs1671151
0.51
0.488273752
1


hCV22273419
rs2304167
hCV1376265
rs1671152
0.51
0.488273752
0.8131


hCV22273419
rs2304167
hCV1376266
rs1654413
0.51
0.488273752
1


hCV22273419
rs2304167
hCV1376342
rs1654416
0.51
0.488273752
0.9724


hCV22273419
rs2304167
hCV1376359
rs2886412
0.51
0.488273752
1


hCV22273419
rs2304167
hCV16044361
rs2569513
0.51
0.488273752
0.639


hCV22273419
rs2304167
hCV26895244
rs1671153
0.51
0.488273752
1


hCV22273419
rs2304167
hCV26895257
rs2886415
0.51
0.488273752
1


hCV22273419
rs2304167
hCV29271569
rs1626971
0.51
0.488273752
0.7325


hCV22273419
rs2304167
hCV31722831
rs11671922
0.51
0.488273752
1


hCV22273419
rs2304167
hCV31722832
rs11084381
0.51
0.488273752
0.8942


hCV22273419
rs2304167
hCV31722834
rs11084382
0.51
0.488273752
0.783


hCV22273419
rs2304167
hCV31722835
rs11668169
0.51
0.488273752
0.8939


hCV22273419
rs2304167
hCV31722836
rs11672026
0.51
0.488273752
0.8884


hCV22273419
rs2304167
hCV7841075
rs1671196
0.51
0.488273752
0.8942


hCV22273419
rs2304167
hCV8703249
rs1654444
0.51
0.488273752
0.633


hCV22273419
rs2304167
hCV8717752
rs1671217
0.51
0.488273752
0.7325


hCV22273419
rs2304167
hCV8717761
rs1654439
0.51
0.488273752
0.5719


hCV22273419
rs2304167
hCV8717793
rs1654433
0.51
0.488273752
0.639


hCV22273419
rs2304167
hCV8717794
rs1654432
0.51
0.488273752
0.639


hCV22273419
rs2304167
hCV8717845
rs892090
0.51
0.488273752
0.7101


hCV22273419
rs2304167
hCV8717846
rs892089
0.51
0.488273752
1


hCV22273419
rs2304167
hCV8717871
rs1654421
0.51
0.488273752
0.754


hCV22273419
rs2304167
hCV8717873
rs1613662
0.51
0.488273752
0.7101


hCV22273419
rs2304167
hCV8717881
rs1654420
0.51
0.488273752
0.8939


hCV22273419
rs2304167
hCV8717893
rs1671192
0.51
0.488273752
1


hCV22273419
rs2304167
hCV8718961
rs1654451
0.51
0.488273752
0.5646


hCV22273419
rs2304167
hCV8718972
rs1654447
0.51
0.488273752
0.6147


hCV22273419
rs2304167
hCV9490926
rs1654419
0.51
0.488273752
0.8939


hCV2303891
rs1801690
hCV2658414
rs8178851
0.51
0.431588444
0.7358


hCV2303891
rs1801690
hCV2658416
rs8178853
0.51
0.431588444
0.7358


hCV2303891
rs1801690
hCV2658437
rs11651658
0.51
0.431588444
0.858


hCV2303891
rs1801690
hCV2658444
rs7209242
0.51
0.431588444
0.497


hCV2303891
rs1801690
hCV2658455
rs11658189
0.51
0.431588444
0.9185


hCV2303891
rs1801690
hCV26589423
rs1014399
0.51
0.431588444
0.574


hCV2303891
rs1801690
hCV27842286
rs8178822
0.51
0.431588444
0.778


hCV2303891
rs1801690
hCV29176910
rs7211380
0.51
0.431588444
0.7358


hCV2303891
rs1801690
hCV29577360
rs9910950
0.51
0.431588444
0.9185


hCV2303891
rs1801690
hCV29866571
rs9891968
0.51
0.431588444
0.8255


hCV2303891
rs1801690
hCV29992830
rs8178839
0.51
0.431588444
0.497


hCV2303891
rs1801690
hCV30064665
rs9902706
0.51
0.431588444
0.9185


hCV2303891
rs1801690
hCV30082731
rs8178838
0.51
0.431588444
0.8247


hCV2303891
rs1801690
hCV30118779
rs8178841
0.51
0.431588444
0.778


hCV2303891
rs1801690
hCV30298770
rs8178842
0.51
0.431588444
0.7215


hCV2303891
rs1801690
hCV30352818
rs8178847
0.51
0.431588444
0.778


hCV2303891
rs1801690
hCV30443106
rs7213041
0.51
0.431588444
0.778


hCV2303891
rs1801690
hCV30551147
rs9908597
0.51
0.431588444
0.8255


hCV2303891
rs1801690
hCV31400900
rs7216660
0.51
0.431588444
0.9185


hCV2303891
rs1801690
hDV70764335
rs16958979
0.51
0.431588444
0.7777


hCV2303891
rs1801690
hDV70764357
rs16959006
0.51
0.431588444
1


hCV233148
rs1417121
hCV12073836
rs1008173
0.51
0.233111365
0.4803


hCV233148
rs1417121
hCV12073840
rs14403
0.51
0.233111365
0.8606


hCV233148
rs1417121
hCV15760229
rs3006939
0.51
0.233111365
0.6414


hCV233148
rs1417121
hCV15760238
rs3006936
0.51
0.233111365
0.6656


hCV233148
rs1417121
hCV15760239
rs3006923
0.51
0.233111365
0.7633


hCV233148
rs1417121
hCV15760280
rs3006940
0.51
0.233111365
0.6414


hCV233148
rs1417121
hCV15823024
rs2125230
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV15885425
rs2290754
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV15953071
rs2953329
0.51
0.233111365
0.238


hCV233148
rs1417121
hCV15965338
rs2291410
0.51
0.233111365
0.4485


hCV233148
rs1417121
hCV16082410
rs2881275
0.51
0.233111365
0.4499


hCV233148
rs1417121
hCV16189408
rs2994320
0.51
0.233111365
0.4425


hCV233148
rs1417121
hCV1678656
rs1458024
0.51
0.233111365
0.4499


hCV233148
rs1417121
hCV1678674
rs1458023
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV1678687
rs320305
0.51
0.233111365
0.3115


hCV233148
rs1417121
hCV26034142
rs9428576
0.51
0.233111365
0.4375


hCV233148
rs1417121
hCV26034157
rs2994329
0.51
0.233111365
0.4814


hCV233148
rs1417121
hCV26034158
rs4515770
0.51
0.233111365
0.6414


hCV233148
rs1417121
hCV26034160
rs2994327
0.51
0.233111365
0.7257


hCV233148
rs1417121
hCV26338482
rs10803143
0.51
0.233111365
0.2626


hCV233148
rs1417121
hCV26338512
rs2994339
0.51
0.233111365
0.4425


hCV233148
rs1417121
hCV26338513
rs3006917
0.51
0.233111365
0.4425


hCV233148
rs1417121
hCV26719082
rs10927046
0.51
0.233111365
0.3102


hCV233148
rs1417121
hCV26719085
rs10927047
0.51
0.233111365
0.3441


hCV233148
rs1417121
hCV26719107
rs7538011
0.51
0.233111365
0.3776


hCV233148
rs1417121
hCV26719108
rs10927035
0.51
0.233111365
0.2612


hCV233148
rs1417121
hCV26719113
rs7517340
0.51
0.233111365
0.3991


hCV233148
rs1417121
hCV26719116
rs10927039
0.51
0.233111365
0.49


hCV233148
rs1417121
hCV26719120
rs10927040
0.51
0.233111365
0.4485


hCV233148
rs1417121
hCV26719121
rs10927041
0.51
0.233111365
0.4485


hCV233148
rs1417121
hCV26719149
rs6675851
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV26719162
rs4132509
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV26719176
rs10927076
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV26719192
rs10803161
0.51
0.233111365
0.4774


hCV233148
rs1417121
hCV26719201
rs4478795
0.51
0.233111365
0.2532


hCV233148
rs1417121
hCV26719219
rs9782958
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV26719222
rs4553169
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV26719227
rs10927065
0.51
0.233111365
0.3115


hCV233148
rs1417121
hCV26719232
rs10803158
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV26719233
rs10927067
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV27498250
rs3766673
0.51
0.233111365
0.4485


hCV233148
rs1417121
hCV29210363
rs6656918
0.51
0.233111365
0.6414


hCV233148
rs1417121
hCV29542869
rs7534117
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV29560960
rs7519673
0.51
0.233111365
0.3115


hCV233148
rs1417121
hCV29741723
rs7517921
0.51
0.233111365
0.3711


hCV233148
rs1417121
hCV29994467
rs6694738
0.51
0.233111365
0.3776


hCV233148
rs1417121
hCV30084348
rs9287269
0.51
0.233111365
0.4111


hCV233148
rs1417121
hCV30372886
rs9782883
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV30382231
rs9428966
0.51
0.233111365
1


hCV233148
rs1417121
hCV30690777
rs12045585
0.51
0.233111365
0.3015


hCV233148
rs1417121
hCV30690778
rs12140414
0.51
0.233111365
0.5616


hCV233148
rs1417121
hCV30690780
rs10737888
0.51
0.233111365
0.6414


hCV233148
rs1417121
hCV30690784
rs4658574
0.51
0.233111365
0.7257


hCV233148
rs1417121
hCV31056133
rs10927006
0.51
0.233111365
0.2564


hCV233148
rs1417121
hCV31056162
rs12049318
0.51
0.233111365
0.2564


hCV233148
rs1417121
hCV31523557
rs10754807
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV31523563
rs10927051
0.51
0.233111365
0.4633


hCV233148
rs1417121
hCV31523638
rs12037013
0.51
0.233111365
0.3441


hCV233148
rs1417121
hCV31523639
rs12034588
0.51
0.233111365
0.4326


hCV233148
rs1417121
hCV31523643
rs6671475
0.51
0.233111365
0.4485


hCV233148
rs1417121
hCV31523650
rs12048930
0.51
0.233111365
0.3711


hCV233148
rs1417121
hCV31523658
rs12047209
0.51
0.233111365
0.317


hCV233148
rs1417121
hCV31523688
rs12049228
0.51
0.233111365
0.4351


hCV233148
rs1417121
hCV31523691
rs12021907
0.51
0.233111365
0.3115


hCV233148
rs1417121
hCV31523707
rs10803152
0.51
0.233111365
0.3441


hCV233148
rs1417121
hCV31523710
rs10927059
0.51
0.233111365
0.4131


hCV233148
rs1417121
hCV31523723
rs12140040
0.51
0.233111365
0.3202


hCV233148
rs1417121
hCV31523736
rs12124113
0.51
0.233111365
0.3115


hCV233148
rs1417121
hCV31523740
rs12032342
0.51
0.233111365
0.4499


hCV233148
rs1417121
hCV31523744
rs12031994
0.51
0.233111365
0.3115


hCV233148
rs1417121
hCV804126
rs320320
0.51
0.233111365
0.4499


hCV233148
rs1417121
hCV8688079
rs884808
0.51
0.233111365
0.7257


hCV233148
rs1417121
hCV8688080
rs884328
0.51
0.233111365
0.7257


hCV233148
rs1417121
hCV8688111
rs1578275
0.51
0.233111365
0.5616


hCV233148
rs1417121
hCV9493073
rs1058305
0.51
0.233111365
1


hCV233148
rs1417121
hCV9493081
rs1058304
0.51
0.233111365
1


hCV233148
rs1417121
hCV97631
rs1538773
0.51
0.233111365
0.6414


hCV233148
rs1417121
hDV71836703
rs6429433
0.51
0.233111365
0.4157


hCV233148
rs1417121
hDV90784784
rs320339
0.51
0.233111365
0.3409


hCV2442143
rs12544854
hCV15753018
rs2299606
0.51
0.805894186
0.9649


hCV2442143
rs12544854
hCV15844343
rs2427746
0.51
0.805894186
0.8982


hCV2442143
rs12544854
hCV2442136
rs12155668
0.51
0.805894186
1


hCV2442143
rs12544854
hCV2442137
rs12155885
0.51
0.805894186
1


hCV2442143
rs12544854
hCV2442146
rs966118
0.51
0.805894186
1


hCV2442143
rs12544854
hCV2442155
rs3753117
0.51
0.805894186
1


hCV2442143
rs12544854
hCV2442156
rs35573135
0.51
0.805894186
0.841


hCV2442143
rs12544854
hCV26696706
rs2299607
0.51
0.805894186
1


hCV2442143
rs12544854
hCV27474371
rs3753116
0.51
0.805894186
1


hCV2442143
rs12544854
hCV31495915
rs3753115
0.51
0.805894186
1


hCV2442143
rs12544854
hCV31495928
rs12548139
0.51
0.805894186
1


hCV2442143
rs12544854
hCV8947815
rs1049874
0.51
0.805894186
1


hCV2499170
rs169713
hCV2238240
rs209773
0.51
0.626344353
0.9402


hCV2499170
rs169713
hCV2238245
rs23805
0.51
0.626344353
0.8916


hCV2499170
rs169713
hCV2238247
rs209778
0.51
0.626344353
0.6678


hCV2499170
rs169713
hCV2238250
rs209780
0.51
0.626344353
0.8809


hCV2499170
rs169713
hCV2238261
rs209814
0.51
0.626344353
0.6439


hCV2499170
rs169713
hCV2238263
rs209812
0.51
0.626344353
0.6422


hCV2499170
rs169713
hCV2499165
rs209774
0.51
0.626344353
1


hCV2499170
rs169713
hCV2499169
rs85219
0.51
0.626344353
1


hCV2499170
rs169713
hCV2499176
rs9380643
0.51
0.626344353
0.6493


hCV2499170
rs169713
hCV2499198
rs1205883
0.51
0.626344353
0.6439


hCV2499170
rs169713
hCV2499199
rs1205884
0.51
0.626344353
0.6439


hCV2499170
rs169713
hCV2499201
rs1205887
0.51
0.626344353
0.6439


hCV2499170
rs169713
hCV31001553
rs10947661
0.51
0.626344353
0.8779


hCV2499170
rs169713
hCV7465311
rs1205863
0.51
0.626344353
0.6439


hCV2499170
rs169713
hCV7465312
rs864245
0.51
0.626344353
0.6439


hCV2499170
rs169713
hCV7465347
rs1205852
0.51
0.626344353
0.6439


hCV2499170
rs169713
hCV7465349
rs1205850
0.51
0.626344353
0.8424


hCV2499170
rs169713
hCV7465354
rs1205849
0.51
0.626344353
0.8932


hCV2499170
rs169713
hCV7465364
rs864244
0.51
0.626344353
0.9459


hCV2499170
rs169713
hCV7465377
rs1210621
0.51
0.626344353
0.9438


hCV2499170
rs169713
hCV7465418
rs876828
0.51
0.626344353
0.7396


hCV2499170
rs169713
hDV101721202
rs9394412
0.51
0.626344353
0.8779


hCV2532034
rs6003
hCV11888484
rs6694672
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV11888496
rs7554757
0.51
0.719447218
1


hCV2532034
rs6003
hCV11888533
rs1115247
0.51
0.719447218
1


hCV2532034
rs6003
hCV11888556
rs7542397
0.51
0.719447218
1


hCV2532034
rs6003
hCV11888566
rs1888991
0.51
0.719447218
0.9451


hCV2532034
rs6003
hCV15832928
rs2151133
0.51
0.719447218
0.8803


hCV2532034
rs6003
hCV15832929
rs2151134
0.51
0.719447218
1


hCV2532034
rs6003
hCV1648949
rs6692162
0.51
0.719447218
1


hCV2532034
rs6003
hCV1739697
rs10429911
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV1739698
rs1415217
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV1739699
rs7520503
0.51
0.719447218
0.945


hCV2532034
rs6003
hCV1739712
rs510135
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV1742489
rs476390
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV1742520
rs615647
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV1742521
rs518149
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV1742540
rs10754219
0.51
0.719447218
0.8802


hCV2532034
rs6003
hCV201028
rs10733087
0.51
0.719447218
0.8803


hCV2532034
rs6003
hCV201029
rs10754213
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV209646
rs12734260
0.51
0.719447218
0.8013


hCV2532034
rs6003
hCV240531
rs6703400
0.51
0.719447218
1


hCV2532034
rs6003
hCV240532
rs2026429
0.51
0.719447218
1


hCV2532034
rs6003
hCV247773
rs1332663
0.51
0.719447218
1


hCV2532034
rs6003
hCV2532031
rs1412632
0.51
0.719447218
1


hCV2532034
rs6003
hCV2532032
rs4915148
0.51
0.719447218
1


hCV2532034
rs6003
hCV2532033
rs1759006
0.51
0.719447218
1


hCV2532034
rs6003
hCV2532038
rs1759008
0.51
0.719447218
1


hCV2532034
rs6003
hCV2532039
rs1759009
0.51
0.719447218
1


hCV2532034
rs6003
hCV2532061
rs857021
0.51
0.719447218
0.9424


hCV2532034
rs6003
hCV2532062
rs1332669
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV26753641
rs10801590
0.51
0.719447218
1


hCV2532034
rs6003
hCV268763
rs4350226
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV26961419
rs10732296
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV26961484
rs4915379
0.51
0.719447218
0.945


hCV2532034
rs6003
hCV2759661
rs12731209
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759662
rs1170880
0.51
0.719447218
0.9395


hCV2532034
rs6003
hCV2759663
rs928440
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759664
rs928439
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759671
rs2336595
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759673
rs1412639
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759676
rs4915156
0.51
0.719447218
0.8803


hCV2532034
rs6003
hCV2759677
rs10801588
0.51
0.719447218
0.8486


hCV2532034
rs6003
hCV2759678
rs1571964
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759679
rs6677082
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759685
rs877897
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759688
rs10922169
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759691
rs4915337
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759693
rs10754215
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759696
rs7411719
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759703
rs1412640
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759704
rs1953064
0.51
0.719447218
0.8803


hCV2532034
rs6003
hCV2759709
rs4915313
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759711
rs4915309
0.51
0.719447218
1


hCV2532034
rs6003
hCV2759725
rs6670056
0.51
0.719447218
1


hCV2532034
rs6003
hCV27898326
rs4915316
0.51
0.719447218
0.9396


hCV2532034
rs6003
hCV27898327
rs4915327
0.51
0.719447218
1


hCV2532034
rs6003
hCV28005188
rs4342879
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV29222813
rs4915315
0.51
0.719447218
0.8023


hCV2532034
rs6003
hCV29222814
rs6428387
0.51
0.719447218
0.8803


hCV2532034
rs6003
hCV29222817
rs6656858
0.51
0.719447218
1


hCV2532034
rs6003
hCV29295007
rs6656448
0.51
0.719447218
0.88


hCV2532034
rs6003
hCV29491389
rs7513826
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV29633649
rs7539642
0.51
0.719447218
0.8803


hCV2532034
rs6003
hCV29724082
rs9427661
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV29796191
rs9427660
0.51
0.719447218
1


hCV2532034
rs6003
hCV29904681
rs6680497
0.51
0.719447218
1


hCV2532034
rs6003
hCV29922678
rs9427940
0.51
0.719447218
0.8911


hCV2532034
rs6003
hCV30321245
rs7523013
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV30373286
rs6702340
0.51
0.719447218
1


hCV2532034
rs6003
hCV30391085
rs9427656
0.51
0.719447218
0.7282


hCV2532034
rs6003
hCV30391086
rs9427942
0.51
0.719447218
0.9396


hCV2532034
rs6003
hCV30589276
rs9427657
0.51
0.719447218
0.7525


hCV2532034
rs6003
hCV3091554
rs5997
0.51
0.719447218
1


hCV2532034
rs6003
hCV31565477
rs10801587
0.51
0.719447218
0.8802


hCV2532034
rs6003
hCV31565478
rs10754214
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV31565485
rs10922166
0.51
0.719447218
1


hCV2532034
rs6003
hCV31565488
rs6671696
0.51
0.719447218
1


hCV2532034
rs6003
hCV31565509
rs12092294
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV31565527
rs12039586
0.51
0.719447218
1


hCV2532034
rs6003
hCV31795582
rs6678066
0.51
0.719447218
0.8913


hCV2532034
rs6003
hCV32375831
rs4915378
0.51
0.719447218
0.7347


hCV2532034
rs6003
hCV356522
rs10732295
0.51
0.719447218
0.9451


hCV2532034
rs6003
hCV406628
rs1576879
0.51
0.719447218
1


hCV2532034
rs6003
hCV489039
rs6679189
0.51
0.719447218
1


hCV2532034
rs6003
hCV65774
rs7534353
0.51
0.719447218
1


hCV2532034
rs6003
hCV8348876
rs1332662
0.51
0.719447218
1


hCV2532034
rs6003
hCV8350834
rs1764629
0.51
0.719447218
0.9451


hCV2532034
rs6003
hCV8350843
rs1556763
0.51
0.719447218
0.945


hCV2532034
rs6003
hCV8356383
rs1764800
0.51
0.719447218
0.945


hCV2532034
rs6003
hCV8356417
rs12677
0.51
0.719447218
1


hCV2532034
rs6003
hCV8356418
rs1537319
0.51
0.719447218
0.8803


hCV2532034
rs6003
hCV8356419
rs1412631
0.51
0.719447218
1


hCV2532034
rs6003
hCV8356425
rs1627765
0.51
0.719447218
0.9451


hCV2532034
rs6003
hCV8356430
rs1759007
0.51
0.719447218
1


hCV2532034
rs6003
hCV8356446
rs1412634
0.51
0.719447218
1


hCV2532034
rs6003
hCV8356520
rs1170881
0.51
0.719447218
1


hCV2532034
rs6003
hCV836489
rs616675
0.51
0.719447218
0.8903


hCV2532034
rs6003
hCV87892
rs2336597
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV9114466
rs3891964
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV9114630
rs1576880
0.51
0.719447218
1


hCV2532034
rs6003
hCV9114656
rs9427662
0.51
0.719447218
0.9425


hCV2532034
rs6003
hCV9114658
rs13376702
0.51
0.719447218
0.7419


hCV25474413
rs3822057
hCV11786147
rs4862662
0.51
0.057574841
0.2412


hCV25474413
rs3822057
hCV11786258
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0.2622


hCV25474413
rs3822057
hCV11786259
rs4253304
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0.057574841
0.2992


hCV25474413
rs3822057
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0.0942


hCV25474413
rs3822057
hCV11786301
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0.0764


hCV25474413
rs3822057
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rs1062547
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0.4723


hCV25474413
rs3822057
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0.0838


hCV25474413
rs3822057
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0.2298


hCV25474413
rs3822057
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0.1289


hCV25474413
rs3822057
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0.3088


hCV25474413
rs3822057
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0.3323


hCV25474413
rs3822057
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0.057574841
0.9449


hCV25474413
rs3822057
hCV12066129
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0.1397


hCV25474413
rs3822057
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rs1877321
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0.0612


hCV25474413
rs3822057
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0.1042


hCV25474413
rs3822057
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0.0982


hCV25474413
rs3822057
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0.169


hCV25474413
rs3822057
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0.1853


hCV25474413
rs3822057
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0.1541


hCV25474413
rs3822057
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0.313


hCV25474413
rs3822057
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0.0626


hCV25474413
rs3822057
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0.0581


hCV25474413
rs3822057
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0.4618


hCV25474413
rs3822057
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0.9811


hCV25474413
rs3822057
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0.057574841
0.0598


hCV25474413
rs3822057
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0.1442


hCV25474413
rs3822057
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0.2797


hCV25474413
rs3822057
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0.4611


hCV25474413
rs3822057
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0.0612


hCV25474413
rs3822057
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0.312


hCV25474413
rs3822057
hCV25474414
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0.596


hCV25474413
rs3822057
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rs4253241
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0.057574841
0.0739


hCV25474413
rs3822057
hCV25988221
rs9995366
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0.057574841
0.0873


hCV25474413
rs3822057
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0.057574841
0.1706


hCV25474413
rs3822057
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rs4253405
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0.057574841
0.6414


hCV25474413
rs3822057
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rs7684025
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0.2834


hCV25474413
rs3822057
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0.1491


hCV25474413
rs3822057
hCV27473099
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0.057574841
0.1093


hCV25474413
rs3822057
hCV27474895
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0.51
0.057574841
0.5232


hCV25474413
rs3822057
hCV27477533
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0.51
0.057574841
0.577


hCV25474413
rs3822057
hCV27482765
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0.51
0.057574841
0.0626


hCV25474413
rs3822057
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rs3822058
0.51
0.057574841
0.477


hCV25474413
rs3822057
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0.51
0.057574841
0.1222


hCV25474413
rs3822057
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0.51
0.057574841
0.0873


hCV25474413
rs3822057
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0.057574841
0.1514


hCV25474413
rs3822057
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rs6844764
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0.057574841
0.1108


hCV25474413
rs3822057
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0.057574841
0.1042


hCV25474413
rs3822057
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0.057574841
0.2192


hCV25474413
rs3822057
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rs4253244
0.51
0.057574841
0.1369


hCV25474413
rs3822057
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rs10029715
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0.057574841
0.0904


hCV25474413
rs3822057
hCV29718000
rs4253238
0.51
0.057574841
0.3736


hCV25474413
rs3822057
hCV29826351
rs10025990
0.51
0.057574841
0.1507


hCV25474413
rs3822057
hCV29877725
rs4253295
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0.057574841
0.2932


hCV25474413
rs3822057
hCV30307525
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0.057574841
0.0904


hCV25474413
rs3822057
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0.057574841
0.1042


hCV25474413
rs3822057
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0.057574841
0.0597


hCV25474413
rs3822057
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rs4862668
0.51
0.057574841
0.1289


hCV25474413
rs3822057
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rs4253246
0.51
0.057574841
0.0739


hCV25474413
rs3822057
hCV30983927
rs6552962
0.51
0.057574841
0.0626


hCV25474413
rs3822057
hCV32209629
rs12715865
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0.057574841
0.1687


hCV25474413
rs3822057
hCV32209636
rs11132387
0.51
0.057574841
0.4496


hCV25474413
rs3822057
hCV32209637
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0.51
0.057574841
0.302


hCV25474413
rs3822057
hCV32209638
rs12507040
0.51
0.057574841
0.3609


hCV25474413
rs3822057
hCV32291217
rs4253323
0.51
0.057574841
0.0626


hCV25474413
rs3822057
hCV32291256
rs4253406
0.51
0.057574841
0.0668


hCV25474413
rs3822057
hCV32291269
rs4253417
0.51
0.057574841
0.419


hCV25474413
rs3822057
hCV32291286
rs4253422
0.51
0.057574841
0.2386


hCV25474413
rs3822057
hCV32291287
rs4253423
0.51
0.057574841
0.2386


hCV25474413
rs3822057
hCV32291295
rs4253292
0.51
0.057574841
0.1106


hCV25474413
rs3822057
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rs4253302
0.51
0.057574841
0.0583


hCV25474413
rs3822057
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rs4253260
0.51
0.057574841
0.0626


hCV25474413
rs3822057
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rs4241815
0.51
0.057574841
0.312


hCV25474413
rs3822057
hCV3229992
rs3775298
0.51
0.057574841
0.312


hCV25474413
rs3822057
hCV3229995
rs11132382
0.51
0.057574841
0.3554


hCV25474413
rs3822057
hCV3230000
rs4253294
0.51
0.057574841
0.1258


hCV25474413
rs3822057
hCV3230001
rs4253296
0.51
0.057574841
0.0739


hCV25474413
rs3822057
hCV3230002
rs4253297
0.51
0.057574841
0.2517


hCV25474413
rs3822057
hCV3230003
rs2304595
0.51
0.057574841
0.3609


hCV25474413
rs3822057
hCV3230004
rs4253301
0.51
0.057574841
0.0995


hCV25474413
rs3822057
hCV3230006
rs4253308
0.51
0.057574841
0.2932


hCV25474413
rs3822057
hCV3230007
rs4253311
0.51
0.057574841
0.312


hCV25474413
rs3822057
hCV3230011
rs4253320
0.51
0.057574841
0.2517


hCV25474413
rs3822057
hCV3230013
rs3775303
0.51
0.057574841
0.2992


hCV25474413
rs3822057
hCV3230014
rs4861709
0.51
0.057574841
0.1258


hCV25474413
rs3822057
hCV3230017
rs4253327
0.51
0.057574841
0.0594


hCV25474413
rs3822057
hCV3230018
rs925453
0.51
0.057574841
0.1356


hCV25474413
rs3822057
hCV3230019
rs4253332
0.51
0.057574841
0.1286


hCV25474413
rs3822057
hCV3230021
rs13135645
0.51
0.057574841
0.1443


hCV25474413
rs3822057
hCV3230022
rs11132383
0.51
0.057574841
0.1929


hCV25474413
rs3822057
hCV3230025
rs3756009
0.51
0.057574841
0.6037


hCV25474413
rs3822057
hCV3230030
rs4253408
0.51
0.057574841
0.0716


hCV25474413
rs3822057
hCV3230031
rs4253419
0.51
0.057574841
0.2386


hCV25474413
rs3822057
hCV3230032
rs5974
0.51
0.057574841
0.0838


hCV25474413
rs3822057
hCV3230038
rs2289252
0.51
0.057574841
0.4122


hCV25474413
rs3822057
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rs10013653
0.51
0.057574841
0.3369


hCV25474413
rs3822057
hCV3230084
rs7682918
0.51
0.057574841
0.2521


hCV25474413
rs3822057
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rs7687818
0.51
0.057574841
0.3057


hCV25474413
rs3822057
hCV3230096
rs3817184
0.51
0.057574841
0.2412


hCV25474413
rs3822057
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rs3736455
0.51
0.057574841
0.2152


hCV25474413
rs3822057
hCV3230101
rs6835839
0.51
0.057574841
0.0843


hCV25474413
rs3822057
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rs1473597
0.51
0.057574841
0.1509


hCV25474413
rs3822057
hCV3230110
rs2276917
0.51
0.057574841
0.1608


hCV25474413
rs3822057
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rs1053094
0.51
0.057574841
0.2648


hCV25474413
rs3822057
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rs4253429
0.51
0.057574841
0.2386


hCV25474413
rs3822057
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rs4253430
0.51
0.057574841
0.4654


hCV25474413
rs3822057
hCV3230121
rs4253431
0.51
0.057574841
0.0838


hCV25474413
rs3822057
hCV3230125
rs11938564
0.51
0.057574841
0.2911


hCV25474413
rs3822057
hCV3230131
rs13136269
0.51
0.057574841
0.3609


hCV25474413
rs3822057
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rs12511874
0.51
0.057574841
0.3083


hCV25474413
rs3822057
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rs12500151
0.51
0.057574841
0.3453


hCV25474413
rs3822057
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rs13116273
0.51
0.057574841
0.3534


hCV25474413
rs3822057
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rs4253248
0.51
0.057574841
0.3617


hCV25474413
rs3822057
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rs4862666
0.51
0.057574841
0.0873


hCV25474413
rs3822057
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rs4253239
0.51
0.057574841
0.1106


hCV25474413
rs3822057
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rs4253255
0.51
0.057574841
0.2992


hCV25474413
rs3822057
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rs4253256
0.51
0.057574841
0.1464


hCV25474413
rs3822057
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rs907439
0.51
0.057574841
0.1491


hCV25474413
rs3822057
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rs925451
0.51
0.057574841
0.596


hCV25474413
rs3822057
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rs1511802
0.51
0.057574841
0.3119


hCV25474413
rs3822057
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rs1511801
0.51
0.057574841
0.3142


hCV25474413
rs3822057
hCV8241633
rs1511800
0.51
0.057574841
0.0873


hCV25474413
rs3822057
hDV71222711
rs4253252
0.51
0.057574841
0.3617


hCV25597241
rs3782320
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rs2878772
0.51
0.904876352
1


hCV25597241
rs3782320
hCV27481297
rs3782318
0.51
0.904876352
1


hCV25597241
rs3782320
hDV70885868
rs17124174
0.51
0.904876352
1


hCV25597241
rs3782320
hDV70885870
rs17124176
0.51
0.904876352
1


hCV25610857
rs8176693
hCV11571465
rs2301612
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0.148365232
0.1634


hCV25610857
rs8176693
hCV11840510
rs9411367
0.51
0.148365232
0.4123


hCV25610857
rs8176693
hCV153353
rs7469576
0.51
0.148365232
0.4257


hCV25610857
rs8176693
hCV15862346
rs2073934
0.51
0.148365232
0.207


hCV25610857
rs8176693
hCV2535958
rs2519198
0.51
0.148365232
0.1685


hCV25610857
rs8176693
hCV25610771
rs8176751
0.51
0.148365232
0.8731


hCV25610857
rs8176693
hCV25610772
rs8176746
0.51
0.148365232
1


hCV25610857
rs8176693
hCV25610773
rs8176747
0.51
0.148365232
0.6839


hCV25610857
rs8176693
hCV25610781
rs8176749
0.51
0.148365232
1


hCV25610857
rs8176693
hCV25610791
rs8176743
0.51
0.148365232
1


hCV25610857
rs8176693
hCV25757025
rs2269894
0.51
0.148365232
0.1542


hCV25610857
rs8176693
hCV25987572
rs4310274
0.51
0.148365232
0.3888


hCV25610857
rs8176693
hCV26744892
rs11244079
0.51
0.148365232
0.8127


hCV25610857
rs8176693
hCV26744899
rs10751505
0.51
0.148365232
0.1768


hCV25610857
rs8176693
hCV27224736
rs2073870
0.51
0.148365232
0.3707


hCV25610857
rs8176693
hCV27224742
rs4454354
0.51
0.148365232
0.234


hCV25610857
rs8176693
hCV27224746
rs10793959
0.51
0.148365232
0.2969


hCV25610857
rs8176693
hCV27224748
rs4246169
0.51
0.148365232
0.3912


hCV25610857
rs8176693
hCV27224776
rs7852396
0.51
0.148365232
0.3577


hCV25610857
rs8176693
hCV27224778
rs11244041
0.51
0.148365232
0.3526


hCV25610857
rs8176693
hCV27478783
rs3761823
0.51
0.148365232
0.2233


hCV25610857
rs8176693
hCV27859399
rs7853989
0.51
0.148365232
0.817


hCV25610857
rs8176693
hCV27886018
rs4962104
0.51
0.148365232
0.2333


hCV25610857
rs8176693
hCV27936941
rs4379511
0.51
0.148365232
0.4056


hCV25610857
rs8176693
hCV27936942
rs4424335
0.51
0.148365232
0.7914


hCV25610857
rs8176693
hCV28002068
rs4322078
0.51
0.148365232
0.3912


hCV25610857
rs8176693
hCV29393501
rs4507838
0.51
0.148365232
0.4037


hCV25610857
rs8176693
hCV29393505
rs4962039
0.51
0.148365232
0.773


hCV25610857
rs8176693
hCV29393508
rs7046863
0.51
0.148365232
0.4262


hCV25610857
rs8176693
hCV29531061
rs9411464
0.51
0.148365232
0.6098


hCV25610857
rs8176693
hCV29549191
rs9411468
0.51
0.148365232
0.4483


hCV25610857
rs8176693
hCV29597378
rs8176672
0.51
0.148365232
1


hCV25610857
rs8176693
hCV29711974
rs7855466
0.51
0.148365232
0.4729


hCV25610857
rs8176693
hCV2980259
rs3761821
0.51
0.148365232
0.2969


hCV25610857
rs8176693
hCV30504633
rs9919007
0.51
0.148365232
0.4404


hCV25610857
rs8176693
hCV30613004
rs7855713
0.51
0.148365232
0.8222


hCV25610857
rs8176693
hCV3183094
rs8176731
0.51
0.148365232
0.1683


hCV25610857
rs8176693
hCV3183096
rs8176730
0.51
0.148365232
0.8013


hCV25610857
rs8176693
hCV3183097
rs8176725
0.51
0.148365232
0.802


hCV25610857
rs8176693
hCV3183099
rs8176722
0.51
0.148365232
0.8856


hCV25610857
rs8176693
hCV3183100
rs8176720
0.51
0.148365232
0.1485


hCV25610857
rs8176693
hCV3183111
rs643434
0.51
0.148365232
0.1634


hCV25610857
rs8176693
hCV3183117
rs545971
0.51
0.148365232
0.1765


hCV25610857
rs8176693
hCV3183164
rs529565
0.51
0.148365232
0.1765


hCV25610857
rs8176693
hCV3183246
rs10901263
0.51
0.148365232
0.2682


hCV25610857
rs8176693
hCV3183251
rs529309
0.51
0.148365232
0.1698


hCV25610857
rs8176693
hCV3183341
rs2285489
0.51
0.148365232
0.15


hCV25610857
rs8176693
hCV3183366
rs2073933
0.51
0.148365232
0.1731


hCV25610857
rs8176693
hCV32126435
rs11244034
0.51
0.148365232
0.3883


hCV25610857
rs8176693
hCV32126442
rs7864821
0.51
0.148365232
0.2969


hCV25610857
rs8176693
hCV32126443
rs10793957
0.51
0.148365232
0.2998


hCV25610857
rs8176693
hCV32126447
rs6597610
0.51
0.148365232
0.2969


hCV25610857
rs8176693
hCV32126454
rs13300535
0.51
0.148365232
0.2819


hCV25610857
rs8176693
hCV32126487
rs10901250
0.51
0.148365232
0.4799


hCV25610857
rs8176693
hCV442675
rs9411471
0.51
0.148365232
0.4262


hCV25610857
rs8176693
hCV7481808
rs886082
0.51
0.148365232
0.3072


hCV25610857
rs8176693
hCV7948166
rs9411463
0.51
0.148365232
0.8913


hCV25610857
rs8176693
hCV7948171
rs4246170
0.51
0.148365232
0.876


hCV25610857
rs8176693
hCV8784837
rs886090
0.51
0.148365232
0.1807


hCV25610857
rs8176693
hCV9326428
rs687289
0.51
0.148365232
0.1765


hCV25610857
rs8176693
hCV9326429
rs687621
0.51
0.148365232
0.1821


hCV25610857
rs8176693
hCV9327931
rs17150482
0.51
0.148365232
0.2489


hCV25610857
rs8176693
hCV997908
rs514659
0.51
0.148365232
0.175


hCV25610857
rs8176693
hCV997918
rs674302
0.51
0.148365232
0.1765


hCV25610857
rs8176693
hCV998010
rs493014
0.51
0.148365232
0.1498


hCV25610857
rs8176693
hDV72329597
rs28793911
0.51
0.148365232
0.1731


hCV25620145
rs867186
hCV11189166
rs11906318
0.51
0.329132176
1


hCV25620145
rs867186
hCV11189205
rs7261312
0.51
0.329132176
1


hCV25620145
rs867186
hCV1271665
rs17092456
0.51
0.329132176
1


hCV25620145
rs867186
hCV1348012
rs6060230
0.51
0.329132176
1


hCV25620145
rs867186
hCV1348016
rs6060246
0.51
0.329132176
1


hCV25620145
rs867186
hCV1348030
rs11908683
0.51
0.329132176
1


hCV25620145
rs867186
hCV1348034
rs2295888
0.51
0.329132176
1


hCV25620145
rs867186
hCV16189181
rs2295097
0.51
0.329132176
0.576


hCV25620145
rs867186
hCV1825062
rs6087685
0.51
0.329132176
0.3794


hCV25620145
rs867186
hCV25472481
rs2275274
0.51
0.329132176
0.5913


hCV25620145
rs867186
hCV25952685
rs17092297
0.51
0.329132176
1


hCV25620145
rs867186
hCV27167646
rs11699306
0.51
0.329132176
0.6217


hCV25620145
rs867186
hCV27167730
rs2889873
0.51
0.329132176
1


hCV25620145
rs867186
hCV29372789
rs7274866
0.51
0.329132176
1


hCV25620145
rs867186
hCV29372790
rs6579211
0.51
0.329132176
1


hCV25620145
rs867186
hCV29372796
rs7261167
0.51
0.329132176
1


hCV25620145
rs867186
hCV29373046
rs8119351
0.51
0.329132176
1


hCV25620145
rs867186
hCV29373059
rs8117847
0.51
0.329132176
1


hCV25620145
rs867186
hCV29729417
rs6060240
0.51
0.329132176
0.6395


hCV25620145
rs867186
hCV29765455
rs6058181
0.51
0.329132176
0.6863


hCV25620145
rs867186
hCV30180149
rs9941751
0.51
0.329132176
1


hCV25620145
rs867186
hCV30270043
rs6060257
0.51
0.329132176
0.8996


hCV25620145
rs867186
hCV30342001
rs10485508
0.51
0.329132176
1


hCV25620145
rs867186
hCV30342056
rs6060245
0.51
0.329132176
1


hCV25620145
rs867186
hCV30342057
rs6060239
0.51
0.329132176
0.6573


hCV25620145
rs867186
hCV30540318
rs6060244
0.51
0.329132176
1


hCV25620145
rs867186
hCV30576442
rs6120843
0.51
0.329132176
0.8996


hCV25620145
rs867186
hCV32066118
rs7271729
0.51
0.329132176
1


hCV25620145
rs867186
hCV32066123
rs7273734
0.51
0.329132176
1


hCV25620145
rs867186
hCV32066133
rs11906160
0.51
0.329132176
0.816


hCV25620145
rs867186
hCV32066684
rs11167260
0.51
0.329132176
1


hCV25620145
rs867186
hCV32066690
rs7265317
0.51
0.329132176
1


hCV25620145
rs867186
hCV32066710
rs11907010
0.51
0.329132176
1


hCV25620145
rs867186
hCV32066768
rs7263253
0.51
0.329132176
1


hCV25620145
rs867186
hCV624499
rs717593
0.51
0.329132176
1


hCV25620145
rs867186
hCV7593265
rs1033799
0.51
0.329132176
0.8996


hCV25620145
rs867186
hCV7593267
rs1033797
0.51
0.329132176
1


hCV25620145
rs867186
hDV70862590
rs17092215
0.51
0.329132176
1


hCV25620145
rs867186
hDV70936222
rs17309872
0.51
0.329132176
0.5774


hCV25620145
rs867186
hDV70936327
rs17310467
0.51
0.329132176
0.9424


hCV25620145
rs867186
hDV70948869
rs17401737
0.51
0.329132176
1


hCV25620145
rs867186
hDV70949473
rs17406518
0.51
0.329132176
0.709


hCV25620145
rs867186
hDV72054460
rs8117100
0.51
0.329132176
1


hCV25620145
rs867186
hDV75209987
rs2069940
0.51
0.329132176
0.9474


hCV25748719
hCV25748719
hCV11828144
rs11679975
0.51
0.912579748
1


hCV25748719
hCV25748719
hCV11828147
rs10496693
0.51
0.912579748
0.9529


hCV25748719
hCV25748719
hCV2163177
rs12618525
0.51
0.912579748
0.9518


hCV25748719
hCV25748719
hCV25749343
rs16841277
0.51
0.912579748
1


hCV25748719
hCV25748719
hCV3212676
rs4143562
0.51
0.912579748
1


hCV25748719
hCV25748719
hCV7479717
rs1367392
0.51
0.912579748
1


hCV25748719
hCV25748719
hDV70679361
rs16841210
0.51
0.912579748
1


hCV25990131
rs13146272
hCV11786147
rs4862662
0.51
0.143358157
0.4248


hCV25990131
rs13146272
hCV11786258
rs4253303
0.51
0.143358157
0.3213


hCV25990131
rs13146272
hCV11786259
rs4253304
0.51
0.143358157
0.2413


hCV25990131
rs13146272
hCV12066116
rs1877320
0.51
0.143358157
0.1908


hCV25990131
rs13146272
hCV12066118
rs2048
0.51
0.143358157
0.1915


hCV25990131
rs13146272
hCV12066119
rs1912826
0.51
0.143358157
0.1697


hCV25990131
rs13146272
hCV12066124
rs2036914
0.51
0.143358157
0.1776


hCV25990131
rs13146272
hCV12066129
rs1593
0.51
0.143358157
0.1539


hCV25990131
rs13146272
hCV15793897
rs3087505
0.51
0.143358157
0.1528


hCV25990131
rs13146272
hCV15811716
rs2102575
0.51
0.143358157
0.144


hCV25990131
rs13146272
hCV15882886
rs2276916
0.51
0.143358157
0.1604


hCV25990131
rs13146272
hCV15968025
rs2292425
0.51
0.143358157
1


hCV25990131
rs13146272
hCV15968026
rs2292426
0.51
0.143358157
0.8904


hCV25990131
rs13146272
hCV15968043
rs2292423
0.51
0.143358157
0.2261


hCV25990131
rs13146272
hCV15975109
rs2304596
0.51
0.143358157
0.3895


hCV25990131
rs13146272
hCV2103343
rs4241824
0.51
0.143358157
0.1563


hCV25990131
rs13146272
hCV2103392
rs12500826
0.51
0.143358157
0.1597


hCV25990131
rs13146272
hCV22272267
rs3733402
0.51
0.143358157
0.1915


hCV25990131
rs13146272
hCV25474413
rs3822057
0.51
0.143358157
0.1706


hCV25990131
rs13146272
hCV25988221
rs9995366
0.51
0.143358157
0.1617


hCV25990131
rs13146272
hCV25989001
hCV25989001
0.51
0.143358157
0.3491


hCV25990131
rs13146272
hCV26265231
rs7684025
0.51
0.143358157
0.3297


hCV25990131
rs13146272
hCV27477533
rs3756008
0.51
0.143358157
0.1634


hCV25990131
rs13146272
hCV27482765
rs3775301
0.51
0.143358157
0.3895


hCV25990131
rs13146272
hCV27902803
rs4862665
0.51
0.143358157
0.1617


hCV25990131
rs13146272
hCV27902808
rs4253236
0.51
0.143358157
0.3974


hCV25990131
rs13146272
hCV28960679
rs6844764
0.51
0.143358157
0.1752


hCV25990131
rs13146272
hCV29053261
rs6842047
0.51
0.143358157
0.1528


hCV25990131
rs13146272
hCV29053264
rs7667777
0.51
0.143358157
0.4279


hCV25990131
rs13146272
hCV29053265
rs4253244
0.51
0.143358157
0.3445


hCV25990131
rs13146272
hCV29053266
rs7687961
0.51
0.143358157
0.2979


hCV25990131
rs13146272
hCV29718000
rs4253238
0.51
0.143358157
0.2008


hCV25990131
rs13146272
hCV29826351
rs10025990
0.51
0.143358157
0.1633


hCV25990131
rs13146272
hCV29877725
rs4253295
0.51
0.143358157
0.3626


hCV25990131
rs13146272
hCV30492573
rs10471184
0.51
0.143358157
0.1528


hCV25990131
rs13146272
hCV30983902
rs4862668
0.51
0.143358157
0.1908


hCV25990131
rs13146272
hCV30983927
rs6552962
0.51
0.143358157
0.3677


hCV25990131
rs13146272
hCV32209815
rs7660915
0.51
0.143358157
0.1573


hCV25990131
rs13146272
hCV32291217
rs4253323
0.51
0.143358157
0.3895


hCV25990131
rs13146272
hCV32291295
rs4253292
0.51
0.143358157
0.4332


hCV25990131
rs13146272
hCV32291301
rs4253302
0.51
0.143358157
0.3944


hCV25990131
rs13146272
hCV32295028
rs4253260
0.51
0.143358157
0.3895


hCV25990131
rs13146272
hCV3229991
rs4241815
0.51
0.143358157
0.1915


hCV25990131
rs13146272
hCV3229992
rs3775298
0.51
0.143358157
0.1915


hCV25990131
rs13146272
hCV3229995
rs11132382
0.51
0.143358157
0.1909


hCV25990131
rs13146272
hCV3230002
rs4253297
0.51
0.143358157
0.3314


hCV25990131
rs13146272
hCV3230003
rs2304595
0.51
0.143358157
0.2642


hCV25990131
rs13146272
hCV3230006
rs4253308
0.51
0.143358157
0.3626


hCV25990131
rs13146272
hCV3230007
rs4253311
0.51
0.143358157
0.1915


hCV25990131
rs13146272
hCV3230011
rs4253320
0.51
0.143358157
0.3314


hCV25990131
rs13146272
hCV3230013
rs3775303
0.51
0.143358157
0.2413


hCV25990131
rs13146272
hCV3230025
rs3756009
0.51
0.143358157
0.2436


hCV25990131
rs13146272
hCV3230083
rs10013653
0.51
0.143358157
0.3137


hCV25990131
rs13146272
hCV3230084
rs7682918
0.51
0.143358157
0.4336


hCV25990131
rs13146272
hCV3230094
rs7687818
0.51
0.143358157
0.3187


hCV25990131
rs13146272
hCV3230096
rs3817184
0.51
0.143358157
0.4248


hCV25990131
rs13146272
hCV3230097
rs3736455
0.51
0.143358157
0.8444


hCV25990131
rs13146272
hCV3230113
rs1053094
0.51
0.143358157
0.1593


hCV25990131
rs13146272
hCV32313006
rs4253248
0.51
0.143358157
0.1954


hCV25990131
rs13146272
hCV32313007
rs4862666
0.51
0.143358157
0.1617


hCV25990131
rs13146272
hCV32313024
rs4253239
0.51
0.143358157
0.4332


hCV25990131
rs13146272
hCV32358975
rs4253255
0.51
0.143358157
0.1791


hCV25990131
rs13146272
hCV32358984
rs4253256
0.51
0.143358157
0.3717


hCV25990131
rs13146272
hCV8241630
rs925451
0.51
0.143358157
0.1564


hCV25990131
rs13146272
hCV8241631
rs1511802
0.51
0.143358157
0.3665


hCV25990131
rs13146272
hCV8241632
rs1511801
0.51
0.143358157
0.193


hCV25990131
rs13146272
hCV8241633
rs1511800
0.51
0.143358157
0.1617


hCV25990131
rs13146272
hDV71222711
rs4253252
0.51
0.143358157
0.1954


hCV25990131
rs13146272
hDV76175111
rs35079309
0.51
0.143358157
0.1697


hCV263841
rs1523127
hCV105917
rs9289134
0.51
0.401557164
0.4905


hCV263841
rs1523127
hCV11230788
rs7643038
0.51
0.401557164
1


hCV263841
rs1523127
hCV134275
rs9847068
0.51
0.401557164
0.4525


hCV263841
rs1523127
hCV134278
rs9848716
0.51
0.401557164
0.4627


hCV263841
rs1523127
hCV15882316
rs2276706
0.51
0.401557164
1


hCV263841
rs1523127
hCV178227
rs13070374
0.51
0.401557164
0.5348


hCV263841
rs1523127
hCV178228
rs4687882
0.51
0.401557164
0.5054


hCV263841
rs1523127
hCV1833991
rs11926554
0.51
0.401557164
0.5461


hCV263841
rs1523127
hCV1834237
rs9865270
0.51
0.401557164
0.4905


hCV263841
rs1523127
hCV1834240
rs1581451
0.51
0.401557164
1


hCV263841
rs1523127
hCV1834242
rs11712308
0.51
0.401557164
0.4291


hCV263841
rs1523127
hCV1834243
rs9682652
0.51
0.401557164
0.5871


hCV263841
rs1523127
hCV1834252
rs10934498
0.51
0.401557164
0.9212


hCV263841
rs1523127
hCV1834256
rs2472662
0.51
0.401557164
0.4402


hCV263841
rs1523127
hCV1834260
rs4688033
0.51
0.401557164
0.5676


hCV263841
rs1523127
hCV192027
rs9821892
0.51
0.401557164
0.5871


hCV263841
rs1523127
hCV255886
rs10511394
0.51
0.401557164
0.569


hCV263841
rs1523127
hCV27504984
rs3814055
0.51
0.401557164
1


hCV263841
rs1523127
hCV278948
rs1464599
0.51
0.401557164
0.569


hCV263841
rs1523127
hCV29841665
rs7623217
0.51
0.401557164
0.5802


hCV263841
rs1523127
hCV30562884
rs9815093
0.51
0.401557164
0.4905


hCV263841
rs1523127
hCV30699687
rs11711386
0.51
0.401557164
0.4402


hCV263841
rs1523127
hCV30747432
rs12488820
0.51
0.401557164
0.9212


hCV263841
rs1523127
hCV9152783
rs1523130
0.51
0.401557164
0.9003


hCV27474895
rs3756011
hCV11786147
rs4862662
0.51
0.046522553
0.1651


hCV27474895
rs3756011
hCV11786235
rs4253287
0.51
0.046522553
0.096


hCV27474895
rs3756011
hCV11786258
rs4253303
0.51
0.046522553
0.1518


hCV27474895
rs3756011
hCV11786259
rs4253304
0.51
0.046522553
0.2126


hCV27474895
rs3756011
hCV11786295
rs4253421
0.51
0.046522553
0.0964


hCV27474895
rs3756011
hCV11786301
rs5970
0.51
0.046522553
0.0964


hCV27474895
rs3756011
hCV11786307
rs1062547
0.51
0.046522553
0.3474


hCV27474895
rs3756011
hCV11786311
rs13145616
0.51
0.046522553
0.0964


hCV27474895
rs3756011
hCV11786327
rs13133050
0.51
0.046522553
0.2195


hCV27474895
rs3756011
hCV12066116
rs1877320
0.51
0.046522553
0.0698


hCV27474895
rs3756011
hCV12066118
rs2048
0.51
0.046522553
0.0958


hCV27474895
rs3756011
hCV12066119
rs1912826
0.51
0.046522553
0.1115


hCV27474895
rs3756011
hCV12066124
rs2036914
0.51
0.046522553
0.4851


hCV27474895
rs3756011
hCV12066129
rs1593
0.51
0.046522553
0.0705


hCV27474895
rs3756011
hCV1333076
rs7656944
0.51
0.046522553
0.0488


hCV27474895
rs3756011
hCV1333077
rs7656763
0.51
0.046522553
0.0488


hCV27474895
rs3756011
hCV1333078
rs9998003
0.51
0.046522553
0.0625


hCV27474895
rs3756011
hCV1333102
rs10016252
0.51
0.046522553
0.0488


hCV27474895
rs3756011
hCV15793897
rs3087505
0.51
0.046522553
0.0748


hCV27474895
rs3756011
hCV15811716
rs2102575
0.51
0.046522553
0.0679


hCV27474895
rs3756011
hCV15880920
rs2289253
0.51
0.046522553
0.0479


hCV27474895
rs3756011
hCV15968025
rs2292425
0.51
0.046522553
0.138


hCV27474895
rs3756011
hCV15968026
rs2292426
0.51
0.046522553
0.1681


hCV27474895
rs3756011
hCV15968043
rs2292423
0.51
0.046522553
0.1967


hCV27474895
rs3756011
hCV16172925
rs2241818
0.51
0.046522553
0.095


hCV27474895
rs3756011
hCV16172935
rs2241817
0.51
0.046522553
0.3529


hCV27474895
rs3756011
hCV194962
rs6552954
0.51
0.046522553
0.0471


hCV27474895
rs3756011
hCV2103343
rs4241824
0.51
0.046522553
0.5177


hCV27474895
rs3756011
hCV2103388
rs4613610
0.51
0.046522553
0.1053


hCV27474895
rs3756011
hCV2103391
rs1008728
0.51
0.046522553
0.3064


hCV27474895
rs3756011
hCV2103392
rs12500826
0.51
0.046522553
0.286


hCV27474895
rs3756011
hCV22272267
rs3733402
0.51
0.046522553
0.0893


hCV27474895
rs3756011
hCV25474413
rs3822057
0.51
0.046522553
0.5232


hCV27474895
rs3756011
hCV25474414
rs4253399
0.51
0.046522553
0.7565


hCV27474895
rs3756011
hCV25634754
rs4253331
0.51
0.046522553
0.0475


hCV27474895
rs3756011
hCV25988221
rs9995366
0.51
0.046522553
0.0748


hCV27474895
rs3756011
hCV25990131
rs13146272
0.51
0.046522553
0.1401


hCV27474895
rs3756011
hCV26038139
rs4253405
0.51
0.046522553
0.2975


hCV27474895
rs3756011
hCV26265231
rs7684025
0.51
0.046522553
0.2227


hCV27474895
rs3756011
hCV27309991
rs4572916
0.51
0.046522553
0.1096


hCV27474895
rs3756011
hCV27473099
rs3733403
0.51
0.046522553
0.0591


hCV27474895
rs3756011
hCV27477533
rs3756008
0.51
0.046522553
0.7565


hCV27474895
rs3756011
hCV27490984
rs3822058
0.51
0.046522553
0.3739


hCV27474895
rs3756011
hCV27902803
rs4862665
0.51
0.046522553
0.0748


hCV27474895
rs3756011
hCV27902808
rs4253236
0.51
0.046522553
0.0489


hCV27474895
rs3756011
hCV28960679
rs6844764
0.51
0.046522553
0.1341


hCV27474895
rs3756011
hCV29053261
rs6842047
0.51
0.046522553
0.0748


hCV27474895
rs3756011
hCV29053264
rs7667777
0.51
0.046522553
0.1527


hCV27474895
rs3756011
hCV29053266
rs7687961
0.51
0.046522553
0.0784


hCV27474895
rs3756011
hCV29640635
rs10029715
0.51
0.046522553
0.1232


hCV27474895
rs3756011
hCV29718000
rs4253238
0.51
0.046522553
0.1192


hCV27474895
rs3756011
hCV29826351
rs10025990
0.51
0.046522553
0.078


hCV27474895
rs3756011
hCV29877725
rs4253295
0.51
0.046522553
0.2015


hCV27474895
rs3756011
hCV30307525
rs10025152
0.51
0.046522553
0.1232


hCV27474895
rs3756011
hCV30492573
rs10471184
0.51
0.046522553
0.0748


hCV27474895
rs3756011
hCV30562347
rs4253418
0.51
0.046522553
0.0479


hCV27474895
rs3756011
hCV30983902
rs4862668
0.51
0.046522553
0.0667


hCV27474895
rs3756011
hCV30983927
rs6552962
0.51
0.046522553
0.0811


hCV27474895
rs3756011
hCV32209629
rs12715865
0.51
0.046522553
0.1297


hCV27474895
rs3756011
hCV32209635
rs6848311
0.51
0.046522553
0.1065


hCV27474895
rs3756011
hCV32209636
rs11132387
0.51
0.046522553
0.44


hCV27474895
rs3756011
hCV32209637
rs13143773
0.51
0.046522553
0.2103


hCV27474895
rs3756011
hCV32209638
rs12507040
0.51
0.046522553
0.2952


hCV27474895
rs3756011
hCV32291256
rs4253406
0.51
0.046522553
0.0719


hCV27474895
rs3756011
hCV32291269
rs4253417
0.51
0.046522553
0.9279


hCV27474895
rs3756011
hCV32291286
rs4253422
0.51
0.046522553
0.1355


hCV27474895
rs3756011
hCV32291287
rs4253423
0.51
0.046522553
0.1355


hCV27474895
rs3756011
hCV3229991
rs4241815
0.51
0.046522553
0.0893


hCV27474895
rs3756011
hCV3229992
rs3775298
0.51
0.046522553
0.0893


hCV27474895
rs3756011
hCV3229995
rs11132382
0.51
0.046522553
0.1192


hCV27474895
rs3756011
hCV3230002
rs4253297
0.51
0.046522553
0.1602


hCV27474895
rs3756011
hCV3230003
rs2304595
0.51
0.046522553
0.2636


hCV27474895
rs3756011
hCV3230006
rs4253308
0.51
0.046522553
0.2015


hCV27474895
rs3756011
hCV3230007
rs4253311
0.51
0.046522553
0.0893


hCV27474895
rs3756011
hCV3230010
rs4253315
0.51
0.046522553
0.0729


hCV27474895
rs3756011
hCV3230011
rs4253320
0.51
0.046522553
0.1602


hCV27474895
rs3756011
hCV3230013
rs3775303
0.51
0.046522553
0.2126


hCV27474895
rs3756011
hCV3230016
rs4253325
0.51
0.046522553
0.0964


hCV27474895
rs3756011
hCV3230017
rs4253327
0.51
0.046522553
0.0647


hCV27474895
rs3756011
hCV3230021
rs13135645
0.51
0.046522553
0.0602


hCV27474895
rs3756011
hCV3230022
rs11132383
0.51
0.046522553
0.1964


hCV27474895
rs3756011
hCV3230025
rs3756009
0.51
0.046522553
0.8008


hCV27474895
rs3756011
hCV3230030
rs4253408
0.51
0.046522553
0.0889


hCV27474895
rs3756011
hCV3230031
rs4253419
0.51
0.046522553
0.1355


hCV27474895
rs3756011
hCV3230032
rs5974
0.51
0.046522553
0.0964


hCV27474895
rs3756011
hCV3230038
rs2289252
0.51
0.046522553
1


hCV27474895
rs3756011
hCV3230083
rs10013653
0.51
0.046522553
0.2455


hCV27474895
rs3756011
hCV3230084
rs7682918
0.51
0.046522553
0.1899


hCV27474895
rs3756011
hCV3230094
rs7687818
0.51
0.046522553
0.2475


hCV27474895
rs3756011
hCV3230096
rs3817184
0.51
0.046522553
0.1852


hCV27474895
rs3756011
hCV3230097
rs3736455
0.51
0.046522553
0.181


hCV27474895
rs3756011
hCV3230113
rs1053094
0.51
0.046522553
0.1126


hCV27474895
rs3756011
hCV3230118
rs4253429
0.51
0.046522553
0.1355


hCV27474895
rs3756011
hCV3230119
rs4253430
0.51
0.046522553
0.3739


hCV27474895
rs3756011
hCV3230121
rs4253431
0.51
0.046522553
0.0964


hCV27474895
rs3756011
hCV3230125
rs11938564
0.51
0.046522553
0.198


hCV27474895
rs3756011
hCV3230131
rs13136269
0.51
0.046522553
0.2952


hCV27474895
rs3756011
hCV3230133
rs12511874
0.51
0.046522553
0.2952


hCV27474895
rs3756011
hCV3230134
rs12500151
0.51
0.046522553
0.2952


hCV27474895
rs3756011
hCV3230136
rs13116273
0.51
0.046522553
0.2675


hCV27474895
rs3756011
hCV32313006
rs4253248
0.51
0.046522553
0.1192


hCV27474895
rs3756011
hCV32313007
rs4862666
0.51
0.046522553
0.0748


hCV27474895
rs3756011
hCV32313014
rs4253243
0.51
0.046522553
0.0475


hCV27474895
rs3756011
hCV32358975
rs4253255
0.51
0.046522553
0.0845


hCV27474895
rs3756011
hCV8241628
rs907439
0.51
0.046522553
0.1096


hCV27474895
rs3756011
hCV8241630
rs925451
0.51
0.046522553
0.7876


hCV27474895
rs3756011
hCV8241631
rs1511802
0.51
0.046522553
0.2015


hCV27474895
rs3756011
hCV8241632
rs1511801
0.51
0.046522553
0.083


hCV27474895
rs3756011
hCV8241633
rs1511800
0.51
0.046522553
0.0748


hCV27474895
rs3756011
hCV8241668
rs1401570
0.51
0.046522553
0.0565


hCV27474895
rs3756011
hDV68550952
rs4253289
0.51
0.046522553
0.0624


hCV27474895
rs3756011
hDV71222711
rs4253252
0.51
0.046522553
0.1192


hCV27474984
rs3756668
hCV11824867
rs256507
0.51
0.529595036
0.7675


hCV27474984
rs3756668
hCV1988068
rs1445760
0.51
0.529595036
0.7246


hCV27474984
rs3756668
hCV3164046
rs9291926
0.51
0.529595036
0.8067


hCV27474984
rs3756668
hCV3164066
rs34292
0.51
0.529595036
0.7511


hCV27474984
rs3756668
hCV977979
rs256508
0.51
0.529595036
0.751


hCV27477533
rs3756008
hCV11786147
rs4862662
0.51
0.052089996
0.2067


hCV27477533
rs3756008
hCV11786235
rs4253287
0.51
0.052089996
0.09


hCV27477533
rs3756008
hCV11786258
rs4253303
0.51
0.052089996
0.315


hCV27477533
rs3756008
hCV11786259
rs4253304
0.51
0.052089996
0.3791


hCV27477533
rs3756008
hCV11786295
rs4253421
0.51
0.052089996
0.0524


hCV27477533
rs3756008
hCV11786307
rs1062547
0.51
0.052089996
0.273


hCV27477533
rs3756008
hCV11786327
rs13133050
0.51
0.052089996
0.1451


hCV27477533
rs3756008
hCV12066116
rs1877320
0.51
0.052089996
0.0836


hCV27477533
rs3756008
hCV12066118
rs2048
0.51
0.052089996
0.1524


hCV27477533
rs3756008
hCV12066119
rs1912826
0.51
0.052089996
0.1565


hCV27477533
rs3756008
hCV12066124
rs2036914
0.51
0.052089996
0.5443


hCV27477533
rs3756008
hCV12066129
rs1593
0.51
0.052089996
0.0893


hCV27477533
rs3756008
hCV1333090
rs6816112
0.51
0.052089996
0.0736


hCV27477533
rs3756008
hCV1333099
rs10020635
0.51
0.052089996
0.0654


hCV27477533
rs3756008
hCV15793897
rs3087505
0.51
0.052089996
0.0633


hCV27477533
rs3756008
hCV15811716
rs2102575
0.51
0.052089996
0.0597


hCV27477533
rs3756008
hCV15968025
rs2292425
0.51
0.052089996
0.156


hCV27477533
rs3756008
hCV15968026
rs2292426
0.51
0.052089996
0.2168


hCV27477533
rs3756008
hCV15968034
rs2292428
0.51
0.052089996
0.1109


hCV27477533
rs3756008
hCV15968043
rs2292423
0.51
0.052089996
0.3624


hCV27477533
rs3756008
hCV16172925
rs2241818
0.51
0.052089996
0.0782


hCV27477533
rs3756008
hCV16172935
rs2241817
0.51
0.052089996
0.2699


hCV27477533
rs3756008
hCV2103343
rs4241824
0.51
0.052089996
0.5858


hCV27477533
rs3756008
hCV2103348
rs11931515
0.51
0.052089996
0.0563


hCV27477533
rs3756008
hCV2103388
rs4613610
0.51
0.052089996
0.0953


hCV27477533
rs3756008
hCV2103391
rs1008728
0.51
0.052089996
0.1778


hCV27477533
rs3756008
hCV2103392
rs12500826
0.51
0.052089996
0.3498


hCV27477533
rs3756008
hCV22272267
rs3733402
0.51
0.052089996
0.1577


hCV27477533
rs3756008
hCV25474413
rs3822057
0.51
0.052089996
0.577


hCV27477533
rs3756008
hCV25474414
rs4253399
0.51
0.052089996
0.9414


hCV27477533
rs3756008
hCV25634754
rs4253331
0.51
0.052089996
0.1183


hCV27477533
rs3756008
hCV25988221
rs9995366
0.51
0.052089996
0.067


hCV27477533
rs3756008
hCV25990131
rs13146272
0.51
0.052089996
0.1634


hCV27477533
rs3756008
hCV26038139
rs4253405
0.51
0.052089996
0.3634


hCV27477533
rs3756008
hCV26265231
rs7684025
0.51
0.052089996
0.2597


hCV27477533
rs3756008
hCV27309972
rs13101296
0.51
0.052089996
0.1249


hCV27477533
rs3756008
hCV27309991
rs4572916
0.51
0.052089996
0.1028


hCV27477533
rs3756008
hCV27473099
rs3733403
0.51
0.052089996
0.081


hCV27477533
rs3756008
hCV27474895
rs3756011
0.51
0.052089996
0.7565


hCV27477533
rs3756008
hCV27490984
rs3822058
0.51
0.052089996
0.2804


hCV27477533
rs3756008
hCV27521729
rs3822056
0.51
0.052089996
0.0979


hCV27477533
rs3756008
hCV27902803
rs4862665
0.51
0.052089996
0.067


hCV27477533
rs3756008
hCV27902808
rs4253236
0.51
0.052089996
0.0524


hCV27477533
rs3756008
hCV28960679
rs6844764
0.51
0.052089996
0.1972


hCV27477533
rs3756008
hCV29053261
rs6842047
0.51
0.052089996
0.0633


hCV27477533
rs3756008
hCV29053264
rs7667777
0.51
0.052089996
0.2846


hCV27477533
rs3756008
hCV29053265
rs4253244
0.51
0.052089996
0.0589


hCV27477533
rs3756008
hCV29718000
rs4253238
0.51
0.052089996
0.1722


hCV27477533
rs3756008
hCV29826351
rs10025990
0.51
0.052089996
0.0992


hCV27477533
rs3756008
hCV29877725
rs4253295
0.51
0.052089996
0.248


hCV27477533
rs3756008
hCV30492573
rs10471184
0.51
0.052089996
0.0633


hCV27477533
rs3756008
hCV30983902
rs4862668
0.51
0.052089996
0.0836


hCV27477533
rs3756008
hCV30983927
rs6552962
0.51
0.052089996
0.0937


hCV27477533
rs3756008
hCV32209629
rs12715865
0.51
0.052089996
0.1094


hCV27477533
rs3756008
hCV32209636
rs11132387
0.51
0.052089996
0.3591


hCV27477533
rs3756008
hCV32209637
rs13143773
0.51
0.052089996
0.1889


hCV27477533
rs3756008
hCV32209638
rs12507040
0.51
0.052089996
0.19


hCV27477533
rs3756008
hCV32291256
rs4253406
0.51
0.052089996
0.1099


hCV27477533
rs3756008
hCV32291269
rs4253417
0.51
0.052089996
0.7459


hCV27477533
rs3756008
hCV32291286
rs4253422
0.51
0.052089996
0.145


hCV27477533
rs3756008
hCV32291287
rs4253423
0.51
0.052089996
0.145


hCV27477533
rs3756008
hCV32291295
rs4253292
0.51
0.052089996
0.0659


hCV27477533
rs3756008
hCV3229991
rs4241815
0.51
0.052089996
0.1577


hCV27477533
rs3756008
hCV3229992
rs3775298
0.51
0.052089996
0.1577


hCV27477533
rs3756008
hCV3229995
rs11132382
0.51
0.052089996
0.1702


hCV27477533
rs3756008
hCV3230000
rs4253294
0.51
0.052089996
0.0691


hCV27477533
rs3756008
hCV3230002
rs4253297
0.51
0.052089996
0.3082


hCV27477533
rs3756008
hCV3230003
rs2304595
0.51
0.052089996
0.3373


hCV27477533
rs3756008
hCV3230004
rs4253301
0.51
0.052089996
0.0562


hCV27477533
rs3756008
hCV3230006
rs4253308
0.51
0.052089996
0.248


hCV27477533
rs3756008
hCV3230007
rs4253311
0.51
0.052089996
0.1577


hCV27477533
rs3756008
hCV3230010
rs4253315
0.51
0.052089996
0.0836


hCV27477533
rs3756008
hCV3230011
rs4253320
0.51
0.052089996
0.3082


hCV27477533
rs3756008
hCV3230013
rs3775303
0.51
0.052089996
0.3791


hCV27477533
rs3756008
hCV3230014
rs4861709
0.51
0.052089996
0.0691


hCV27477533
rs3756008
hCV3230016
rs4253325
0.51
0.052089996
0.0821


hCV27477533
rs3756008
hCV3230017
rs4253327
0.51
0.052089996
0.117


hCV27477533
rs3756008
hCV3230018
rs925453
0.51
0.052089996
0.0596


hCV27477533
rs3756008
hCV3230019
rs4253332
0.51
0.052089996
0.0555


hCV27477533
rs3756008
hCV3230021
rs13135645
0.51
0.052089996
0.0833


hCV27477533
rs3756008
hCV3230022
rs11132383
0.51
0.052089996
0.3776


hCV27477533
rs3756008
hCV3230025
rs3756009
0.51
0.052089996
1


hCV27477533
rs3756008
hCV3230030
rs4253408
0.51
0.052089996
0.1104


hCV27477533
rs3756008
hCV3230031
rs4253419
0.51
0.052089996
0.145


hCV27477533
rs3756008
hCV3230038
rs2289252
0.51
0.052089996
0.7249


hCV27477533
rs3756008
hCV3230051
rs4862658
0.51
0.052089996
0.0568


hCV27477533
rs3756008
hCV3230083
rs10013653
0.51
0.052089996
0.3055


hCV27477533
rs3756008
hCV3230084
rs7682918
0.51
0.052089996
0.2208


hCV27477533
rs3756008
hCV3230094
rs7687818
0.51
0.052089996
0.3169


hCV27477533
rs3756008
hCV3230096
rs3817184
0.51
0.052089996
0.2279


hCV27477533
rs3756008
hCV3230097
rs3736455
0.51
0.052089996
0.2223


hCV27477533
rs3756008
hCV3230101
rs6835839
0.51
0.052089996
0.0923


hCV27477533
rs3756008
hCV3230106
rs1473597
0.51
0.052089996
0.1308


hCV27477533
rs3756008
hCV3230110
rs2276917
0.51
0.052089996
0.1218


hCV27477533
rs3756008
hCV3230113
rs1053094
0.51
0.052089996
0.2208


hCV27477533
rs3756008
hCV3230118
rs4253429
0.51
0.052089996
0.145


hCV27477533
rs3756008
hCV3230119
rs4253430
0.51
0.052089996
0.2733


hCV27477533
rs3756008
hCV3230125
rs11938564
0.51
0.052089996
0.1934


hCV27477533
rs3756008
hCV3230131
rs13136269
0.51
0.052089996
0.19


hCV27477533
rs3756008
hCV3230133
rs12511874
0.51
0.052089996
0.1373


hCV27477533
rs3756008
hCV3230134
rs12500151
0.51
0.052089996
0.196


hCV27477533
rs3756008
hCV3230136
rs13116273
0.51
0.052089996
0.1995


hCV27477533
rs3756008
hCV32313006
rs4253248
0.51
0.052089996
0.1794


hCV27477533
rs3756008
hCV32313007
rs4862666
0.51
0.052089996
0.067


hCV27477533
rs3756008
hCV32313014
rs4253243
0.51
0.052089996
0.1183


hCV27477533
rs3756008
hCV32313024
rs4253239
0.51
0.052089996
0.0659


hCV27477533
rs3756008
hCV32358975
rs4253255
0.51
0.052089996
0.1561


hCV27477533
rs3756008
hCV32358984
rs4253256
0.51
0.052089996
0.0676


hCV27477533
rs3756008
hCV8241628
rs907439
0.51
0.052089996
0.1028


hCV27477533
rs3756008
hCV8241630
rs925451
0.51
0.052089996
0.9804


hCV27477533
rs3756008
hCV8241631
rs1511802
0.51
0.052089996
0.265


hCV27477533
rs3756008
hCV8241632
rs1511801
0.51
0.052089996
0.1877


hCV27477533
rs3756008
hCV8241633
rs1511800
0.51
0.052089996
0.067


hCV27477533
rs3756008
hDV68550952
rs4253289
0.51
0.052089996
0.0687


hCV27477533
rs3756008
hDV71222711
rs4253252
0.51
0.052089996
0.1794


hCV27859399
rs7853989
hCV11840510
rs9411367
0.51
0.17565711
0.389


hCV27859399
rs7853989
hCV153353
rs7469576
0.51
0.17565711
0.4123


hCV27859399
rs7853989
hCV16199728
rs3025336
0.51
0.17565711
0.1833


hCV27859399
rs7853989
hCV25610771
rs8176751
0.51
0.17565711
1


hCV27859399
rs7853989
hCV25610772
rs8176746
0.51
0.17565711
0.817


hCV27859399
rs7853989
hCV25610773
rs8176747
0.51
0.17565711
0.6864


hCV27859399
rs7853989
hCV25610781
rs8176749
0.51
0.17565711
0.817


hCV27859399
rs7853989
hCV25610791
rs8176743
0.51
0.17565711
0.8167


hCV27859399
rs7853989
hCV25610857
rs8176693
0.51
0.17565711
0.817


hCV27859399
rs7853989
hCV25987572
rs4310274
0.51
0.17565711
0.297


hCV27859399
rs7853989
hCV26744892
rs11244079
0.51
0.17565711
0.6338


hCV27859399
rs7853989
hCV27224736
rs2073870
0.51
0.17565711
0.297


hCV27859399
rs7853989
hCV27224742
rs4454354
0.51
0.17565711
0.2157


hCV27859399
rs7853989
hCV27224746
rs10793959
0.51
0.17565711
0.2143


hCV27859399
rs7853989
hCV27224748
rs4246169
0.51
0.17565711
0.3057


hCV27859399
rs7853989
hCV27224776
rs7852396
0.51
0.17565711
0.3126


hCV27859399
rs7853989
hCV27224778
rs11244041
0.51
0.17565711
0.2967


hCV27859399
rs7853989
hCV27478783
rs3761823
0.51
0.17565711
0.2284


hCV27859399
rs7853989
hCV27886018
rs4962104
0.51
0.17565711
0.2137


hCV27859399
rs7853989
hCV27936941
rs4379511
0.51
0.17565711
0.2938


hCV27859399
rs7853989
hCV27936942
rs4424335
0.51
0.17565711
0.7126


hCV27859399
rs7853989
hCV28002068
rs4322078
0.51
0.17565711
0.3057


hCV27859399
rs7853989
hCV29393501
rs4507838
0.51
0.17565711
0.2887


hCV27859399
rs7853989
hCV29393505
rs4962039
0.51
0.17565711
0.5726


hCV27859399
rs7853989
hCV29393508
rs7046863
0.51
0.17565711
0.4137


hCV27859399
rs7853989
hCV29531061
rs9411464
0.51
0.17565711
0.6331


hCV27859399
rs7853989
hCV29549191
rs9411468
0.51
0.17565711
0.4432


hCV27859399
rs7853989
hCV29597378
rs8176672
0.51
0.17565711
0.817


hCV27859399
rs7853989
hCV29711974
rs7855466
0.51
0.17565711
0.3655


hCV27859399
rs7853989
hCV2980259
rs3761821
0.51
0.17565711
0.2256


hCV27859399
rs7853989
hCV30504633
rs9919007
0.51
0.17565711
0.4396


hCV27859399
rs7853989
hCV30613004
rs7855713
0.51
0.17565711
0.6426


hCV27859399
rs7853989
hCV3183094
rs8176731
0.51
0.17565711
0.1975


hCV27859399
rs7853989
hCV3183096
rs8176730
0.51
0.17565711
1


hCV27859399
rs7853989
hCV3183097
rs8176725
0.51
0.17565711
1


hCV27859399
rs7853989
hCV3183098
rs2073824
0.51
0.17565711
0.1773


hCV27859399
rs7853989
hCV3183099
rs8176722
0.51
0.17565711
1


hCV27859399
rs7853989
hCV3183100
rs8176720
0.51
0.17565711
0.2078


hCV27859399
rs7853989
hCV3183111
rs643434
0.51
0.17565711
0.1852


hCV27859399
rs7853989
hCV3183246
rs10901263
0.51
0.17565711
0.2412


hCV27859399
rs7853989
hCV32126435
rs11244034
0.51
0.17565711
0.297


hCV27859399
rs7853989
hCV32126442
rs7864821
0.51
0.17565711
0.2143


hCV27859399
rs7853989
hCV32126443
rs10793957
0.51
0.17565711
0.2286


hCV27859399
rs7853989
hCV32126447
rs6597610
0.51
0.17565711
0.2143


hCV27859399
rs7853989
hCV32126454
rs13300535
0.51
0.17565711
0.2888


hCV27859399
rs7853989
hCV32126487
rs10901250
0.51
0.17565711
0.3729


hCV27859399
rs7853989
hCV442675
rs9411471
0.51
0.17565711
0.4137


hCV27859399
rs7853989
hCV7481808
rs886082
0.51
0.17565711
0.2759


hCV27859399
rs7853989
hCV7948166
rs9411463
0.51
0.17565711
0.7297


hCV27859399
rs7853989
hCV7948171
rs4246170
0.51
0.17565711
0.6426


hCV27859399
rs7853989
hCV9327931
rs17150482
0.51
0.17565711
0.1872


hCV27859399
rs7853989
hCV997907
rs657152
0.51
0.17565711
0.2


hCV27859399
rs7853989
hCV997909
rs644234
0.51
0.17565711
0.2


hCV27902808
rs4253236
hCV11786147
rs4862662
0.51
0.163416276
0.2369


hCV27902808
rs4253236
hCV11786203
rs4253251
0.51
0.163416276
0.3848


hCV27902808
rs4253236
hCV11786258
rs4253303
0.51
0.163416276
0.366


hCV27902808
rs4253236
hCV11786259
rs4253304
0.51
0.163416276
0.4346


hCV27902808
rs4253236
hCV11786327
rs13133050
0.51
0.163416276
0.1961


hCV27902808
rs4253236
hCV12066118
rs2048
0.51
0.163416276
0.6716


hCV27902808
rs4253236
hCV12066119
rs1912826
0.51
0.163416276
0.6075


hCV27902808
rs4253236
hCV12066124
rs2036914
0.51
0.163416276
0.1725


hCV27902808
rs4253236
hCV12066129
rs1593
0.51
0.163416276
0.2043


hCV27902808
rs4253236
hCV15968025
rs2292425
0.51
0.163416276
0.399


hCV27902808
rs4253236
hCV15968026
rs2292426
0.51
0.163416276
0.4275


hCV27902808
rs4253236
hCV15968043
rs2292423
0.51
0.163416276
0.4376


hCV27902808
rs4253236
hCV15975109
rs2304596
0.51
0.163416276
0.364


hCV27902808
rs4253236
hCV2103392
rs12500826
0.51
0.163416276
0.192


hCV27902808
rs4253236
hCV22271609
rs4253326
0.51
0.163416276
0.3079


hCV27902808
rs4253236
hCV22272267
rs3733402
0.51
0.163416276
0.6716


hCV27902808
rs4253236
hCV25634781
rs4253299
0.51
0.163416276
0.3286


hCV27902808
rs4253236
hCV25989001
hCV25989001
0.51
0.163416276
0.3848


hCV27902808
rs4253236
hCV25990131
rs13146272
0.51
0.163416276
0.3974


hCV27902808
rs4253236
hCV26265197
rs10014399
0.51
0.163416276
0.3848


hCV27902808
rs4253236
hCV26265199
rs2221843
0.51
0.163416276
0.3286


hCV27902808
rs4253236
hCV26265231
rs7684025
0.51
0.163416276
0.3223


hCV27902808
rs4253236
hCV27482765
rs3775301
0.51
0.163416276
0.364


hCV27902808
rs4253236
hCV27506149
rs3822055
0.51
0.163416276
0.3286


hCV27902808
rs4253236
hCV29053260
rs4861707
0.51
0.163416276
0.164


hCV27902808
rs4253236
hCV29053264
rs7667777
0.51
0.163416276
0.2382


hCV27902808
rs4253236
hCV29053265
rs4253244
0.51
0.163416276
0.9634


hCV27902808
rs4253236
hCV29718000
rs4253238
0.51
0.163416276
0.6557


hCV27902808
rs4253236
hCV29826351
rs10025990
0.51
0.163416276
0.2048


hCV27902808
rs4253236
hCV29877725
rs4253295
0.51
0.163416276
0.3822


hCV27902808
rs4253236
hCV32291217
rs4253323
0.51
0.163416276
0.364


hCV27902808
rs4253236
hCV32291295
rs4253292
0.51
0.163416276
0.4307


hCV27902808
rs4253236
hCV32291301
rs4253302
0.51
0.163416276
0.3677


hCV27902808
rs4253236
hCV32295028
rs4253260
0.51
0.163416276
0.364


hCV27902808
rs4253236
hCV3229991
rs4241815
0.51
0.163416276
0.6716


hCV27902808
rs4253236
hCV3229992
rs3775298
0.51
0.163416276
0.6716


hCV27902808
rs4253236
hCV3229995
rs11132382
0.51
0.163416276
0.6412


hCV27902808
rs4253236
hCV3230002
rs4253297
0.51
0.163416276
0.3878


hCV27902808
rs4253236
hCV3230003
rs2304595
0.51
0.163416276
0.4392


hCV27902808
rs4253236
hCV3230006
rs4253308
0.51
0.163416276
0.3822


hCV27902808
rs4253236
hCV3230007
rs4253311
0.51
0.163416276
0.6716


hCV27902808
rs4253236
hCV3230011
rs4253320
0.51
0.163416276
0.3878


hCV27902808
rs4253236
hCV3230012
rs4241821
0.51
0.163416276
0.3286


hCV27902808
rs4253236
hCV3230013
rs3775303
0.51
0.163416276
0.4346


hCV27902808
rs4253236
hCV3230083
rs10013653
0.51
0.163416276
0.2827


hCV27902808
rs4253236
hCV3230084
rs7682918
0.51
0.163416276
0.2441


hCV27902808
rs4253236
hCV3230094
rs7687818
0.51
0.163416276
0.2896


hCV27902808
rs4253236
hCV3230096
rs3817184
0.51
0.163416276
0.2369


hCV27902808
rs4253236
hCV3230097
rs3736455
0.51
0.163416276
0.4807


hCV27902808
rs4253236
hCV3230113
rs1053094
0.51
0.163416276
0.3483


hCV27902808
rs4253236
hCV32313006
rs4253248
0.51
0.163416276
0.6434


hCV27902808
rs4253236
hCV32313024
rs4253239
0.51
0.163416276
0.4307


hCV27902808
rs4253236
hCV32358975
rs4253255
0.51
0.163416276
0.6676


hCV27902808
rs4253236
hCV32358984
rs4253256
0.51
0.163416276
1


hCV27902808
rs4253236
hCV8241631
rs1511802
0.51
0.163416276
0.3786


hCV27902808
rs4253236
hCV8241632
rs1511801
0.51
0.163416276
0.6346


hCV27902808
rs4253236
hDV71222711
rs4253252
0.51
0.163416276
0.6434


hCV2892877
rs6050
hCV11503382
rs1873369
0.51
0.118446629
0.2903


hCV2892877
rs6050
hCV11503414
rs2066865
0.51
0.118446629
0.873


hCV2892877
rs6050
hCV11503416
rs2066864
0.51
0.118446629
0.8694


hCV2892877
rs6050
hCV11503431
rs2066861
0.51
0.118446629
0.8734


hCV2892877
rs6050
hCV11503469
rs2066854
0.51
0.118446629
0.8287


hCV2892877
rs6050
hCV11503470
rs1800788
0.51
0.118446629
0.5042


hCV2892877
rs6050
hCV11853378
rs1907154
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV11853384
rs12646456
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV11853387
rs1490683
0.51
0.118446629
0.1884


hCV2892877
rs6050
hCV11853483
rs12644950
0.51
0.118446629
0.863


hCV2892877
rs6050
hCV11853489
rs7681423
0.51
0.118446629
0.8694


hCV2892877
rs6050
hCV11853496
rs7654093
0.51
0.118446629
0.8734


hCV2892877
rs6050
hCV11853631
rs12651106
0.51
0.118446629
0.1417


hCV2892877
rs6050
hCV1190572
rs1032335
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV15860433
rs2070006
0.51
0.118446629
0.4576


hCV2892877
rs6050
hCV21680
rs7666020
0.51
0.118446629
0.1673


hCV2892877
rs6050
hCV21681
rs6536018
0.51
0.118446629
0.2886


hCV2892877
rs6050
hCV24834
rs4235247
0.51
0.118446629
0.4645


hCV2892877
rs6050
hCV26019871
rs4547780
0.51
0.118446629
0.3118


hCV2892877
rs6050
hCV26024202
rs11731813
0.51
0.118446629
0.2608


hCV2892877
rs6050
hCV265748
rs12500118
0.51
0.118446629
0.1425


hCV2892877
rs6050
hCV27020269
rs7659613
0.51
0.118446629
0.4867


hCV2892877
rs6050
hCV27020277
rs6825454
0.51
0.118446629
0.948


hCV2892877
rs6050
hCV27020280
rs4463047
0.51
0.118446629
0.2695


hCV2892877
rs6050
hCV27905214
rs4323084
0.51
0.118446629
0.3304


hCV2892877
rs6050
hCV27907560
rs4696576
0.51
0.118446629
0.1284


hCV2892877
rs6050
hCV27937396
rs4634201
0.51
0.118446629
0.4655


hCV2892877
rs6050
hCV286004
rs1118824
0.51
0.118446629
0.1344


hCV2892877
rs6050
hCV2892855
rs6536024
0.51
0.118446629
0.1935


hCV2892877
rs6050
hCV2892858
rs12648395
0.51
0.118446629
0.1344


hCV2892877
rs6050
hCV2892859
rs13130318
0.51
0.118446629
0.7297


hCV2892877
rs6050
hCV2892863
rs1049636
0.51
0.118446629
0.1344


hCV2892877
rs6050
hCV2892869
rs13109457
0.51
0.118446629
0.9105


hCV2892877
rs6050
hCV2892870
rs2070011
0.51
0.118446629
0.477


hCV2892877
rs6050
hCV2892893
rs12648258
0.51
0.118446629
0.4392


hCV2892877
rs6050
hCV2892905
rs12642770
0.51
0.118446629
0.4305


hCV2892877
rs6050
hCV2892918
rs12511469
0.51
0.118446629
0.4276


hCV2892877
rs6050
hCV2892923
rs13435192
0.51
0.118446629
0.1513


hCV2892877
rs6050
hCV2892924
rs13435101
0.51
0.118446629
0.15


hCV2892877
rs6050
hCV2892925
rs7689945
0.51
0.118446629
0.1457


hCV2892877
rs6050
hCV2892926
rs7662567
0.51
0.118446629
0.4373


hCV2892877
rs6050
hCV2892927
rs13123551
0.51
0.118446629
0.1818


hCV2892877
rs6050
hCV2892928
rs13147579
0.51
0.118446629
0.4507


hCV2892877
rs6050
hCV28953838
rs7690851
0.51
0.118446629
0.3195


hCV2892877
rs6050
hCV28953840
rs6536017
0.51
0.118446629
0.1303


hCV2892877
rs6050
hCV28966638
rs7676857
0.51
0.118446629
0.1381


hCV2892877
rs6050
hCV29420822
rs4642230
0.51
0.118446629
0.5295


hCV2892877
rs6050
hCV29983641
rs10008078
0.51
0.118446629
0.5304


hCV2892877
rs6050
hCV30679164
rs12649437
0.51
0.118446629
0.1198


hCV2892877
rs6050
hCV30679170
rs13148992
0.51
0.118446629
0.2697


hCV2892877
rs6050
hCV30711231
rs12642469
0.51
0.118446629
0.5304


hCV2892877
rs6050
hCV31863979
rs12186294
0.51
0.118446629
0.212


hCV2892877
rs6050
hCV31863982
rs7659024
0.51
0.118446629
0.8734


hCV2892877
rs6050
hCV32212659
rs4622984
0.51
0.118446629
0.2094


hCV2892877
rs6050
hCV354895
rs11737226
0.51
0.118446629
0.2405


hCV2892877
rs6050
hCV354896
rs7690972
0.51
0.118446629
0.2405


hCV2892877
rs6050
hCV426173
rs12504201
0.51
0.118446629
0.1904


hCV2892877
rs6050
hCV426175
rs9884952
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV426176
rs9884775
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV426178
rs9884570
0.51
0.118446629
0.123


hCV2892877
rs6050
hCV426181
rs11099955
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV426182
rs10014536
0.51
0.118446629
0.1443


hCV2892877
rs6050
hCV426183
rs10014635
0.51
0.118446629
0.1452


hCV2892877
rs6050
hCV426184
rs1032336
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV470979
rs1490672
0.51
0.118446629
0.2588


hCV2892877
rs6050
hCV7429780
rs1800792
0.51
0.118446629
0.1939


hCV2892877
rs6050
hCV7429782
rs1118823
0.51
0.118446629
0.1313


hCV2892877
rs6050
hCV7429793
rs1025154
0.51
0.118446629
0.5304


hCV2892877
rs6050
hCV7430148
rs1490685
0.51
0.118446629
0.1345


hCV2892877
rs6050
hCV7430158
rs1466662
0.51
0.118446629
0.1425


hCV2892877
rs6050
hDV70945235
rs17373860
0.51
0.118446629
0.2179


hCV2915511
rs627530
hCV11470250
rs678276
0.51
0.808781214
1


hCV2915511
rs627530
hCV2406318
rs661315
0.51
0.808781214
1


hCV2915511
rs627530
hCV2414147
rs681747
0.51
0.808781214
1


hCV2915511
rs627530
hCV2414148
rs620698
0.51
0.808781214
1


hCV2915511
rs627530
hCV2414150
rs675291
0.51
0.808781214
1


hCV2915511
rs627530
hCV31716873
rs13403516
0.51
0.808781214
1


hCV2915511
rs627530
hCV7540
rs633200
0.51
0.808781214
1


hCV2915511
rs627530
hCV8840562
rs668034
0.51
0.808781214
1


hCV2986566
rs4149755
hCV1264349
rs12557491
0.51
0.454330944
0.6651


hCV2986566
rs4149755
hCV29394017
rs7058459
0.51
0.454330944
0.4683


hCV30562347
rs4253418
hCV11786295
rs4253421
0.51
0.434589475
0.4975


hCV30562347
rs4253418
hCV12066129
rs1593
0.51
0.434589475
0.4706


hCV30562347
rs4253418
hCV29826351
rs10025990
0.51
0.434589475
0.5058


hCV30690777
rs12045585
hCV15760229
rs3006939
0.51
0.480095851
0.4853


hCV30690777
rs12045585
hCV15760280
rs3006940
0.51
0.480095851
0.4853


hCV30690777
rs12045585
hCV26034158
rs4515770
0.51
0.480095851
0.4853


hCV30690777
rs12045585
hCV29210363
rs6656918
0.51
0.480095851
0.4853


hCV30690777
rs12045585
hCV30690778
rs12140414
0.51
0.480095851
0.5671


hCV30690777
rs12045585
hCV30690780
rs10737888
0.51
0.480095851
0.4853


hCV30690777
rs12045585
hCV8688111
rs1578275
0.51
0.480095851
0.5671


hCV30690777
rs12045585
hCV97631
rs1538773
0.51
0.480095851
0.4853


hCV30690780
rs10737888
hCV12073160
rs1973284
0.51
0.262666713
0.4193


hCV30690780
rs10737888
hCV12073167
rs2034915
0.51
0.262666713
0.4232


hCV30690780
rs10737888
hCV12073172
rs971285
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV12073836
rs1008173
0.51
0.262666713
0.2647


hCV30690780
rs10737888
hCV12073840
rs14403
0.51
0.262666713
0.5374


hCV30690780
rs10737888
hCV15755277
rs3008657
0.51
0.262666713
0.3711


hCV30690780
rs10737888
hCV15760229
rs3006939
0.51
0.262666713
1


hCV30690780
rs10737888
hCV15760238
rs3006936
0.51
0.262666713
1


hCV30690780
rs10737888
hCV15760239
rs3006923
0.51
0.262666713
0.4737


hCV30690780
rs10737888
hCV15760280
rs3006940
0.51
0.262666713
1


hCV30690780
rs10737888
hCV15776869
rs2345994
0.51
0.262666713
0.4139


hCV30690780
rs10737888
hCV15823024
rs2125230
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV15823033
rs2125231
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV15885425
rs2290754
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV15885435
rs2290753
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV15953062
rs2953330
0.51
0.262666713
0.3229


hCV30690780
rs10737888
hCV15953063
rs2953331
0.51
0.262666713
0.3293


hCV30690780
rs10737888
hCV15965328
rs2291409
0.51
0.262666713
0.4454


hCV30690780
rs10737888
hCV15965338
rs2291410
0.51
0.262666713
0.7354


hCV30690780
rs10737888
hCV16082410
rs2881275
0.51
0.262666713
0.6818


hCV30690780
rs10737888
hCV1678656
rs1458024
0.51
0.262666713
0.6818


hCV30690780
rs10737888
hCV1678668
rs1379700
0.51
0.262666713
0.3257


hCV30690780
rs10737888
hCV1678674
rs1458023
0.51
0.262666713
0.7493


hCV30690780
rs10737888
hCV1678683
rs1486475
0.51
0.262666713
0.3257


hCV30690780
rs10737888
hCV1678687
rs320305
0.51
0.262666713
0.6181


hCV30690780
rs10737888
hCV1678723
rs1486472
0.51
0.262666713
0.3224


hCV30690780
rs10737888
hCV233148
rs1417121
0.51
0.262666713
0.6414


hCV30690780
rs10737888
hCV26034142
rs9428576
0.51
0.262666713
0.3104


hCV30690780
rs10737888
hCV26034157
rs2994329
0.51
0.262666713
0.2668


hCV30690780
rs10737888
hCV26034158
rs4515770
0.51
0.262666713
1


hCV30690780
rs10737888
hCV26034160
rs2994327
0.51
0.262666713
0.4781


hCV30690780
rs10737888
hCV26719082
rs10927046
0.51
0.262666713
0.6045


hCV30690780
rs10737888
hCV26719085
rs10927047
0.51
0.262666713
0.635


hCV30690780
rs10737888
hCV26719086
rs4658585
0.51
0.262666713
0.4054


hCV30690780
rs10737888
hCV26719087
rs4658401
0.51
0.262666713
0.2676


hCV30690780
rs10737888
hCV26719107
rs7538011
0.51
0.262666713
0.6653


hCV30690780
rs10737888
hCV26719108
rs10927035
0.51
0.262666713
0.5743


hCV30690780
rs10737888
hCV26719113
rs7517340
0.51
0.262666713
0.617


hCV30690780
rs10737888
hCV26719114
rs7549780
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719116
rs10927039
0.51
0.262666713
0.7747


hCV30690780
rs10737888
hCV26719117
rs12144559
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719120
rs10927040
0.51
0.262666713
0.7881


hCV30690780
rs10737888
hCV26719121
rs10927041
0.51
0.262666713
0.7881


hCV30690780
rs10737888
hCV26719137
rs12136847
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719149
rs6675851
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV26719162
rs4132509
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV26719163
rs6429435
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719171
rs10927075
0.51
0.262666713
0.4054


hCV30690780
rs10737888
hCV26719176
rs10927076
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV26719179
rs6672195
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719192
rs10803161
0.51
0.262666713
0.7097


hCV30690780
rs10737888
hCV26719194
rs10927081
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719197
rs4590656
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719201
rs4478795
0.51
0.262666713
0.4255


hCV30690780
rs10737888
hCV26719202
rs4658588
0.51
0.262666713
0.4232


hCV30690780
rs10737888
hCV26719215
rs12144546
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719217
rs7548254
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719219
rs9782958
0.51
0.262666713
0.7247


hCV30690780
rs10737888
hCV26719222
rs4553169
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV26719225
rs11586029
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV26719227
rs10927065
0.51
0.262666713
0.6111


hCV30690780
rs10737888
hCV26719232
rs10803158
0.51
0.262666713
0.7586


hCV30690780
rs10737888
hCV26719233
rs10927067
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV27170898
rs12753750
0.51
0.262666713
0.3576


hCV30690780
rs10737888
hCV27171350
rs4430311
0.51
0.262666713
0.3794


hCV30690780
rs10737888
hCV27498250
rs3766673
0.51
0.262666713
0.7605


hCV30690780
rs10737888
hCV29210363
rs6656918
0.51
0.262666713
1


hCV30690780
rs10737888
hCV29542869
rs7534117
0.51
0.262666713
0.7586


hCV30690780
rs10737888
hCV29560960
rs7519673
0.51
0.262666713
0.6181


hCV30690780
rs10737888
hCV29741723
rs7517921
0.51
0.262666713
0.7354


hCV30690780
rs10737888
hCV29795761
rs7528450
0.51
0.262666713
0.3632


hCV30690780
rs10737888
hCV29994467
rs6694738
0.51
0.262666713
0.6653


hCV30690780
rs10737888
hCV30012351
rs10158245
0.51
0.262666713
0.2721


hCV30690780
rs10737888
hCV30084348
rs9287269
0.51
0.262666713
0.7625


hCV30690780
rs10737888
hCV30372886
rs9782883
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV30382231
rs9428966
0.51
0.262666713
0.687


hCV30690780
rs10737888
hCV30690777
rs12045585
0.51
0.262666713
0.4853


hCV30690780
rs10737888
hCV30690778
rs12140414
0.51
0.262666713
0.8652


hCV30690780
rs10737888
hCV30690784
rs4658574
0.51
0.262666713
0.4781


hCV30690780
rs10737888
hCV31523552
rs12739344
0.51
0.262666713
0.4405


hCV30690780
rs10737888
hCV31523555
rs12749316
0.51
0.262666713
0.3008


hCV30690780
rs10737888
hCV31523557
rs10754807
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV31523563
rs10927051
0.51
0.262666713
0.6787


hCV30690780
rs10737888
hCV31523573
rs11589907
0.51
0.262666713
0.2935


hCV30690780
rs10737888
hCV31523576
rs12691548
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV31523608
rs12744297
0.51
0.262666713
0.3354


hCV30690780
rs10737888
hCV31523624
rs10927044
0.51
0.262666713
0.4405


hCV30690780
rs10737888
hCV31523638
rs12037013
0.51
0.262666713
0.6415


hCV30690780
rs10737888
hCV31523639
rs12034588
0.51
0.262666713
0.6809


hCV30690780
rs10737888
hCV31523643
rs6671475
0.51
0.262666713
0.7881


hCV30690780
rs10737888
hCV31523650
rs12048930
0.51
0.262666713
0.7354


hCV30690780
rs10737888
hCV31523658
rs12047209
0.51
0.262666713
0.4836


hCV30690780
rs10737888
hCV31523688
rs12049228
0.51
0.262666713
0.6692


hCV30690780
rs10737888
hCV31523691
rs12021907
0.51
0.262666713
0.6181


hCV30690780
rs10737888
hCV31523707
rs10803152
0.51
0.262666713
0.6415


hCV30690780
rs10737888
hCV31523710
rs10927059
0.51
0.262666713
0.763


hCV30690780
rs10737888
hCV31523723
rs12140040
0.51
0.262666713
0.4909


hCV30690780
rs10737888
hCV31523736
rs12124113
0.51
0.262666713
0.6181


hCV30690780
rs10737888
hCV31523737
rs12117580
0.51
0.262666713
0.3458


hCV30690780
rs10737888
hCV31523740
rs12032342
0.51
0.262666713
0.6818


hCV30690780
rs10737888
hCV31523744
rs12031994
0.51
0.262666713
0.6181


hCV30690780
rs10737888
hCV804126
rs320320
0.51
0.262666713
0.6818


hCV30690780
rs10737888
hCV8688079
rs884808
0.51
0.262666713
0.5066


hCV30690780
rs10737888
hCV8688080
rs884328
0.51
0.262666713
0.5066


hCV30690780
rs10737888
hCV8688098
rs1531244
0.51
0.262666713
0.4026


hCV30690780
rs10737888
hCV8688111
rs1578275
0.51
0.262666713
0.8627


hCV30690780
rs10737888
hCV8688770
rs3856231
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV8689016
rs897959
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hCV9115290
rs1352162
0.51
0.262666713
0.429


hCV30690780
rs10737888
hCV9493073
rs1058305
0.51
0.262666713
0.6914


hCV30690780
rs10737888
hCV9493081
rs1058304
0.51
0.262666713
0.6914


hCV30690780
rs10737888
hCV97631
rs1538773
0.51
0.262666713
1


hCV30690780
rs10737888
hDV69368808
rs12145558
0.51
0.262666713
0.4257


hCV30690780
rs10737888
hDV71836703
rs6429433
0.51
0.262666713
0.6326


hCV30690780
rs10737888
hDV90784784
rs320339
0.51
0.262666713
0.713


hCV30710896
rs3136520
hCV31699700
rs11039103
0.51
0.599559553
0.8293


hCV30710896
rs3136520
hCV31699705
rs11039099
0.51
0.599559553
1


hCV30710896
rs3136520
hCV31699798
rs11039049
0.51
0.599559553
1


hCV30710896
rs3136520
hCV32292446
rs3136524
0.51
0.599559553
1


hCV30710896
rs3136520
hCV32368695
rs7938933
0.51
0.599559553
0.6861


hCV30747430
rs11712211
hCV11906384
rs2472670
0.51
0.337199375
1


hCV30747430
rs11712211
hCV11906385
rs2472671
0.51
0.337199375
1


hCV30747430
rs11712211
hCV11906386
rs2056530
0.51
0.337199375
1


hCV30747430
rs11712211
hCV16090105
rs2873951
0.51
0.337199375
1


hCV30747430
rs11712211
hCV26079834
rs2472672
0.51
0.337199375
1


hCV30747430
rs11712211
hCV27986929
rs4688030
0.51
0.337199375
0.3388


hCV30747430
rs11712211
hCV28031759
rs4234666
0.51
0.337199375
1


hCV30747430
rs11712211
hCV30526128
rs9841230
0.51
0.337199375
0.3388


hCV30747430
rs11712211
hCV30747431
rs13071341
0.51
0.337199375
1


hCV30747430
rs11712211
hCV8760915
rs1403527
0.51
0.337199375
1


hCV31523608
rs12744297
hCV12073160
rs1973284
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV12073167
rs2034915
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV12073172
rs971285
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV12073180
rs1870272
0.51
0.302208039
0.9599


hCV31523608
rs12744297
hCV15755277
rs3008657
0.51
0.302208039
0.6842


hCV31523608
rs12744297
hCV15760229
rs3006939
0.51
0.302208039
0.3354


hCV31523608
rs12744297
hCV15760280
rs3006940
0.51
0.302208039
0.3354


hCV31523608
rs12744297
hCV15776869
rs2345994
0.51
0.302208039
0.9118


hCV31523608
rs12744297
hCV15823016
rs2125229
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV15823024
rs2125230
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV15823033
rs2125231
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV15885425
rs2290754
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV15885435
rs2290753
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV15953062
rs2953330
0.51
0.302208039
0.5697


hCV31523608
rs12744297
hCV15953063
rs2953331
0.51
0.302208039
0.717


hCV31523608
rs12744297
hCV15953071
rs2953329
0.51
0.302208039
0.4589


hCV31523608
rs12744297
hCV15965328
rs2291409
0.51
0.302208039
1


hCV31523608
rs12744297
hCV15965338
rs2291410
0.51
0.302208039
0.3872


hCV31523608
rs12744297
hCV16082410
rs2881275
0.51
0.302208039
0.4269


hCV31523608
rs12744297
hCV16082411
rs2881274
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV1678656
rs1458024
0.51
0.302208039
0.4269


hCV31523608
rs12744297
hCV1678658
rs897960
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV1678668
rs1379700
0.51
0.302208039
0.829


hCV31523608
rs12744297
hCV1678674
rs1458023
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV1678683
rs1486475
0.51
0.302208039
0.829


hCV31523608
rs12744297
hCV1678687
rs320305
0.51
0.302208039
0.3415


hCV31523608
rs12744297
hCV1678723
rs1486472
0.51
0.302208039
0.7959


hCV31523608
rs12744297
hCV26034158
rs4515770
0.51
0.302208039
0.3354


hCV31523608
rs12744297
hCV26719082
rs10927046
0.51
0.302208039
0.3415


hCV31523608
rs12744297
hCV26719085
rs10927047
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV26719086
rs4658585
0.51
0.302208039
0.9119


hCV31523608
rs12744297
hCV26719087
rs4658401
0.51
0.302208039
0.9056


hCV31523608
rs12744297
hCV26719102
rs10927056
0.51
0.302208039
0.8824


hCV31523608
rs12744297
hCV26719107
rs7538011
0.51
0.302208039
0.4024


hCV31523608
rs12744297
hCV26719108
rs10927035
0.51
0.302208039
0.8066


hCV31523608
rs12744297
hCV26719113
rs7517340
0.51
0.302208039
0.3842


hCV31523608
rs12744297
hCV26719114
rs7549780
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719116
rs10927039
0.51
0.302208039
0.3861


hCV31523608
rs12744297
hCV26719117
rs12144559
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719120
rs10927040
0.51
0.302208039
0.4658


hCV31523608
rs12744297
hCV26719121
rs10927041
0.51
0.302208039
0.4658


hCV31523608
rs12744297
hCV26719137
rs12136847
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719140
rs320323
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV26719149
rs6675851
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV26719161
rs6682456
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV26719162
rs4132509
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV26719163
rs6429435
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719171
rs10927075
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719176
rs10927076
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV26719179
rs6672195
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719184
rs4658593
0.51
0.302208039
0.3334


hCV31523608
rs12744297
hCV26719192
rs10803161
0.51
0.302208039
0.4124


hCV31523608
rs12744297
hCV26719193
rs6429439
0.51
0.302208039
0.372


hCV31523608
rs12744297
hCV26719194
rs10927081
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719197
rs4590656
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719202
rs4658588
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719215
rs12144546
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719217
rs7548254
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719218
rs4658403
0.51
0.302208039
0.4141


hCV31523608
rs12744297
hCV26719219
rs9782958
0.51
0.302208039
0.3872


hCV31523608
rs12744297
hCV26719222
rs4553169
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV26719225
rs11586029
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV26719227
rs10927065
0.51
0.302208039
0.3415


hCV31523608
rs12744297
hCV26719232
rs10803158
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV26719233
rs10927067
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV27170898
rs12753750
0.51
0.302208039
0.717


hCV31523608
rs12744297
hCV27171311
rs4322213
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV27171350
rs4430311
0.51
0.302208039
0.6842


hCV31523608
rs12744297
hCV27498250
rs3766673
0.51
0.302208039
0.4658


hCV31523608
rs12744297
hCV27511819
rs3753549
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV29210363
rs6656918
0.51
0.302208039
0.3354


hCV31523608
rs12744297
hCV29210367
rs4518884
0.51
0.302208039
0.9599


hCV31523608
rs12744297
hCV29210368
rs4313380
0.51
0.302208039
0.3279


hCV31523608
rs12744297
hCV29210370
rs6676779
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV29542869
rs7534117
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV29560960
rs7519673
0.51
0.302208039
0.3415


hCV31523608
rs12744297
hCV29633221
rs10157763
0.51
0.302208039
0.9589


hCV31523608
rs12744297
hCV29669242
rs7547861
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV29723686
rs7512207
0.51
0.302208039
0.4007


hCV31523608
rs12744297
hCV29741723
rs7517921
0.51
0.302208039
0.3872


hCV31523608
rs12744297
hCV29795761
rs7528450
0.51
0.302208039
1


hCV31523608
rs12744297
hCV29831992
rs7523198
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV29859556
rs6704286
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV29958244
rs4614244
0.51
0.302208039
0.312


hCV31523608
rs12744297
hCV29994467
rs6694738
0.51
0.302208039
0.4024


hCV31523608
rs12744297
hCV30012351
rs10158245
0.51
0.302208039
0.9568


hCV31523608
rs12744297
hCV30048213
rs7552982
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV30048215
rs6703013
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV30084348
rs9287269
0.51
0.302208039
0.432


hCV31523608
rs12744297
hCV30210344
rs9428970
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV30228080
rs4593807
0.51
0.302208039
0.3842


hCV31523608
rs12744297
hCV30264437
rs7514510
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV30354518
rs7517732
0.51
0.302208039
0.3399


hCV31523608
rs12744297
hCV30372886
rs9782883
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV30390695
rs7553458
0.51
0.302208039
0.3992


hCV31523608
rs12744297
hCV30462455
rs6686591
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV30606791
rs6688135
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV30690780
rs10737888
0.51
0.302208039
0.3354


hCV31523608
rs12744297
hCV31523552
rs12739344
0.51
0.302208039
1


hCV31523608
rs12744297
hCV31523555
rs12749316
0.51
0.302208039
0.9202


hCV31523608
rs12744297
hCV31523557
rs10754807
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV31523563
rs10927051
0.51
0.302208039
0.4005


hCV31523608
rs12744297
hCV31523573
rs11589907
0.51
0.302208039
0.9599


hCV31523608
rs12744297
hCV31523576
rs12691548
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV31523624
rs10927044
0.51
0.302208039
1


hCV31523608
rs12744297
hCV31523638
rs12037013
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV31523639
rs12034588
0.51
0.302208039
0.4302


hCV31523608
rs12744297
hCV31523643
rs6671475
0.51
0.302208039
0.4658


hCV31523608
rs12744297
hCV31523650
rs12048930
0.51
0.302208039
0.3872


hCV31523608
rs12744297
hCV31523658
rs12047209
0.51
0.302208039
0.3058


hCV31523608
rs12744297
hCV31523659
rs10733129
0.51
0.302208039
0.312


hCV31523608
rs12744297
hCV31523680
rs4484910
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV31523688
rs12049228
0.51
0.302208039
0.4319


hCV31523608
rs12744297
hCV31523691
rs12021907
0.51
0.302208039
0.3415


hCV31523608
rs12744297
hCV31523692
rs10927082
0.51
0.302208039
0.3582


hCV31523608
rs12744297
hCV31523707
rs10803152
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV31523710
rs10927059
0.51
0.302208039
0.4338


hCV31523608
rs12744297
hCV31523723
rs12140040
0.51
0.302208039
0.3192


hCV31523608
rs12744297
hCV31523725
rs10927060
0.51
0.302208039
0.9599


hCV31523608
rs12744297
hCV31523731
rs10803155
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV31523736
rs12124113
0.51
0.302208039
0.3415


hCV31523608
rs12744297
hCV31523737
rs12117580
0.51
0.302208039
0.8702


hCV31523608
rs12744297
hCV31523740
rs12032342
0.51
0.302208039
0.4269


hCV31523608
rs12744297
hCV31523744
rs12031994
0.51
0.302208039
0.3415


hCV31523608
rs12744297
hCV804118
rs320342
0.51
0.302208039
0.3279


hCV31523608
rs12744297
hCV804120
rs320344
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV804121
rs320345
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV804126
rs320320
0.51
0.302208039
0.4269


hCV31523608
rs12744297
hCV804128
rs167661
0.51
0.302208039
0.372


hCV31523608
rs12744297
hCV804132
rs406323
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV804139
rs320302
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV804146
rs320308
0.51
0.302208039
0.312


hCV31523608
rs12744297
hCV804147
rs320309
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV804156
rs320316
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV804160
rs320331
0.51
0.302208039
0.3324


hCV31523608
rs12744297
hCV804166
rs320334
0.51
0.302208039
0.372


hCV31523608
rs12744297
hCV8688098
rs1531244
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV8688110
rs946824
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV8688770
rs3856231
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV8688837
rs320318
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV8688866
rs1531243
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV8689005
rs1458022
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV8689016
rs897959
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hCV8689017
rs1458021
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV8689027
rs1545654
0.51
0.302208039
0.3716


hCV31523608
rs12744297
hCV9115290
rs1352162
0.51
0.302208039
0.9555


hCV31523608
rs12744297
hCV97631
rs1538773
0.51
0.302208039
0.3354


hCV31523608
rs12744297
hDV69368808
rs12145558
0.51
0.302208039
0.9556


hCV31523608
rs12744297
hDV71836703
rs6429433
0.51
0.302208039
0.3315


hCV31523608
rs12744297
hDV90784784
rs320339
0.51
0.302208039
0.3699


hCV31523650
rs12048930
hCV12073160
rs1973284
0.51
0.430712711
0.5233


hCV31523650
rs12048930
hCV12073167
rs2034915
0.51
0.430712711
0.5107


hCV31523650
rs12048930
hCV12073172
rs971285
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV15760229
rs3006939
0.51
0.430712711
0.7354


hCV31523650
rs12048930
hCV15760238
rs3006936
0.51
0.430712711
0.6267


hCV31523650
rs12048930
hCV15760280
rs3006940
0.51
0.430712711
0.7354


hCV31523650
rs12048930
hCV15776869
rs2345994
0.51
0.430712711
0.4998


hCV31523650
rs12048930
hCV15823024
rs2125230
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV15823033
rs2125231
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV15885425
rs2290754
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV15885435
rs2290753
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV15965328
rs2291409
0.51
0.430712711
0.4977


hCV31523650
rs12048930
hCV15965338
rs2291410
0.51
0.430712711
0.9368


hCV31523650
rs12048930
hCV16082410
rs2881275
0.51
0.430712711
0.9314


hCV31523650
rs12048930
hCV1678656
rs1458024
0.51
0.430712711
0.9314


hCV31523650
rs12048930
hCV1678674
rs1458023
0.51
0.430712711
0.9658


hCV31523650
rs12048930
hCV1678687
rs320305
0.51
0.430712711
0.7842


hCV31523650
rs12048930
hCV26034158
rs4515770
0.51
0.430712711
0.7354


hCV31523650
rs12048930
hCV26719082
rs10927046
0.51
0.430712711
0.7744


hCV31523650
rs12048930
hCV26719085
rs10927047
0.51
0.430712711
0.8098


hCV31523650
rs12048930
hCV26719086
rs4658585
0.51
0.430712711
0.4932


hCV31523650
rs12048930
hCV26719107
rs7538011
0.51
0.430712711
0.7825


hCV31523650
rs12048930
hCV26719113
rs7517340
0.51
0.430712711
0.8564


hCV31523650
rs12048930
hCV26719114
rs7549780
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719116
rs10927039
0.51
0.430712711
0.7976


hCV31523650
rs12048930
hCV26719117
rs12144559
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719120
rs10927040
0.51
0.430712711
0.9368


hCV31523650
rs12048930
hCV26719121
rs10927041
0.51
0.430712711
0.9368


hCV31523650
rs12048930
hCV26719137
rs12136847
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719149
rs6675851
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV26719162
rs4132509
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV26719163
rs6429435
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719171
rs10927075
0.51
0.430712711
0.4932


hCV31523650
rs12048930
hCV26719176
rs10927076
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV26719179
rs6672195
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719192
rs10803161
0.51
0.430712711
0.9274


hCV31523650
rs12048930
hCV26719194
rs10927081
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719197
rs4590656
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719201
rs4478795
0.51
0.430712711
0.7041


hCV31523650
rs12048930
hCV26719202
rs4658588
0.51
0.430712711
0.5107


hCV31523650
rs12048930
hCV26719215
rs12144546
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719217
rs7548254
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719219
rs9782958
0.51
0.430712711
0.9337


hCV31523650
rs12048930
hCV26719222
rs4553169
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV26719225
rs11586029
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV26719227
rs10927065
0.51
0.430712711
0.7793


hCV31523650
rs12048930
hCV26719232
rs10803158
0.51
0.430712711
0.9674


hCV31523650
rs12048930
hCV26719233
rs10927067
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV27170898
rs12753750
0.51
0.430712711
0.4449


hCV31523650
rs12048930
hCV27171350
rs4430311
0.51
0.430712711
0.4349


hCV31523650
rs12048930
hCV27498250
rs3766673
0.51
0.430712711
0.9071


hCV31523650
rs12048930
hCV29210363
rs6656918
0.51
0.430712711
0.7354


hCV31523650
rs12048930
hCV29542869
rs7534117
0.51
0.430712711
0.9674


hCV31523650
rs12048930
hCV29560960
rs7519673
0.51
0.430712711
0.7842


hCV31523650
rs12048930
hCV29741723
rs7517921
0.51
0.430712711
0.9368


hCV31523650
rs12048930
hCV29994467
rs6694738
0.51
0.430712711
0.7825


hCV31523650
rs12048930
hCV30084348
rs9287269
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV30372886
rs9782883
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV30382231
rs9428966
0.51
0.430712711
0.489


hCV31523650
rs12048930
hCV30690778
rs12140414
0.51
0.430712711
0.5857


hCV31523650
rs12048930
hCV30690780
rs10737888
0.51
0.430712711
0.7354


hCV31523650
rs12048930
hCV31523552
rs12739344
0.51
0.430712711
0.4932


hCV31523650
rs12048930
hCV31523557
rs10754807
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV31523563
rs10927051
0.51
0.430712711
1


hCV31523650
rs12048930
hCV31523576
rs12691548
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV31523624
rs10927044
0.51
0.430712711
0.4932


hCV31523650
rs12048930
hCV31523638
rs12037013
0.51
0.430712711
0.814


hCV31523650
rs12048930
hCV31523639
rs12034588
0.51
0.430712711
0.9312


hCV31523650
rs12048930
hCV31523643
rs6671475
0.51
0.430712711
0.9368


hCV31523650
rs12048930
hCV31523658
rs12047209
0.51
0.430712711
0.6687


hCV31523650
rs12048930
hCV31523688
rs12049228
0.51
0.430712711
0.9276


hCV31523650
rs12048930
hCV31523691
rs12021907
0.51
0.430712711
0.7842


hCV31523650
rs12048930
hCV31523707
rs10803152
0.51
0.430712711
0.814


hCV31523650
rs12048930
hCV31523710
rs10927059
0.51
0.430712711
0.9681


hCV31523650
rs12048930
hCV31523723
rs12140040
0.51
0.430712711
0.6706


hCV31523650
rs12048930
hCV31523736
rs12124113
0.51
0.430712711
0.7842


hCV31523650
rs12048930
hCV31523740
rs12032342
0.51
0.430712711
0.9314


hCV31523650
rs12048930
hCV31523744
rs12031994
0.51
0.430712711
0.7842


hCV31523650
rs12048930
hCV804126
rs320320
0.51
0.430712711
0.9314


hCV31523650
rs12048930
hCV8688098
rs1531244
0.51
0.430712711
0.4837


hCV31523650
rs12048930
hCV8688111
rs1578275
0.51
0.430712711
0.5771


hCV31523650
rs12048930
hCV8688770
rs3856231
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV8689016
rs897959
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hCV9115290
rs1352162
0.51
0.430712711
0.484


hCV31523650
rs12048930
hCV9493073
rs1058305
0.51
0.430712711
0.4963


hCV31523650
rs12048930
hCV9493081
rs1058304
0.51
0.430712711
0.4963


hCV31523650
rs12048930
hCV97631
rs1538773
0.51
0.430712711
0.7354


hCV31523650
rs12048930
hDV69368808
rs12145558
0.51
0.430712711
0.5119


hCV31523650
rs12048930
hDV71836703
rs6429433
0.51
0.430712711
0.7322


hCV31523650
rs12048930
hDV90784784
rs320339
0.51
0.430712711
0.9053


hCV32291301
rs4253302
hCV15968025
rs2292425
0.51
0.239176625
0.382


hCV32291301
rs4253302
hCV15968026
rs2292426
0.51
0.239176625
0.4222


hCV32291301
rs4253302
hCV15968034
rs2292428
0.51
0.239176625
0.3408


hCV32291301
rs4253302
hCV15975109
rs2304596
0.51
0.239176625
1


hCV32291301
rs4253302
hCV22272267
rs3733402
0.51
0.239176625
0.2397


hCV32291301
rs4253302
hCV25989001
hCV25989001
0.51
0.239176625
0.9447


hCV32291301
rs4253302
hCV25990131
rs13146272
0.51
0.239176625
0.3944


hCV32291301
rs4253302
hCV27482765
rs3775301
0.51
0.239176625
1


hCV32291301
rs4253302
hCV27902808
rs4253236
0.51
0.239176625
0.3677


hCV32291301
rs4253302
hCV28960679
rs6844764
0.51
0.239176625
0.2663


hCV32291301
rs4253302
hCV29053265
rs4253244
0.51
0.239176625
0.3178


hCV32291301
rs4253302
hCV29718000
rs4253238
0.51
0.239176625
0.2447


hCV32291301
rs4253302
hCV32291217
rs4253323
0.51
0.239176625
1


hCV32291301
rs4253302
hCV32291286
rs4253422
0.51
0.239176625
0.3885


hCV32291301
rs4253302
hCV32291287
rs4253423
0.51
0.239176625
0.3885


hCV32291301
rs4253302
hCV32291295
rs4253292
0.51
0.239176625
1


hCV32291301
rs4253302
hCV32295028
rs4253260
0.51
0.239176625
1


hCV32291301
rs4253302
hCV3229991
rs4241815
0.51
0.239176625
0.2397


hCV32291301
rs4253302
hCV3229992
rs3775298
0.51
0.239176625
0.2397


hCV32291301
rs4253302
hCV3229995
rs11132382
0.51
0.239176625
0.2447


hCV32291301
rs4253302
hCV3230007
rs4253311
0.51
0.239176625
0.2397


hCV32291301
rs4253302
hCV3230031
rs4253419
0.51
0.239176625
0.3885


hCV32291301
rs4253302
hCV3230097
rs3736455
0.51
0.239176625
0.4296


hCV32291301
rs4253302
hCV3230101
rs6835839
0.51
0.239176625
0.327


hCV32291301
rs4253302
hCV3230106
rs1473597
0.51
0.239176625
0.3407


hCV32291301
rs4253302
hCV3230110
rs2276917
0.51
0.239176625
0.3408


hCV32291301
rs4253302
hCV3230118
rs4253429
0.51
0.239176625
0.3885


hCV32291301
rs4253302
hCV3230125
rs11938564
0.51
0.239176625
0.2776


hCV32291301
rs4253302
hCV32313006
rs4253248
0.51
0.239176625
0.2447


hCV32291301
rs4253302
hCV32313024
rs4253239
0.51
0.239176625
1


hCV32291301
rs4253302
hCV32358984
rs4253256
0.51
0.239176625
0.3641


hCV32291301
rs4253302
hDV71222711
rs4253252
0.51
0.239176625
0.2447


hCV3230038
rs2289252
hCV11786147
rs4862662
0.51
0.044201827
0.1313


hCV3230038
rs2289252
hCV11786235
rs4253287
0.51
0.044201827
0.106


hCV3230038
rs2289252
hCV11786258
rs4253303
0.51
0.044201827
0.1956


hCV3230038
rs2289252
hCV11786259
rs4253304
0.51
0.044201827
0.2636


hCV3230038
rs2289252
hCV11786295
rs4253421
0.51
0.044201827
0.075


hCV3230038
rs2289252
hCV11786301
rs5970
0.51
0.044201827
0.0938


hCV3230038
rs2289252
hCV11786307
rs1062547
0.51
0.044201827
0.3739


hCV3230038
rs2289252
hCV11786311
rs13145616
0.51
0.044201827
0.1125


hCV3230038
rs2289252
hCV11786327
rs13133050
0.51
0.044201827
0.1784


hCV3230038
rs2289252
hCV12066116
rs1877320
0.51
0.044201827
0.0748


hCV3230038
rs2289252
hCV12066118
rs2048
0.51
0.044201827
0.1136


hCV3230038
rs2289252
hCV12066119
rs1912826
0.51
0.044201827
0.1027


hCV3230038
rs2289252
hCV12066124
rs2036914
0.51
0.044201827
0.3834


hCV3230038
rs2289252
hCV12066129
rs1593
0.51
0.044201827
0.0795


hCV3230038
rs2289252
hCV1333083
rs10022988
0.51
0.044201827
0.0488


hCV3230038
rs2289252
hCV1333090
rs6816112
0.51
0.044201827
0.0764


hCV3230038
rs2289252
hCV1333097
rs4862680
0.51
0.044201827
0.0488


hCV3230038
rs2289252
hCV1333099
rs10020635
0.51
0.044201827
0.0659


hCV3230038
rs2289252
hCV15793897
rs3087505
0.51
0.044201827
0.0486


hCV3230038
rs2289252
hCV15811716
rs2102575
0.51
0.044201827
0.0448


hCV3230038
rs2289252
hCV15968025
rs2292425
0.51
0.044201827
0.0893


hCV3230038
rs2289252
hCV15968026
rs2292426
0.51
0.044201827
0.181


hCV3230038
rs2289252
hCV15968034
rs2292428
0.51
0.044201827
0.0718


hCV3230038
rs2289252
hCV15968043
rs2292423
0.51
0.044201827
0.2462


hCV3230038
rs2289252
hCV16172925
rs2241818
0.51
0.044201827
0.1263


hCV3230038
rs2289252
hCV16172935
rs2241817
0.51
0.044201827
0.3937


hCV3230038
rs2289252
hCV194962
rs6552954
0.51
0.044201827
0.0482


hCV3230038
rs2289252
hCV2103343
rs4241824
0.51
0.044201827
0.4188


hCV3230038
rs2289252
hCV2103388
rs4613610
0.51
0.044201827
0.1193


hCV3230038
rs2289252
hCV2103391
rs1008728
0.51
0.044201827
0.2177


hCV3230038
rs2289252
hCV2103392
rs12500826
0.51
0.044201827
0.3222


hCV3230038
rs2289252
hCV22272267
rs3733402
0.51
0.044201827
0.1192


hCV3230038
rs2289252
hCV25474413
rs3822057
0.51
0.044201827
0.4122


hCV3230038
rs2289252
hCV25474414
rs4253399
0.51
0.044201827
0.7079


hCV3230038
rs2289252
hCV25634754
rs4253331
0.51
0.044201827
0.0636


hCV3230038
rs2289252
hCV25988221
rs9995366
0.51
0.044201827
0.0512


hCV3230038
rs2289252
hCV25990131
rs13146272
0.51
0.044201827
0.0944


hCV3230038
rs2289252
hCV26038139
rs4253405
0.51
0.044201827
0.2621


hCV3230038
rs2289252
hCV26265231
rs7684025
0.51
0.044201827
0.1744


hCV3230038
rs2289252
hCV27309972
rs13101296
0.51
0.044201827
0.1074


hCV3230038
rs2289252
hCV27309991
rs4572916
0.51
0.044201827
0.1232


hCV3230038
rs2289252
hCV27474895
rs3756011
0.51
0.044201827
1


hCV3230038
rs2289252
hCV27477533
rs3756008
0.51
0.044201827
0.7249


hCV3230038
rs2289252
hCV27490984
rs3822058
0.51
0.044201827
0.4054


hCV3230038
rs2289252
hCV27521729
rs3822056
0.51
0.044201827
0.0849


hCV3230038
rs2289252
hCV27902803
rs4862665
0.51
0.044201827
0.0512


hCV3230038
rs2289252
hCV28960679
rs6844764
0.51
0.044201827
0.1196


hCV3230038
rs2289252
hCV29053261
rs6842047
0.51
0.044201827
0.0472


hCV3230038
rs2289252
hCV29053264
rs7667777
0.51
0.044201827
0.1852


hCV3230038
rs2289252
hCV29640635
rs10029715
0.51
0.044201827
0.0679


hCV3230038
rs2289252
hCV29718000
rs4253238
0.51
0.044201827
0.1009


hCV3230038
rs2289252
hCV29826351
rs10025990
0.51
0.044201827
0.0882


hCV3230038
rs2289252
hCV29877725
rs4253295
0.51
0.044201827
0.1339


hCV3230038
rs2289252
hCV30307525
rs10025152
0.51
0.044201827
0.0679


hCV3230038
rs2289252
hCV30492573
rs10471184
0.51
0.044201827
0.0472


hCV3230038
rs2289252
hCV30983902
rs4862668
0.51
0.044201827
0.0748


hCV3230038
rs2289252
hCV30983927
rs6552962
0.51
0.044201827
0.0784


hCV3230038
rs2289252
hCV32209629
rs12715865
0.51
0.044201827
0.1373


hCV3230038
rs2289252
hCV32209636
rs11132387
0.51
0.044201827
0.435


hCV3230038
rs2289252
hCV32209637
rs13143773
0.51
0.044201827
0.2331


hCV3230038
rs2289252
hCV32209638
rs12507040
0.51
0.044201827
0.2973


hCV3230038
rs2289252
hCV32291256
rs4253406
0.51
0.044201827
0.0781


hCV3230038
rs2289252
hCV32291269
rs4253417
0.51
0.044201827
0.9433


hCV3230038
rs2289252
hCV32291286
rs4253422
0.51
0.044201827
0.1539


hCV3230038
rs2289252
hCV32291287
rs4253423
0.51
0.044201827
0.1539


hCV3230038
rs2289252
hCV3229991
rs4241815
0.51
0.044201827
0.1192


hCV3230038
rs2289252
hCV3229992
rs3775298
0.51
0.044201827
0.1192


hCV3230038
rs2289252
hCV3229995
rs11132382
0.51
0.044201827
0.0979


hCV3230038
rs2289252
hCV3230002
rs4253297
0.51
0.044201827
0.2015


hCV3230038
rs2289252
hCV3230003
rs2304595
0.51
0.044201827
0.2003


hCV3230038
rs2289252
hCV3230006
rs4253308
0.51
0.044201827
0.1339


hCV3230038
rs2289252
hCV3230007
rs4253311
0.51
0.044201827
0.1192


hCV3230038
rs2289252
hCV3230010
rs4253315
0.51
0.044201827
0.0748


hCV3230038
rs2289252
hCV3230011
rs4253320
0.51
0.044201827
0.2015


hCV3230038
rs2289252
hCV3230013
rs3775303
0.51
0.044201827
0.2636


hCV3230038
rs2289252
hCV3230016
rs4253325
0.51
0.044201827
0.0662


hCV3230038
rs2289252
hCV3230017
rs4253327
0.51
0.044201827
0.0771


hCV3230038
rs2289252
hCV3230021
rs13135645
0.51
0.044201827
0.0564


hCV3230038
rs2289252
hCV3230022
rs11132383
0.51
0.044201827
0.2455


hCV3230038
rs2289252
hCV3230025
rs3756009
0.51
0.044201827
0.7937


hCV3230038
rs2289252
hCV3230030
rs4253408
0.51
0.044201827
0.0719


hCV3230038
rs2289252
hCV3230031
rs4253419
0.51
0.044201827
0.1539


hCV3230038
rs2289252
hCV3230032
rs5974
0.51
0.044201827
0.1125


hCV3230038
rs2289252
hCV3230083
rs10013653
0.51
0.044201827
0.2181


hCV3230038
rs2289252
hCV3230084
rs7682918
0.51
0.044201827
0.1434


hCV3230038
rs2289252
hCV3230094
rs7687818
0.51
0.044201827
0.2201


hCV3230038
rs2289252
hCV3230096
rs3817184
0.51
0.044201827
0.1484


hCV3230038
rs2289252
hCV3230097
rs3736455
0.51
0.044201827
0.1419


hCV3230038
rs2289252
hCV3230101
rs6835839
0.51
0.044201827
0.0447


hCV3230038
rs2289252
hCV3230106
rs1473597
0.51
0.044201827
0.0873


hCV3230038
rs2289252
hCV3230110
rs2276917
0.51
0.044201827
0.0803


hCV3230038
rs2289252
hCV3230113
rs1053094
0.51
0.044201827
0.1432


hCV3230038
rs2289252
hCV3230118
rs4253429
0.51
0.044201827
0.1539


hCV3230038
rs2289252
hCV3230119
rs4253430
0.51
0.044201827
0.3973


hCV3230038
rs2289252
hCV3230121
rs4253431
0.51
0.044201827
0.0887


hCV3230038
rs2289252
hCV3230125
rs11938564
0.51
0.044201827
0.2052


hCV3230038
rs2289252
hCV3230131
rs13136269
0.51
0.044201827
0.2973


hCV3230038
rs2289252
hCV3230133
rs12511874
0.51
0.044201827
0.2104


hCV3230038
rs2289252
hCV3230134
rs12500151
0.51
0.044201827
0.3043


hCV3230038
rs2289252
hCV3230136
rs13116273
0.51
0.044201827
0.2952


hCV3230038
rs2289252
hCV32313006
rs4253248
0.51
0.044201827
0.1068


hCV3230038
rs2289252
hCV32313007
rs4862666
0.51
0.044201827
0.0512


hCV3230038
rs2289252
hCV32313014
rs4253243
0.51
0.044201827
0.0636


hCV3230038
rs2289252
hCV32358975
rs4253255
0.51
0.044201827
0.1152


hCV3230038
rs2289252
hCV32358984
rs4253256
0.51
0.044201827
0.0489


hCV3230038
rs2289252
hCV8241628
rs907439
0.51
0.044201827
0.1232


hCV3230038
rs2289252
hCV8241630
rs925451
0.51
0.044201827
0.7423


hCV3230038
rs2289252
hCV8241631
rs1511802
0.51
0.044201827
0.1452


hCV3230038
rs2289252
hCV8241632
rs1511801
0.51
0.044201827
0.1183


hCV3230038
rs2289252
hCV8241633
rs1511800
0.51
0.044201827
0.0512


hCV3230038
rs2289252
hDV68550952
rs4253289
0.51
0.044201827
0.0632


hCV3230038
rs2289252
hDV71222711
rs4253252
0.51
0.044201827
0.1068


hCV3230096
rs3817184
hCV11786147
rs4862662
0.51
0.10562155
0.9607


hCV3230096
rs3817184
hCV11786235
rs4253287
0.51
0.10562155
0.1611


hCV3230096
rs3817184
hCV11786258
rs4253303
0.51
0.10562155
0.7346


hCV3230096
rs3817184
hCV11786259
rs4253304
0.51
0.10562155
0.6556


hCV3230096
rs3817184
hCV12066106
rs1914926
0.51
0.10562155
0.1148


hCV3230096
rs3817184
hCV12066118
rs2048
0.51
0.10562155
0.3722


hCV3230096
rs3817184
hCV12066119
rs1912826
0.51
0.10562155
0.3754


hCV3230096
rs3817184
hCV12066124
rs2036914
0.51
0.10562155
0.2824


hCV3230096
rs3817184
hCV15968025
rs2292425
0.51
0.10562155
0.414


hCV3230096
rs3817184
hCV15968026
rs2292426
0.51
0.10562155
0.3737


hCV3230096
rs3817184
hCV15968034
rs2292428
0.51
0.10562155
0.4839


hCV3230096
rs3817184
hCV15968043
rs2292423
0.51
0.10562155
0.6453


hCV3230096
rs3817184
hCV15975109
rs2304596
0.51
0.10562155
0.1582


hCV3230096
rs3817184
hCV2103343
rs4241824
0.51
0.10562155
0.2431


hCV3230096
rs3817184
hCV22272267
rs3733402
0.51
0.10562155
0.3722


hCV3230096
rs3817184
hCV25474413
rs3822057
0.51
0.10562155
0.2412


hCV3230096
rs3817184
hCV25474414
rs4253399
0.51
0.10562155
0.1977


hCV3230096
rs3817184
hCV25989001
hCV25989001
0.51
0.10562155
0.1672


hCV3230096
rs3817184
hCV25990131
rs13146272
0.51
0.10562155
0.4248


hCV3230096
rs3817184
hCV26038139
rs4253405
0.51
0.10562155
0.1427


hCV3230096
rs3817184
hCV26265231
rs7684025
0.51
0.10562155
0.7723


hCV3230096
rs3817184
hCV27474895
rs3756011
0.51
0.10562155
0.1852


hCV3230096
rs3817184
hCV27477533
rs3756008
0.51
0.10562155
0.2279


hCV3230096
rs3817184
hCV27482765
rs3775301
0.51
0.10562155
0.1582


hCV3230096
rs3817184
hCV27902808
rs4253236
0.51
0.10562155
0.2369


hCV3230096
rs3817184
hCV28960679
rs6844764
0.51
0.10562155
0.4298


hCV3230096
rs3817184
hCV29053260
rs4861707
0.51
0.10562155
0.2941


hCV3230096
rs3817184
hCV29053264
rs7667777
0.51
0.10562155
1


hCV3230096
rs3817184
hCV29053265
rs4253244
0.51
0.10562155
0.2244


hCV3230096
rs3817184
hCV29053266
rs7687961
0.51
0.10562155
0.1405


hCV3230096
rs3817184
hCV29053271
rs6814261
0.51
0.10562155
0.1124


hCV3230096
rs3817184
hCV29718000
rs4253238
0.51
0.10562155
0.3705


hCV3230096
rs3817184
hCV29877725
rs4253295
0.51
0.10562155
0.7382


hCV3230096
rs3817184
hCV30983927
rs6552962
0.51
0.10562155
0.1582


hCV3230096
rs3817184
hCV32209636
rs11132387
0.51
0.10562155
0.1797


hCV3230096
rs3817184
hCV32209638
rs12507040
0.51
0.10562155
0.1135


hCV3230096
rs3817184
hCV32291217
rs4253323
0.51
0.10562155
0.1582


hCV3230096
rs3817184
hCV32291269
rs4253417
0.51
0.10562155
0.1798


hCV3230096
rs3817184
hCV32291295
rs4253292
0.51
0.10562155
0.1783


hCV3230096
rs3817184
hCV32291301
rs4253302
0.51
0.10562155
0.1573


hCV3230096
rs3817184
hCV32295028
rs4253260
0.51
0.10562155
0.1582


hCV3230096
rs3817184
hCV3229991
rs4241815
0.51
0.10562155
0.3722


hCV3230096
rs3817184
hCV3229992
rs3775298
0.51
0.10562155
0.3722


hCV3230096
rs3817184
hCV3229995
rs11132382
0.51
0.10562155
0.3745


hCV3230096
rs3817184
hCV3230000
rs4253294
0.51
0.10562155
0.1467


hCV3230096
rs3817184
hCV3230002
rs4253297
0.51
0.10562155
0.7524


hCV3230096
rs3817184
hCV3230003
rs2304595
0.51
0.10562155
0.6237


hCV3230096
rs3817184
hCV3230006
rs4253308
0.51
0.10562155
0.7382


hCV3230096
rs3817184
hCV3230007
rs4253311
0.51
0.10562155
0.3722


hCV3230096
rs3817184
hCV3230011
rs4253320
0.51
0.10562155
0.7524


hCV3230096
rs3817184
hCV3230013
rs3775303
0.51
0.10562155
0.6556


hCV3230096
rs3817184
hCV3230014
rs4861709
0.51
0.10562155
0.1467


hCV3230096
rs3817184
hCV3230017
rs4253327
0.51
0.10562155
0.207


hCV3230096
rs3817184
hCV3230018
rs925453
0.51
0.10562155
0.1144


hCV3230096
rs3817184
hCV3230019
rs4253332
0.51
0.10562155
0.1092


hCV3230096
rs3817184
hCV3230022
rs11132383
0.51
0.10562155
0.2117


hCV3230096
rs3817184
hCV3230025
rs3756009
0.51
0.10562155
0.2784


hCV3230096
rs3817184
hCV3230038
rs2289252
0.51
0.10562155
0.1484


hCV3230096
rs3817184
hCV3230079
rs35641294
0.51
0.10562155
0.1147


hCV3230096
rs3817184
hCV3230083
rs10013653
0.51
0.10562155
0.7047


hCV3230096
rs3817184
hCV3230084
rs7682918
0.51
0.10562155
0.8657


hCV3230096
rs3817184
hCV3230094
rs7687818
0.51
0.10562155
0.8722


hCV3230096
rs3817184
hCV3230097
rs3736455
0.51
0.10562155
0.367


hCV3230096
rs3817184
hCV3230101
rs6835839
0.51
0.10562155
0.451


hCV3230096
rs3817184
hCV3230106
rs1473597
0.51
0.10562155
0.4966


hCV3230096
rs3817184
hCV3230110
rs2276917
0.51
0.10562155
0.4746


hCV3230096
rs3817184
hCV3230113
rs1053094
0.51
0.10562155
0.695


hCV3230096
rs3817184
hCV3230125
rs11938564
0.51
0.10562155
0.1059


hCV3230096
rs3817184
hCV3230131
rs13136269
0.51
0.10562155
0.1135


hCV3230096
rs3817184
hCV3230134
rs12500151
0.51
0.10562155
0.1188


hCV3230096
rs3817184
hCV32313006
rs4253248
0.51
0.10562155
0.3803


hCV3230096
rs3817184
hCV32313024
rs4253239
0.51
0.10562155
0.1783


hCV3230096
rs3817184
hCV32358975
rs4253255
0.51
0.10562155
0.3585


hCV3230096
rs3817184
hCV32358984
rs4253256
0.51
0.10562155
0.2382


hCV3230096
rs3817184
hCV8241630
rs925451
0.51
0.10562155
0.2184


hCV3230096
rs3817184
hCV8241631
rs1511802
0.51
0.10562155
0.7356


hCV3230096
rs3817184
hCV8241632
rs1511801
0.51
0.10562155
0.4035


hCV3230096
rs3817184
hDV71222711
rs4253252
0.51
0.10562155
0.3803


hCV3230096
rs3817184
hDV76175111
rs35079309
0.51
0.10562155
0.1765


hCV3230113
rs1053094
hCV11786002
rs4862633
0.51
0.086445499
0.1657


hCV3230113
rs1053094
hCV11786003
rs4608848
0.51
0.086445499
0.1129


hCV3230113
rs1053094
hCV11786022
rs2090628
0.51
0.086445499
0.0928


hCV3230113
rs1053094
hCV11786028
rs6848963
0.51
0.086445499
0.1295


hCV3230113
rs1053094
hCV11786147
rs4862662
0.51
0.086445499
0.6694


hCV3230113
rs1053094
hCV11786203
rs4253251
0.51
0.086445499
0.0997


hCV3230113
rs1053094
hCV11786258
rs4253303
0.51
0.086445499
0.491


hCV3230113
rs1053094
hCV11786259
rs4253304
0.51
0.086445499
0.579


hCV3230113
rs1053094
hCV11786307
rs1062547
0.51
0.086445499
0.1175


hCV3230113
rs1053094
hCV11786327
rs13133050
0.51
0.086445499
0.1384


hCV3230113
rs1053094
hCV12066105
rs1519309
0.51
0.086445499
0.1053


hCV3230113
rs1053094
hCV12066106
rs1914926
0.51
0.086445499
0.1419


hCV3230113
rs1053094
hCV12066116
rs1877320
0.51
0.086445499
0.1094


hCV3230113
rs1053094
hCV12066118
rs2048
0.51
0.086445499
0.5759


hCV3230113
rs1053094
hCV12066119
rs1912826
0.51
0.086445499
0.5742


hCV3230113
rs1053094
hCV12066124
rs2036914
0.51
0.086445499
0.3142


hCV3230113
rs1053094
hCV15811716
rs2102575
0.51
0.086445499
0.1014


hCV3230113
rs1053094
hCV1589303
rs11730434
0.51
0.086445499
0.1249


hCV3230113
rs1053094
hCV1589308
rs9998530
0.51
0.086445499
0.1249


hCV3230113
rs1053094
hCV15968025
rs2292425
0.51
0.086445499
0.1645


hCV3230113
rs1053094
hCV15968026
rs2292426
0.51
0.086445499
0.2198


hCV3230113
rs1053094
hCV15968034
rs2292428
0.51
0.086445499
0.6489


hCV3230113
rs1053094
hCV15968043
rs2292423
0.51
0.086445499
0.59


hCV3230113
rs1053094
hCV15975109
rs2304596
0.51
0.086445499
0.2245


hCV3230113
rs1053094
hCV16172925
rs2241818
0.51
0.086445499
0.0959


hCV3230113
rs1053094
hCV16172935
rs2241817
0.51
0.086445499
0.0973


hCV3230113
rs1053094
hCV2103337
rs13102931
0.51
0.086445499
0.0958


hCV3230113
rs1053094
hCV2103343
rs4241824
0.51
0.086445499
0.2774


hCV3230113
rs1053094
hCV2103391
rs1008728
0.51
0.086445499
0.1352


hCV3230113
rs1053094
hCV2103392
rs12500826
0.51
0.086445499
0.1352


hCV3230113
rs1053094
hCV2103402
rs9993749
0.51
0.086445499
0.115


hCV3230113
rs1053094
hCV22271609
rs4253326
0.51
0.086445499
0.1496


hCV3230113
rs1053094
hCV22272267
rs3733402
0.51
0.086445499
0.5831


hCV3230113
rs1053094
hCV25474413
rs3822057
0.51
0.086445499
0.2648


hCV3230113
rs1053094
hCV25474414
rs4253399
0.51
0.086445499
0.2252


hCV3230113
rs1053094
hCV25634763
rs4253241
0.51
0.086445499
0.1111


hCV3230113
rs1053094
hCV25634781
rs4253299
0.51
0.086445499
0.1041


hCV3230113
rs1053094
hCV25988221
rs9995366
0.51
0.086445499
0.1117


hCV3230113
rs1053094
hCV25989001
hCV25989001
0.51
0.086445499
0.2371


hCV3230113
rs1053094
hCV25990131
rs13146272
0.51
0.086445499
0.1593


hCV3230113
rs1053094
hCV26038139
rs4253405
0.51
0.086445499
0.1405


hCV3230113
rs1053094
hCV26265197
rs10014399
0.51
0.086445499
0.096


hCV3230113
rs1053094
hCV26265199
rs2221843
0.51
0.086445499
0.1041


hCV3230113
rs1053094
hCV26265231
rs7684025
0.51
0.086445499
0.7049


hCV3230113
rs1053094
hCV27310170
rs4862644
0.51
0.086445499
0.1611


hCV3230113
rs1053094
hCV27310180
rs11722584
0.51
0.086445499
0.1383


hCV3230113
rs1053094
hCV27310216
rs10018625
0.51
0.086445499
0.102


hCV3230113
rs1053094
hCV27310218
rs9992614
0.51
0.086445499
0.0932


hCV3230113
rs1053094
hCV27310253
rs13108688
0.51
0.086445499
0.1242


hCV3230113
rs1053094
hCV27310255
rs7657186
0.51
0.086445499
0.1279


hCV3230113
rs1053094
hCV27474895
rs3756011
0.51
0.086445499
0.1126


hCV3230113
rs1053094
hCV27477533
rs3756008
0.51
0.086445499
0.2208


hCV3230113
rs1053094
hCV27482765
rs3775301
0.51
0.086445499
0.2245


hCV3230113
rs1053094
hCV27490984
rs3822058
0.51
0.086445499
0.096


hCV3230113
rs1053094
hCV27506149
rs3822055
0.51
0.086445499
0.1041


hCV3230113
rs1053094
hCV27902803
rs4862665
0.51
0.086445499
0.1117


hCV3230113
rs1053094
hCV27902808
rs4253236
0.51
0.086445499
0.3483


hCV3230113
rs1053094
hCV28960679
rs6844764
0.51
0.086445499
0.1995


hCV3230113
rs1053094
hCV29053260
rs4861707
0.51
0.086445499
0.0954


hCV3230113
rs1053094
hCV29053261
rs6842047
0.51
0.086445499
0.1117


hCV3230113
rs1053094
hCV29053264
rs7667777
0.51
0.086445499
0.6901


hCV3230113
rs1053094
hCV29053265
rs4253244
0.51
0.086445499
0.3493


hCV3230113
rs1053094
hCV29053271
rs6814261
0.51
0.086445499
0.0876


hCV3230113
rs1053094
hCV29718000
rs4253238
0.51
0.086445499
0.552


hCV3230113
rs1053094
hCV29877725
rs4253295
0.51
0.086445499
0.5019


hCV3230113
rs1053094
hCV30492573
rs10471184
0.51
0.086445499
0.1117


hCV3230113
rs1053094
hCV30983902
rs4862668
0.51
0.086445499
0.1111


hCV3230113
rs1053094
hCV30983907
rs4253246
0.51
0.086445499
0.1111


hCV3230113
rs1053094
hCV32209636
rs11132387
0.51
0.086445499
0.1091


hCV3230113
rs1053094
hCV32209637
rs13143773
0.51
0.086445499
0.096


hCV3230113
rs1053094
hCV32209638
rs12507040
0.51
0.086445499
0.0986


hCV3230113
rs1053094
hCV32209919
rs11730526
0.51
0.086445499
0.1298


hCV3230113
rs1053094
hCV32209928
rs13148663
0.51
0.086445499
0.1277


hCV3230113
rs1053094
hCV32291217
rs4253323
0.51
0.086445499
0.2245


hCV3230113
rs1053094
hCV32291269
rs4253417
0.51
0.086445499
0.1699


hCV3230113
rs1053094
hCV32291286
rs4253422
0.51
0.086445499
0.2024


hCV3230113
rs1053094
hCV32291287
rs4253423
0.51
0.086445499
0.2024


hCV3230113
rs1053094
hCV32291295
rs4253292
0.51
0.086445499
0.2276


hCV3230113
rs1053094
hCV32291301
rs4253302
0.51
0.086445499
0.224


hCV3230113
rs1053094
hCV32295028
rs4253260
0.51
0.086445499
0.2245


hCV3230113
rs1053094
hCV3229991
rs4241815
0.51
0.086445499
0.5831


hCV3230113
rs1053094
hCV3229992
rs3775298
0.51
0.086445499
0.5831


hCV3230113
rs1053094
hCV3229995
rs11132382
0.51
0.086445499
0.552


hCV3230113
rs1053094
hCV3230000
rs4253294
0.51
0.086445499
0.2474


hCV3230113
rs1053094
hCV3230001
rs4253296
0.51
0.086445499
0.1111


hCV3230113
rs1053094
hCV3230002
rs4253297
0.51
0.086445499
0.5144


hCV3230113
rs1053094
hCV3230003
rs2304595
0.51
0.086445499
0.573


hCV3230113
rs1053094
hCV3230004
rs4253301
0.51
0.086445499
0.1014


hCV3230113
rs1053094
hCV3230006
rs4253308
0.51
0.086445499
0.5019


hCV3230113
rs1053094
hCV3230007
rs4253311
0.51
0.086445499
0.5831


hCV3230113
rs1053094
hCV3230011
rs4253320
0.51
0.086445499
0.5144


hCV3230113
rs1053094
hCV3230012
rs4241821
0.51
0.086445499
0.1041


hCV3230113
rs1053094
hCV3230013
rs3775303
0.51
0.086445499
0.579


hCV3230113
rs1053094
hCV3230014
rs4861709
0.51
0.086445499
0.2474


hCV3230113
rs1053094
hCV3230017
rs4253327
0.51
0.086445499
0.1179


hCV3230113
rs1053094
hCV3230018
rs925453
0.51
0.086445499
0.2496


hCV3230113
rs1053094
hCV3230019
rs4253332
0.51
0.086445499
0.2496


hCV3230113
rs1053094
hCV3230022
rs11132383
0.51
0.086445499
0.1336


hCV3230113
rs1053094
hCV3230025
rs3756009
0.51
0.086445499
0.1859


hCV3230113
rs1053094
hCV3230031
rs4253419
0.51
0.086445499
0.2024


hCV3230113
rs1053094
hCV3230038
rs2289252
0.51
0.086445499
0.1432


hCV3230113
rs1053094
hCV3230079
rs35641294
0.51
0.086445499
0.0879


hCV3230113
rs1053094
hCV3230081
rs10866290
0.51
0.086445499
0.1232


hCV3230113
rs1053094
hCV3230083
rs10013653
0.51
0.086445499
0.5963


hCV3230113
rs1053094
hCV3230084
rs7682918
0.51
0.086445499
0.5711


hCV3230113
rs1053094
hCV3230094
rs7687818
0.51
0.086445499
0.7766


hCV3230113
rs1053094
hCV3230096
rs3817184
0.51
0.086445499
0.695


hCV3230113
rs1053094
hCV3230097
rs3736455
0.51
0.086445499
0.2344


hCV3230113
rs1053094
hCV3230101
rs6835839
0.51
0.086445499
0.6667


hCV3230113
rs1053094
hCV3230106
rs1473597
0.51
0.086445499
0.6384


hCV3230113
rs1053094
hCV3230110
rs2276917
0.51
0.086445499
0.6489


hCV3230113
rs1053094
hCV3230118
rs4253429
0.51
0.086445499
0.2024


hCV3230113
rs1053094
hCV3230119
rs4253430
0.51
0.086445499
0.096


hCV3230113
rs1053094
hCV3230125
rs11938564
0.51
0.086445499
0.1519


hCV3230113
rs1053094
hCV3230131
rs13136269
0.51
0.086445499
0.0986


hCV3230113
rs1053094
hCV3230133
rs12511874
0.51
0.086445499
0.0986


hCV3230113
rs1053094
hCV3230134
rs12500151
0.51
0.086445499
0.0986


hCV3230113
rs1053094
hCV3230136
rs13116273
0.51
0.086445499
0.1269


hCV3230113
rs1053094
hCV32313006
rs4253248
0.51
0.086445499
0.552


hCV3230113
rs1053094
hCV32313007
rs4862666
0.51
0.086445499
0.1117


hCV3230113
rs1053094
hCV32313024
rs4253239
0.51
0.086445499
0.2276


hCV3230113
rs1053094
hCV32358975
rs4253255
0.51
0.086445499
0.573


hCV3230113
rs1053094
hCV32358984
rs4253256
0.51
0.086445499
0.3678


hCV3230113
rs1053094
hCV441385
rs1983369
0.51
0.086445499
0.1249


hCV3230113
rs1053094
hCV79084
rs1519312
0.51
0.086445499
0.1129


hCV3230113
rs1053094
hCV8241630
rs925451
0.51
0.086445499
0.207


hCV3230113
rs1053094
hCV8241631
rs1511802
0.51
0.086445499
0.5019


hCV3230113
rs1053094
hCV8241632
rs1511801
0.51
0.086445499
0.6225


hCV3230113
rs1053094
hCV8241633
rs1511800
0.51
0.086445499
0.1117


hCV3230113
rs1053094
hCV8241661
rs1715051
0.51
0.086445499
0.1249


hCV3230113
rs1053094
hDV71222711
rs4253252
0.51
0.086445499
0.552


hCV3230113
rs1053094
hDV76175111
rs35079309
0.51
0.086445499
0.2766


hCV596331
rs6048
hCV2288124
rs440051
0.51
0.256432106
0.4103


hCV596331
rs6048
hCV26016183
rs9887617
0.51
0.256432106
0.3131


hCV596331
rs6048
hCV26225376
rs3117074
0.51
0.256432106
0.4074


hCV596331
rs6048
hCV26225377
rs12008759
0.51
0.256432106
0.4103


hCV596331
rs6048
hCV2969899
rs434144
0.51
0.256432106
0.3772


hCV596331
rs6048
hCV2969900
rs434447
0.51
0.256432106
0.4074


hCV596331
rs6048
hCV2986569
rs11095801
0.51
0.256432106
0.4074


hCV596331
rs6048
hCV2986570
rs3117458
0.51
0.256432106
0.3714


hCV596331
rs6048
hCV2986572
rs4149670
0.51
0.256432106
0.4393


hCV596331
rs6048
hCV2986574
rs4149672
0.51
0.256432106
0.602


hCV596331
rs6048
hCV2986575
rs4149674
0.51
0.256432106
0.602


hCV596331
rs6048
hCV596323
rs438601
0.51
0.256432106
0.5056


hCV596331
rs6048
hCV596326
rs398101
0.51
0.256432106
0.8045


hCV596331
rs6048
hCV596330
rs422187
0.51
0.256432106
0.9745


hCV596331
rs6048
hCV596335
rs413957
0.51
0.256432106
0.4074


hCV596331
rs6048
hCV596336
rs110583
0.51
0.256432106
0.4329


hCV596331
rs6048
hCV596337
rs421766
0.51
0.256432106
0.4329


hCV596331
rs6048
hCV596339
rs370713
0.51
0.256432106
0.4103


hCV596331
rs6048
hCV596340
rs413536
0.51
0.256432106
0.3724


hCV596331
rs6048
hCV596344
rs445691
0.51
0.256432106
0.4103


hCV596331
rs6048
hCV596669
rs376165
0.51
0.256432106
0.6589


hCV596331
rs6048
hDV70794854
rs17002122
0.51
0.256432106
0.3457


hCV596331
rs6048
hDV71066592
rs17002116
0.51
0.256432106
0.2766


hCV596331
rs6048
hDV76976791
rs4149758
0.51
0.256432106
0.3068


hCV8241630
rs925451
hCV11786147
rs4862662
0.51
0.047967528
0.1977


hCV8241630
rs925451
hCV11786235
rs4253287
0.51
0.047967528
0.0779


hCV8241630
rs925451
hCV11786258
rs4253303
0.51
0.047967528
0.2889


hCV8241630
rs925451
hCV11786259
rs4253304
0.51
0.047967528
0.3548


hCV8241630
rs925451
hCV11786295
rs4253421
0.51
0.047967528
0.0512


hCV8241630
rs925451
hCV11786307
rs1062547
0.51
0.047967528
0.3046


hCV8241630
rs925451
hCV11786327
rs13133050
0.51
0.047967528
0.1424


hCV8241630
rs925451
hCV12066116
rs1877320
0.51
0.047967528
0.0806


hCV8241630
rs925451
hCV12066118
rs2048
0.51
0.047967528
0.1423


hCV8241630
rs925451
hCV12066119
rs1912826
0.51
0.047967528
0.1513


hCV8241630
rs925451
hCV12066124
rs2036914
0.51
0.047967528
0.5632


hCV8241630
rs925451
hCV12066129
rs1593
0.51
0.047967528
0.0859


hCV8241630
rs925451
hCV1333083
rs10022988
0.51
0.047967528
0.0533


hCV8241630
rs925451
hCV1333090
rs6816112
0.51
0.047967528
0.0839


hCV8241630
rs925451
hCV1333097
rs4862680
0.51
0.047967528
0.0533


hCV8241630
rs925451
hCV1333099
rs10020635
0.51
0.047967528
0.0737


hCV8241630
rs925451
hCV15793897
rs3087505
0.51
0.047967528
0.0621


hCV8241630
rs925451
hCV15811716
rs2102575
0.51
0.047967528
0.0585


hCV8241630
rs925451
hCV15968025
rs2292425
0.51
0.047967528
0.1498


hCV8241630
rs925451
hCV15968026
rs2292426
0.51
0.047967528
0.2045


hCV8241630
rs925451
hCV15968034
rs2292428
0.51
0.047967528
0.1077


hCV8241630
rs925451
hCV15968043
rs2292423
0.51
0.047967528
0.338


hCV8241630
rs925451
hCV16172925
rs2241818
0.51
0.047967528
0.0837


hCV8241630
rs925451
hCV16172935
rs2241817
0.51
0.047967528
0.287


hCV8241630
rs925451
hCV2103343
rs4241824
0.51
0.047967528
0.605


hCV8241630
rs925451
hCV2103348
rs11931515
0.51
0.047967528
0.0499


hCV8241630
rs925451
hCV2103388
rs4613610
0.51
0.047967528
0.0893


hCV8241630
rs925451
hCV2103391
rs1008728
0.51
0.047967528
0.1739


hCV8241630
rs925451
hCV2103392
rs12500826
0.51
0.047967528
0.3352


hCV8241630
rs925451
hCV22272267
rs3733402
0.51
0.047967528
0.1476


hCV8241630
rs925451
hCV25474413
rs3822057
0.51
0.047967528
0.596


hCV8241630
rs925451
hCV25474414
rs4253399
0.51
0.047967528
0.9606


hCV8241630
rs925451
hCV25634754
rs4253331
0.51
0.047967528
0.0907


hCV8241630
rs925451
hCV25988221
rs9995366
0.51
0.047967528
0.0657


hCV8241630
rs925451
hCV25990131
rs13146272
0.51
0.047967528
0.1564


hCV8241630
rs925451
hCV26038139
rs4253405
0.51
0.047967528
0.3823


hCV8241630
rs925451
hCV26265231
rs7684025
0.51
0.047967528
0.2509


hCV8241630
rs925451
hCV27309972
rs13101296
0.51
0.047967528
0.1189


hCV8241630
rs925451
hCV27309991
rs4572916
0.51
0.047967528
0.0972


hCV8241630
rs925451
hCV27473099
rs3733403
0.51
0.047967528
0.078


hCV8241630
rs925451
hCV27474895
rs3756011
0.51
0.047967528
0.7876


hCV8241630
rs925451
hCV27477533
rs3756008
0.51
0.047967528
0.9804


hCV8241630
rs925451
hCV27490984
rs3822058
0.51
0.047967528
0.2976


hCV8241630
rs925451
hCV27521729
rs3822056
0.51
0.047967528
0.096


hCV8241630
rs925451
hCV27902803
rs4862665
0.51
0.047967528
0.0657


hCV8241630
rs925451
hCV27902808
rs4253236
0.51
0.047967528
0.0514


hCV8241630
rs925451
hCV28960679
rs6844764
0.51
0.047967528
0.1817


hCV8241630
rs925451
hCV29053261
rs6842047
0.51
0.047967528
0.0621


hCV8241630
rs925451
hCV29053264
rs7667777
0.51
0.047967528
0.2641


hCV8241630
rs925451
hCV29053265
rs4253244
0.51
0.047967528
0.0566


hCV8241630
rs925451
hCV29718000
rs4253238
0.51
0.047967528
0.1666


hCV8241630
rs925451
hCV29826351
rs10025990
0.51
0.047967528
0.0954


hCV8241630
rs925451
hCV29877725
rs4253295
0.51
0.047967528
0.2376


hCV8241630
rs925451
hCV30492573
rs10471184
0.51
0.047967528
0.0621


hCV8241630
rs925451
hCV30983902
rs4862668
0.51
0.047967528
0.0806


hCV8241630
rs925451
hCV30983927
rs6552962
0.51
0.047967528
0.0884


hCV8241630
rs925451
hCV32209629
rs12715865
0.51
0.047967528
0.1026


hCV8241630
rs925451
hCV32209636
rs11132387
0.51
0.047967528
0.3826


hCV8241630
rs925451
hCV32209637
rs13143773
0.51
0.047967528
0.2155


hCV8241630
rs925451
hCV32209638
rs12507040
0.51
0.047967528
0.2055


hCV8241630
rs925451
hCV32291256
rs4253406
0.51
0.047967528
0.1121


hCV8241630
rs925451
hCV32291269
rs4253417
0.51
0.047967528
0.7639


hCV8241630
rs925451
hCV32291286
rs4253422
0.51
0.047967528
0.1422


hCV8241630
rs925451
hCV32291287
rs4253423
0.51
0.047967528
0.1422


hCV8241630
rs925451
hCV32291295
rs4253292
0.51
0.047967528
0.0633


hCV8241630
rs925451
hCV3229991
rs4241815
0.51
0.047967528
0.1476


hCV8241630
rs925451
hCV3229992
rs3775298
0.51
0.047967528
0.1476


hCV8241630
rs925451
hCV3229995
rs11132382
0.51
0.047967528
0.1645


hCV8241630
rs925451
hCV3230000
rs4253294
0.51
0.047967528
0.0677


hCV8241630
rs925451
hCV3230002
rs4253297
0.51
0.047967528
0.2853


hCV8241630
rs925451
hCV3230003
rs2304595
0.51
0.047967528
0.3258


hCV8241630
rs925451
hCV3230004
rs4253301
0.51
0.047967528
0.0548


hCV8241630
rs925451
hCV3230006
rs4253308
0.51
0.047967528
0.2376


hCV8241630
rs925451
hCV3230007
rs4253311
0.51
0.047967528
0.1476


hCV8241630
rs925451
hCV3230010
rs4253315
0.51
0.047967528
0.0806


hCV8241630
rs925451
hCV3230011
rs4253320
0.51
0.047967528
0.2853


hCV8241630
rs925451
hCV3230013
rs3775303
0.51
0.047967528
0.3548


hCV8241630
rs925451
hCV3230014
rs4861709
0.51
0.047967528
0.0677


hCV8241630
rs925451
hCV3230016
rs4253325
0.51
0.047967528
0.0805


hCV8241630
rs925451
hCV3230017
rs4253327
0.51
0.047967528
0.1125


hCV8241630
rs925451
hCV3230018
rs925453
0.51
0.047967528
0.0593


hCV8241630
rs925451
hCV3230019
rs4253332
0.51
0.047967528
0.0554


hCV8241630
rs925451
hCV3230021
rs13135645
0.51
0.047967528
0.0814


hCV8241630
rs925451
hCV3230022
rs11132383
0.51
0.047967528
0.3677


hCV8241630
rs925451
hCV3230025
rs3756009
0.51
0.047967528
1


hCV8241630
rs925451
hCV3230030
rs4253408
0.51
0.047967528
0.1145


hCV8241630
rs925451
hCV3230031
rs4253419
0.51
0.047967528
0.1422


hCV8241630
rs925451
hCV3230038
rs2289252
0.51
0.047967528
0.7423


hCV8241630
rs925451
hCV3230051
rs4862658
0.51
0.047967528
0.0538


hCV8241630
rs925451
hCV3230083
rs10013653
0.51
0.047967528
0.2951


hCV8241630
rs925451
hCV3230084
rs7682918
0.51
0.047967528
0.2117


hCV8241630
rs925451
hCV3230094
rs7687818
0.51
0.047967528
0.3063


hCV8241630
rs925451
hCV3230096
rs3817184
0.51
0.047967528
0.2184


hCV8241630
rs925451
hCV3230097
rs3736455
0.51
0.047967528
0.2161


hCV8241630
rs925451
hCV3230101
rs6835839
0.51
0.047967528
0.0876


hCV8241630
rs925451
hCV3230106
rs1473597
0.51
0.047967528
0.127


hCV8241630
rs925451
hCV3230110
rs2276917
0.51
0.047967528
0.1184


hCV8241630
rs925451
hCV3230113
rs1053094
0.51
0.047967528
0.207


hCV8241630
rs925451
hCV3230118
rs4253429
0.51
0.047967528
0.1422


hCV8241630
rs925451
hCV3230119
rs4253430
0.51
0.047967528
0.2905


hCV8241630
rs925451
hCV3230125
rs11938564
0.51
0.047967528
0.1896


hCV8241630
rs925451
hCV3230131
rs13136269
0.51
0.047967528
0.2055


hCV8241630
rs925451
hCV3230133
rs12511874
0.51
0.047967528
0.1512


hCV8241630
rs925451
hCV3230134
rs12500151
0.51
0.047967528
0.2115


hCV8241630
rs925451
hCV3230136
rs13116273
0.51
0.047967528
0.229


hCV8241630
rs925451
hCV32313006
rs4253248
0.51
0.047967528
0.1736


hCV8241630
rs925451
hCV32313007
rs4862666
0.51
0.047967528
0.0657


hCV8241630
rs925451
hCV32313014
rs4253243
0.51
0.047967528
0.0907


hCV8241630
rs925451
hCV32313024
rs4253239
0.51
0.047967528
0.0633


hCV8241630
rs925451
hCV32358975
rs4253255
0.51
0.047967528
0.1454


hCV8241630
rs925451
hCV32358984
rs4253256
0.51
0.047967528
0.0647


hCV8241630
rs925451
hCV8241628
rs907439
0.51
0.047967528
0.0972


hCV8241630
rs925451
hCV8241631
rs1511802
0.51
0.047967528
0.2539


hCV8241630
rs925451
hCV8241632
rs1511801
0.51
0.047967528
0.1877


hCV8241630
rs925451
hCV8241633
rs1511800
0.51
0.047967528
0.0657


hCV8241630
rs925451
hDV68550952
rs4253289
0.51
0.047967528
0.0659


hCV8241630
rs925451
hDV71222711
rs4253252
0.51
0.047967528
0.1736


hCV8717873
rs1613662
hCV11977629
rs1654459
0.51
0.291390182
0.824


hCV8717873
rs1613662
hCV1376257
rs10416380
0.51
0.291390182
0.688


hCV8717873
rs1613662
hCV1376262
rs1671150
0.51
0.291390182
0.7101


hCV8717873
rs1613662
hCV1376264
rs1671151
0.51
0.291390182
0.7101


hCV8717873
rs1613662
hCV1376265
rs1671152
0.51
0.291390182
0.881


hCV8717873
rs1613662
hCV1376266
rs1654413
0.51
0.291390182
0.8292


hCV8717873
rs1613662
hCV1376342
rs1654416
0.51
0.291390182
0.7313


hCV8717873
rs1613662
hCV1376359
rs2886412
0.51
0.291390182
0.8039


hCV8717873
rs1613662
hCV1376386
rs1671214
0.51
0.291390182
0.4218


hCV8717873
rs1613662
hCV1376388
rs1671215
0.51
0.291390182
0.4218


hCV8717873
rs1613662
hCV1376414
rs1671171
0.51
0.291390182
0.4652


hCV8717873
rs1613662
hCV15973734
rs2304167
0.51
0.291390182
0.7101


hCV8717873
rs1613662
hCV16044361
rs2569513
0.51
0.291390182
0.8557


hCV8717873
rs1613662
hCV26895244
rs1671153
0.51
0.291390182
0.7101


hCV8717873
rs1613662
hCV26895257
rs2886415
0.51
0.291390182
0.8732


hCV8717873
rs1613662
hCV29271569
rs1626971
0.51
0.291390182
0.8853


hCV8717873
rs1613662
hCV31722831
rs11671922
0.51
0.291390182
0.8358


hCV8717873
rs1613662
hCV31722832
rs11084381
0.51
0.291390182
0.8192


hCV8717873
rs1613662
hCV31722834
rs11084382
0.51
0.291390182
0.7187


hCV8717873
rs1613662
hCV31722835
rs11668169
0.51
0.291390182
0.8188


hCV8717873
rs1613662
hCV31722836
rs11672026
0.51
0.291390182
0.8093


hCV8717873
rs1613662
hCV7841075
rs1671196
0.51
0.291390182
0.8192


hCV8717873
rs1613662
hCV8703249
rs1654444
0.51
0.291390182
0.8822


hCV8717873
rs1613662
hCV8704962
rs775893
0.51
0.291390182
0.5398


hCV8717873
rs1613662
hCV8717751
rs1671218
0.51
0.291390182
0.4141


hCV8717873
rs1613662
hCV8717752
rs1671217
0.51
0.291390182
0.8853


hCV8717873
rs1613662
hCV8717761
rs1654439
0.51
0.291390182
0.776


hCV8717873
rs1613662
hCV8717793
rs1654433
0.51
0.291390182
0.8557


hCV8717873
rs1613662
hCV8717794
rs1654432
0.51
0.291390182
0.8557


hCV8717873
rs1613662
hCV8717845
rs892090
0.51
0.291390182
1


hCV8717873
rs1613662
hCV8717846
rs892089
0.51
0.291390182
0.8358


hCV8717873
rs1613662
hCV8717871
rs1654421
0.51
0.291390182
0.6875


hCV8717873
rs1613662
hCV8717881
rs1654420
0.51
0.291390182
0.8188


hCV8717873
rs1613662
hCV8717893
rs1671192
0.51
0.291390182
0.8737


hCV8717873
rs1613662
hCV8718961
rs1654451
0.51
0.291390182
0.8233


hCV8717873
rs1613662
hCV8718968
rs1671176
0.51
0.291390182
0.4332


hCV8717873
rs1613662
hCV8718972
rs1654447
0.51
0.291390182
0.8825


hCV8717873
rs1613662
hCV9490926
rs1654419
0.51
0.291390182
0.8188


hCV8717873
rs1613662
hDV91225183
rs1671171
0.51
0.291390182
0.4652


hCV8718961
rs1654451
hCV11977629
rs1654459
0.51
0.573058702
1


hCV8718961
rs1654451
hCV1376265
rs1671152
0.51
0.573058702
0.7073


hCV8718961
rs1654451
hCV1376266
rs1654413
0.51
0.573058702
0.7211


hCV8718961
rs1654451
hCV1376342
rs1654416
0.51
0.573058702
0.5824


hCV8718961
rs1654451
hCV1376359
rs2886412
0.51
0.573058702
0.7389


hCV8718961
rs1654451
hCV16044361
rs2569513
0.51
0.573058702
0.9121


hCV8718961
rs1654451
hCV26895257
rs2886415
0.51
0.573058702
0.8105


hCV8718961
rs1654451
hCV29271569
rs1626971
0.51
0.573058702
1


hCV8718961
rs1654451
hCV31722831
rs11671922
0.51
0.573058702
0.7314


hCV8718961
rs1654451
hCV31722832
rs11084381
0.51
0.573058702
0.6692


hCV8718961
rs1654451
hCV31722834
rs11084382
0.51
0.573058702
0.584


hCV8718961
rs1654451
hCV31722835
rs11668169
0.51
0.573058702
0.6692


hCV8718961
rs1654451
hCV31722836
rs11672026
0.51
0.573058702
0.7025


hCV8718961
rs1654451
hCV7841075
rs1671196
0.51
0.573058702
0.6692


hCV8718961
rs1654451
hCV8703249
rs1654444
0.51
0.573058702
0.9398


hCV8718961
rs1654451
hCV8717752
rs1671217
0.51
0.573058702
1


hCV8718961
rs1654451
hCV8717761
rs1654439
0.51
0.573058702
0.8855


hCV8718961
rs1654451
hCV8717793
rs1654433
0.51
0.573058702
0.9121


hCV8718961
rs1654451
hCV8717794
rs1654432
0.51
0.573058702
0.9121


hCV8718961
rs1654451
hCV8717845
rs892090
0.51
0.573058702
0.8233


hCV8718961
rs1654451
hCV8717846
rs892089
0.51
0.573058702
0.7314


hCV8718961
rs1654451
hCV8717873
rs1613662
0.51
0.573058702
0.8233


hCV8718961
rs1654451
hCV8717881
rs1654420
0.51
0.573058702
0.6692


hCV8718961
rs1654451
hCV8717893
rs1671192
0.51
0.573058702
0.756


hCV8718961
rs1654451
hCV8718972
rs1654447
0.51
0.573058702
0.94


hCV8718961
rs1654451
hCV9490926
rs1654419
0.51
0.573058702
0.6692


hCV8911768
rs941988
hCV11342529
rs1951627
0.51
0.228649809
0.3108


hCV8911768
rs941988
hCV11975630
rs2065170
0.51
0.228649809
1


hCV8911768
rs941988
hCV15864094
rs2068871
0.51
0.228649809
0.9425


hCV8911768
rs941988
hCV15956059
rs2227592
0.51
0.228649809
1


hCV8911768
rs941988
hCV16135173
rs2146372
0.51
0.228649809
1


hCV8911768
rs941988
hCV16180170
rs2227589
0.51
0.228649809
1


hCV8911768
rs941988
hCV16290208
rs2759328
0.51
0.228649809
1


hCV8911768
rs941988
hCV1681325
rs898657
0.51
0.228649809
0.288


hCV8911768
rs941988
hCV1681328
rs10912647
0.51
0.228649809
0.2457


hCV8911768
rs941988
hCV25600635
rs7539322
0.51
0.228649809
0.8856


hCV8911768
rs941988
hCV25932979
rs16846809
0.51
0.228649809
0.5549


hCV8911768
rs941988
hCV27483572
rs3791022
0.51
0.228649809
1


hCV8911768
rs941988
hCV28998001
rs6425251
0.51
0.228649809
0.2457


hCV8911768
rs941988
hCV29517287
rs2901747
0.51
0.228649809
0.2436


hCV8911768
rs941988
hCV29989899
rs6685043
0.51
0.228649809
0.6095


hCV8911768
rs941988
hCV30205817
rs10489254
0.51
0.228649809
0.5549


hCV8911768
rs941988
hCV30404194
rs6691053
0.51
0.228649809
0.3572


hCV8911768
rs941988
hCV30472885
rs7520441
0.51
0.228649809
0.315


hCV8911768
rs941988
hCV30804119
rs10912651
0.51
0.228649809
0.2376


hCV8911768
rs941988
hCV30804135
rs12078293
0.51
0.228649809
0.2457


hCV8911768
rs941988
hCV30804139
rs12089930
0.51
0.228649809
0.245


hCV8911768
rs941988
hCV8911729
rs941987
0.51
0.228649809
0.8292


hCV8911768
rs941988
hCV9575253
rs1031751
0.51
0.228649809
0.3146


hCV8911768
rs941988
hCV9575263
rs898658
0.51
0.228649809
0.2457


hCV8911768
rs941988
hDV70683090
rs16846433
0.51
0.228649809
0.9425


hCV8911768
rs941988
hDV70683162
rs16846526
0.51
0.228649809
1


hCV8911768
rs941988
hDV70683177
rs16846546
0.51
0.228649809
1


hCV8911768
rs941988
hDV70683187
rs16846561
0.51
0.228649809
1


hCV8911768
rs941988
hDV70683212
rs16846593
0.51
0.228649809
0.5549


hCV8911768
rs941988
hDV70683382
rs16846815
0.51
0.228649809
0.5078


hCV8911768
rs941988
hDV70934851
rs17301125
0.51
0.228649809
0.2534


hCV8919444
rs4524
hCV11341772
rs4589164
0.51
0.098333329
0.1285


hCV8919444
rs4524
hCV11341879
rs7527703
0.51
0.098333329
0.1112


hCV8919444
rs4524
hCV11341886
rs7539415
0.51
0.098333329
0.1052


hCV8919444
rs4524
hCV11341964
rs12124049
0.51
0.098333329
0.1062


hCV8919444
rs4524
hCV11342057
rs10919186
0.51
0.098333329
0.7473


hCV8919444
rs4524
hCV11975196
rs2040444
0.51
0.098333329
0.358


hCV8919444
rs4524
hCV1264276
rs17345170
0.51
0.098333329
0.1214


hCV8919444
rs4524
hCV15802102
rs2420369
0.51
0.098333329
0.3671


hCV8919444
rs4524
hCV15847759
rs2187952
0.51
0.098333329
1


hCV8919444
rs4524
hCV15852051
rs2213867
0.51
0.098333329
0.8264


hCV8919444
rs4524
hCV15955265
rs2227244
0.51
0.098333329
1


hCV8919444
rs4524
hCV16141160
rs2157597
0.51
0.098333329
0.1285


hCV8919444
rs4524
hCV16175730
rs2239851
0.51
0.098333329
1


hCV8919444
rs4524
hCV16175731
rs2239852
0.51
0.098333329
0.8118


hCV8919444
rs4524
hCV16191269
rs2298909
0.51
0.098333329
0.6586


hCV8919444
rs4524
hCV22274637
rs2301515
0.51
0.098333329
0.7941


hCV8919444
rs4524
hCV2229795
rs723751
0.51
0.098333329
0.4376


hCV8919444
rs4524
hCV2456680
rs6427193
0.51
0.098333329
0.119


hCV8919444
rs4524
hCV2456690
rs6692649
0.51
0.098333329
0.1119


hCV8919444
rs4524
hCV2456692
rs12128350
0.51
0.098333329
0.1136


hCV8919444
rs4524
hCV2456693
rs6672589
0.51
0.098333329
0.1331


hCV8919444
rs4524
hCV2456695
rs10919173
0.51
0.098333329
0.1331


hCV8919444
rs4524
hCV2456709
rs17577184
0.51
0.098333329
0.1068


hCV8919444
rs4524
hCV2456710
rs4656680
0.51
0.098333329
0.1112


hCV8919444
rs4524
hCV2456716
rs12730053
0.51
0.098333329
0.1112


hCV8919444
rs4524
hCV2456722
rs12119479
0.51
0.098333329
0.1112


hCV8919444
rs4524
hCV2456729
rs12143708
0.51
0.098333329
0.1068


hCV8919444
rs4524
hCV2456767
rs2014061
0.51
0.098333329
0.1287


hCV8919444
rs4524
hCV2456774
rs1014965
0.51
0.098333329
0.1025


hCV8919444
rs4524
hCV2456776
rs6669741
0.51
0.098333329
0.1052


hCV8919444
rs4524
hCV2456780
rs7534737
0.51
0.098333329
0.1052


hCV8919444
rs4524
hCV2481727
rs6670407
0.51
0.098333329
0.4176


hCV8919444
rs4524
hCV2481728
rs9332665
0.51
0.098333329
0.7359


hCV8919444
rs4524
hCV2481731
rs9332640
0.51
0.098333329
0.4021


hCV8919444
rs4524
hCV2481732
rs12131397
0.51
0.098333329
0.3978


hCV8919444
rs4524
hCV2481733
rs9332627
0.51
0.098333329
1


hCV8919444
rs4524
hCV2481738
rs4656187
0.51
0.098333329
1


hCV8919444
rs4524
hCV2481741
rs3766109
0.51
0.098333329
1


hCV8919444
rs4524
hCV2481744
rs9332600
0.51
0.098333329
1


hCV8919444
rs4524
hCV2481747
rs9332595
0.51
0.098333329
0.7683


hCV8919444
rs4524
hCV2481748
rs3766110
0.51
0.098333329
0.7683


hCV8919444
rs4524
hCV2481750
rs10800456
0.51
0.098333329
0.6306


hCV8919444
rs4524
hCV2520857
rs12118611
0.51
0.098333329
0.1356


hCV8919444
rs4524
hCV2520872
rs3766090
0.51
0.098333329
0.1059


hCV8919444
rs4524
hCV2520887
rs10442644
0.51
0.098333329
0.1285


hCV8919444
rs4524
hCV2521003
rs2040446
0.51
0.098333329
0.1214


hCV8919444
rs4524
hCV25617181
rs9332620
0.51
0.098333329
1


hCV8919444
rs4524
hCV25922120
rs9332643
0.51
0.098333329
1


hCV8919444
rs4524
hCV27242356
rs12121994
0.51
0.098333329
0.1358


hCV8919444
rs4524
hCV27242515
rs3818844
0.51
0.098333329
0.1009


hCV8919444
rs4524
hCV27242533
rs2138898
0.51
0.098333329
0.1023


hCV8919444
rs4524
hCV27242706
rs7524348
0.51
0.098333329
0.1331


hCV8919444
rs4524
hCV27242809
rs9332630
0.51
0.098333329
0.3659


hCV8919444
rs4524
hCV27490260
rs3820060
0.51
0.098333329
0.8118


hCV8919444
rs4524
hCV275164
rs12140572
0.51
0.098333329
0.1278


hCV8919444
rs4524
hCV27928247
rs4656182
0.51
0.098333329
0.1068


hCV8919444
rs4524
hCV27972646
rs4656677
0.51
0.098333329
0.1112


hCV8919444
rs4524
hCV288901
rs4656671
0.51
0.098333329
0.1112


hCV8919444
rs4524
hCV29621699
rs9332619
0.51
0.098333329
1


hCV8919444
rs4524
hCV30018856
rs6701330
0.51
0.098333329
0.7509


hCV8919444
rs4524
hCV30036717
rs9332653
0.51
0.098333329
0.102


hCV8919444
rs4524
hCV30144962
rs10158595
0.51
0.098333329
0.7453


hCV8919444
rs4524
hCV30234691
rs6662593
0.51
0.098333329
0.9762


hCV8919444
rs4524
hCV30433255
rs9332655
0.51
0.098333329
0.9135


hCV8919444
rs4524
hCV30504827
rs9332608
0.51
0.098333329
0.1235


hCV8919444
rs4524
hCV30577322
rs7516248
0.51
0.098333329
0.1052


hCV8919444
rs4524
hCV32141090
rs12039443
0.51
0.098333329
0.1294


hCV8919444
rs4524
hCV32141333
rs10800446
0.51
0.098333329
0.0998


hCV8919444
rs4524
hCV32141337
rs10919164
0.51
0.098333329
0.115


hCV8919444
rs4524
hCV32141359
rs12022776
0.51
0.098333329
0.0998


hCV8919444
rs4524
hCV32141374
rs10919174
0.51
0.098333329
0.1582


hCV8919444
rs4524
hCV32398607
rs4656658
0.51
0.098333329
0.1214


hCV8919444
rs4524
hCV328321
rs9332667
0.51
0.098333329
1


hCV8919444
rs4524
hCV337817
rs9332586
0.51
0.098333329
0.1619


hCV8919444
rs4524
hCV340605
rs1557572
0.51
0.098333329
0.7416


hCV8919444
rs4524
hCV341935
rs4656685
0.51
0.098333329
0.9762


hCV8919444
rs4524
hCV342590
rs6030
0.51
0.098333329
0.847


hCV8919444
rs4524
hCV475606
rs17349579
0.51
0.098333329
0.105


hCV8919444
rs4524
hCV70275
rs4656687
0.51
0.098333329
0.8118


hCV8919444
rs4524
hCV8006091
rs6656463
0.51
0.098333329
0.1151


hCV8919444
rs4524
hCV8697038
rs961403
0.51
0.098333329
0.1052


hCV8919444
rs4524
hCV8697043
rs1517747
0.51
0.098333329
0.1582


hCV8919444
rs4524
hCV8919166
rs1200139
0.51
0.098333329
0.1536


hCV8919444
rs4524
hCV8919279
rs1200079
0.51
0.098333329
0.2649


hCV8919444
rs4524
hCV8919424
rs974793
0.51
0.098333329
0.9762


hCV8919444
rs4524
hCV8919429
rs970741
0.51
0.098333329
0.9762


hCV8919444
rs4524
hCV8919436
rs916438
0.51
0.098333329
0.8118


hCV8919444
rs4524
hCV8919438
rs1557570
0.51
0.098333329
0.7402


hCV8919444
rs4524
hCV8919441
rs6032
0.51
0.098333329
1


hCV8919444
rs4524
hCV8919442
rs4525
0.51
0.098333329
1


hCV8919444
rs4524
hCV8919446
rs6021
0.51
0.098333329
1


hCV8919444
rs4524
hCV8919450
rs6017
0.51
0.098333329
1


hCV8919444
rs4524
hCV8919451
rs6016
0.51
0.098333329
0.9762


hCV8919444
rs4524
hCV9945852
rs1121789
0.51
0.098333329
1


hCV8919444
rs4524
hDV70942075
rs17349271
0.51
0.098333329
0.1214


hCV8919444
rs4524
hDV70942101
rs17349439
0.51
0.098333329
0.1214


hCV8919444
rs4524
hDV77030721
rs4656664
0.51
0.098333329
0.1224


hCV9102827
rs3795733
hCV11258640
rs6427323
0.51
0.60489105
0.7384


hCV9102827
rs3795733
hCV25989540
rs6682716
0.51
0.60489105
0.6304


hCV9102827
rs3795733
hCV26627664
rs3795727
0.51
0.60489105
0.7186


hCV9102827
rs3795733
hCV26627665
rs2365714
0.51
0.60489105
0.7186


hCV9102827
rs3795733
hCV26627679
rs7536235
0.51
0.60489105
0.7186


hCV9102827
rs3795733
hCV31431594
rs12567958
0.51
0.60489105
0.863


hCV9102827
rs3795733
hCV31431603
rs11264508
0.51
0.60489105
0.7186


hCV9102827
rs3795733
hCV31431609
rs12742817
0.51
0.60489105
0.7186


hCV9102827
rs3795733
hCV31431620
rs12023410
0.51
0.60489105
0.714


hCV9102827
rs3795733
hCV31431621
rs11576266
0.51
0.60489105
1


hCV9102827
rs3795733
hCV9102814
rs879461
0.51
0.60489105
0.8863


hCV9102827
rs3795733
hCV9102822
rs4661052
0.51
0.60489105
0.8863


hCV9102827
rs3795733
hCV9102823
rs12024215
0.51
0.60489105
0.7508


hCV9102827
rs3795733
hCV9102829
rs3795732
0.51
0.60489105
0.8859


hCV9102827
rs3795733
hCV9102841
rs4661188
0.51
0.60489105
0.8863


hCV9102827
rs3795733
hCV9102976
rs10908509
0.51
0.60489105
0.6291


hCV916107
rs670659
hCV1874947
rs494075
0.51
0.426900693
0.4398


hCV916107
rs670659
hCV25653735
rs7520707
0.51
0.426900693
0.5479


hCV916107
rs670659
hCV26887401
rs10802916
0.51
0.426900693
0.4941


hCV916107
rs670659
hCV26887441
rs9786932
0.51
0.426900693
0.5809


hCV916107
rs670659
hCV26887461
rs4660023
0.51
0.426900693
0.7128


hCV916107
rs670659
hCV26887463
rs6680767
0.51
0.426900693
0.7121


hCV916107
rs670659
hCV26887464
rs6669640
0.51
0.426900693
0.6131


hCV916107
rs670659
hCV26887465
rs10802919
0.51
0.426900693
0.5881


hCV916107
rs670659
hCV31714435
rs12143076
0.51
0.426900693
0.463


hCV916107
rs670659
hCV31714436
rs12132113
0.51
0.426900693
0.43


hCV916107
rs670659
hCV31714438
rs12731839
0.51
0.426900693
0.4771


hCV916107
rs670659
hCV31714442
rs12119557
0.51
0.426900693
0.4359


hCV916107
rs670659
hCV31714442
rs12758552
0.51
0.426900693
0.4423


hCV916107
rs670659
hCV31714443
rs12758552
0.51
0.426900693
0.4423


hCV916107
rs670659
hCV31714447
rs10926387
0.51
0.426900693
0.5544


hCV916107
rs670659
hCV31714470
rs10926390
0.51
0.426900693
0.4745


hCV916107
rs670659
hCV31714471
rs10926391
0.51
0.426900693
0.4562


hCV916107
rs670659
hCV916106
rs575226
0.51
0.426900693
1
















TABLE 4





Table 4. Association of statin with VT in 27 SNP genotype subgroups in MEGA



























statin




Risk



users,


hCV #
Gene Symbol (SNP rs #)
Allele
Subgroup
OR (95% CI)
P
cases


















hCV11286902
LOC400499 (rs12932948)
G
GG
0.34
(0.19-0.62)
 4E−04
14
(0.11)





GA
0.6
(0.43-0.82)
0.001
62
(0.5)





AA
0.78
(0.53-1.15)
0.208
47
(0.38)





GA + GG
0.52
(0.4-0.69)
5.E−06





GA + AA
0.66
(0.52-0.85)
 9E−04


hCV11786258
KLKB1 (rs4253303)
A
AA
0.35
(0.19-0.64)
 7E−04
15
(0.12)





AG
0.57
(0.42-0.79)
 6E−04
61
(0.49)





GG
0.73
(0.51-1.06)
0.095
48
(0.39)





AG + AA
0.51
(0.39-0.68)
3.E−06





AG + GG
0.63
(0.5-0.81)
 2E−04


hCV12066124
F11 (rs2036914)
C
CC
0.38
(0.24-0.6)
3.E−05
27
(0.22)





CT
0.66
(0.49-0.9)
0.008
72
(0.59)





TT
0.64
(0.39-1.05)
0.077
23
(0.19)





CT + CC
0.55
(0.43-0.71)
3.E−06





CT + TT
0.66
(0.51-0.85)
0.001


hCV12092542
CASP5 (rs507879)
T
TT
0.75
(0.49-1.15)
0.189
39
(0.33)





TC
0.47
(0.34-0.66)
1.E−05
52
(0.44)





CC
0.94
(0.56-1.58)
0.815
28
(0.24)





TC + TT
0.56
(0.43-0.73)
2.E−05





TC + CC
0.57
(0.43-0.76)
 1E−04


hCV15968043
CYP4V2 (rs2292423)
A
AA
0.33
(0.18-0.61)
 3E−04
15
(0.12)





AT
0.61
(0.45-0.84)
0.002
64
(0.53)





TT
0.67
(0.46-0.98)
0.038
42
(0.35)





AT + AA
0.53
(0.4-0.7)
8.E−06





AT + TT
0.63
(0.5-0.81)
 2E−04


hCV16171263
PRLR (rs16871473)
G
GA
0.2
(0.06-0.68)
0.01 
3
(0.02)





AA
0.61
(0.49-0.77)
2.E−05
122
(0.98)





GA + GG
0.2
(0.06-0.68)
0.01 





GA + AA
0.58
(0.47-0.73)
2.E−06


hCV1859855
GOLGA3 (rs2291260)
C
CC
0.16
(0.04-0.56)
0.004
3
(0.02)





CT
0.6
(0.42-0.86)
0.005
48
(0.39)





TT
0.6
(0.45-0.81)
 8E−04
71
(0.58)





CT + CC
0.52
(0.37-0.73)
 2E−04





CT + TT
0.6
(0.48-0.76)
1.E−05


hCV1948599
CSMD2 (rs504527)
A
AA
0.51
(0.31-0.84)
0.008
24
(0.2)





AC
0.49
(0.35-0.68)
2.E−05
53
(0.43)





CC
0.86
(0.58-1.27)
0.44 
45
(0.37)





AC + AA
0.49
(0.38-0.65)
4.E−07





AC + CC
0.61
(0.47-0.78)
1.E−04


hCV1952126
(rs7223784)
A
AA
0.54
(0.4-0.74)
9.E−05
64
(0.52)





AC
0.52
(0.36-0.75)
 5E−04
43
(0.35)





CC
1.21
(0.61-2.42)
0.584
17
(0.14)





AC + AA
0.53
(0.42-0.67)
2.E−07





AC + CC
0.62
(0.45-0.85)
0.003


hCV22272267
KLKB1 (rs3733402)
A
AA
0.41
(0.26-0.65)
 2E−04
27
(0.22)





AG
0.67
(0.5-0.91)
0.01 
70
(0.56)





GG
0.67
(0.42-1.06)
0.085
28
(0.22)





AG + AA
0.57
(0.44-0.74)
2.E−05





AG + GG
0.67
(0.52-0.86)
0.002


hCV2434510
RNASE7 (rs1243469)
C
CC
0.8
(0.07-9.85)
0.863
1
(0.01)





CT
0.35
(0.2-0.61)
 2E−04
17
(0.14)





TT
0.66
(0.52-0.84)
 9E−04
106
(0.85)





CT + CC
0.36
(0.21-0.62)
 3E−04





CT + TT
0.59
(0.47-0.74)
4.E−06


hCV25610857
(rs8176693)
T
TT
1.61
(0.13-19.25)
0.709
2
(0.02)





TC
0.92
(0.55-1.54)
0.755
31
(0.25)





CC
0.5
(0.39-0.64)
9.E−08
89
(0.73)





TC + TT
0.94
(0.57-1.55)
0.822





TC + CC
0.57
(0.45-0.71)
8.E−07


hCV25631989
ATF6 (rs1135983)
T
TT
0.98
(0.07-12.9)
0.985
1
(0.01)





TC
1.09
(0.66-1.8)
0.725
32
(0.26)





CC
0.49
(0.38-0.63)
5.E−08
88
(0.73)





TC + TT
1.09
(0.67-1.78)
0.723





TC + CC
0.58
(0.46-0.72)
2.E−06


hCV26175114
TUBA4A (rs3731892)
G
GG
1.19
(0.18-7.89)
0.854
3
(0.02)





GA
0.28
(0.14-0.57)
 4E−04
10
(0.08)





AA
0.62
(0.49-0.79)
 1E−04
109
(0.89)





GA + GG
0.34
(0.18-0.64)
 9E−04





GA + AA
0.57
(0.45-0.71)
9.E−07


hCV27474984
PIK3R1 (rs3756668)
A
AA
0.64
(0.39-1.05)
0.079
26
(0.21)





AG
0.41
(0.3-0.57)
9.E−08
54
(0.44)





GG
0.98
(0.66-1.48)
0.94 
43
(0.35)





AG + AA
0.47
(0.36-0.62)
4.E−08





AG + GG
0.57
(0.44-0.73)
1.E−05


hCV27502514
KLF3 (rs3796533)
A
AA
2.69
(0.78-9.27)
0.118
9
(0.07)





AG
0.57
(0.37-0.87)
0.008
36
(0.29)





GG
0.53
(0.4-0.7)
5.E−06
79
(0.64)





AG + AA
0.68
(0.46-1)
0.048





AG + GG
0.54
(0.43-0.68)
1.E−07


hCV3054799
KIF6 (rs20455)
G
GG
0.52
(0.29-0.95)
0.032
17
(0.14)





GA
0.83
(0.6-1.15)
0.261
66
(0.53)





AA
0.41
(0.28-0.58)
1.E−06
42
(0.34)





GA + GG
0.74
(0.56-0.99)
0.041





GA + AA
0.59
(0.47-0.75)
2.E−05


hCV3054805
KIF6 (rs2894424)
G
GG
0.57
(0.34-0.96)
0.035
23
(0.19)





GC
0.78
(0.57-1.08)
0.134
66
(0.55)





CC
0.38
(0.25-0.57)
3.E−06
32
(0.26)





GC + GG
0.72
(0.55-0.95)
0.018





GC + CC
0.58
(0.45-0.74)
2.E−05


hCV3054808
KIF6 (rs9462535)
A
AA
0.49
(0.28-0.87)
0.015
18
(0.15)





AC
0.8
(0.57-1.1)
0.169
64
(0.52)





CC
0.43
(0.3-0.63)
1.E−05
40
(0.33)





AC + AA
0.71
(0.53-0.94)
0.016





AC + CC
0.6
(0.47-0.77)
4.E−05


hCV3054813
KIF6 (rs9471077)
G
GG
0.48
(0.28-0.84)
0.011
19
(0.16)





GA
0.82
(0.6-1.14)
0.246
65
(0.53)





AA
0.41
(0.28-0.6)
5.E−06
38
(0.31)





GA + GG
0.72
(0.54-0.95)
0.021





GA + AA
0.6
(0.47-0.77)
5.E−05


hCV3054822
(rs11751357)
A
AA
0.44
(0.18-1.08)
0.074
7
(0.06)





AT
0.9
(0.65-1.26)
0.542
64
(0.52)





TT
0.42
(0.3-0.58)
2.E−07
51
(0.42)





AT + AA
0.82
(0.6-1.11)
0.2 





AT + TT
0.6
(0.48-0.75)
1.E−05


hCV3230113
CYP4V2 (rs1053094)
T
TT
0.36
(0.22-0.57)
2.E−05
25
(0.21)





TA
0.67
(0.49-0.92)
0.012
64
(0.53)





AA
0.69
(0.45-1.07)
0.096
32
(0.26)





TA + TT
0.54
(0.42-0.71)
5.E−06





TA + AA
0.67
(0.52-0.86)
0.002


hCV470708
THBS2 (rs10945408)
T
TT
0.82
(0.44-1.51)
0.52 
19
(0.15)





TG
0.4
(0.28-0.58)
8.E−07
42
(0.34)





GG
0.73
(0.53-1.01)
0.061
64
(0.51)





TG + TT
0.48
(0.35-0.65)
3.E−06





TG + GG
0.55
(0.44-0.7)
1.E−06


hCV491830
EPS8L2 (rs3087546)
T
TT
0.48
(0.32-0.72)
 4E−04
34
(0.27)





TC
0.55
(0.4-0.75)
 2E−04
62
(0.5)





CC
0.97
(0.59-1.6)
0.919
29
(0.23)





TC + TT
0.52
(0.41-0.67)
3.E−07





TC + CC
0.64
(0.49-0.83)
 9E−04


hCV8241630
F11 (rs925451)
A
AA
0.44
(0.24-0.78)
0.005
18
(0.15)





AG
0.52
(0.37-0.71)
6.E−05
58
(0.47)





GG
0.78
(0.54-1.12)
0.175
47
(0.38)





AG + AA
0.49
(0.37-0.65)
9.E−07





AG + GG
0.61
(0.48-0.78)
7.E−05


hCV8919444
F5 (rs4524)
T
TT
0.66
(0.5-0.87)
0.004
86
(0.69)





TC
0.5
(0.34-0.74)
 5E−04
36
(0.29)





CC
0.2
(0.05-0.89)
0.034
2
(0.02)





TC + TT
0.6
(0.48-0.75)
9.E−06





TC + CC
0.46
(0.32-0.68)
6.E−05


hDV68530934
TF 1208 I/D (hDV68530934)
A
AA
0.78
(0.49-1.23)
0.281
33
(0.26)





AC
0.62
(0.45-0.84)
0.002
66
(0.53)





CC
0.39
(0.25-0.62)
6.E−05
26
(0.21)





AC + AA
0.66
(0.51-0.86)
0.002





AC + CC
0.53
(0.41-0.68)
1.E−06


















statin
statin
statin
p(int)
Comparison




nonuser,
users,
nonusers,
statin*
for p(int)



hCV #
cases
controls
controls
SNP
statin*SNP





















hCV11286902
641
(0.19)
54
(0.22)
793
(0.2)
0.010
GG vs. AA




1668
(0.48)
124
(0.5)
1907
(0.47)
0.168
GA vs. AA




1142
(0.33)
69
(0.28)
1352
(0.33)
ref










0.044
GA + GG vs. AA










0.029
GG vs. GA + AA



hCV11786258
700
(0.2)
41
(0.16)
642
(0.15)
0.035
AA vs. GG




1742
(0.49)
122
(0.47)
2007
(0.48)
0.384
AG vs. GG




1114
(0.31)
94
(0.37)
1552
(0.37)
ref










0.139
AG + AA vs. GG










0.056
AA vs. AG + GG



hCV12066124
1245
(0.35)
68
(0.26)
1138
(0.27)
0.136
CC vs. TT




1679
(0.47)
130
(0.5)
2066
(0.49)
0.662
CT vs. TT




623
(0.18)
61
(0.24)
994
(0.24)
ref










0.740
CT + CC vs. TT










0.022
CC vs. CT + TT



hCV12092542
1025
(0.3)
54
(0.26)
1083
(0.31)
0.602
TT vs. CC




1704
(0.51)
116
(0.57)
1742
(0.49)
0.027
TC vs. CC




638
(0.19)
35
(0.17)
725
(0.2)
ref










0.089
TC + TT vs. CC










0.225
TT vs. TC + CC



hCV15968043
739
(0.21)
44
(0.17)
693
(0.17)
0.040
AA vs. TT




1755
(0.5)
122
(0.48)
2021
(0.48)
0.704
AT vs. TT




1021
(0.29)
90
(0.35)
1456
(0.35)
ref










0.291
AT + AA vs. TT










0.038
AA vs. AT + TT



hCV16171263
207
(0.06)
20
(0.08)
231
(0.06)
0.043
GA vs. AA




3335
(0.94)
238
(0.92)
3951
(0.94)
ref










0.041
GA + GG vs. AA










n/a



hCV1859855
232
(0.07)
14
(0.05)
175
(0.04)
0.049
CC vs. TT




1207
(0.34)
96
(0.37)
1453
(0.35)
0.899
CT vs. TT




2088
(0.59)
147
(0.57)
2522
(0.61)
ref










0.631
CT + CC vs. TT










0.045
CC vs. CT + TT



hCV1948599
765
(0.22)
56
(0.22)
945
(0.22)
0.198
AA vs. CC




1718
(0.49)
137
(0.53)
2113
(0.5)
0.044
AC vs. CC




1005
(0.29)
64
(0.25)
1144
(0.27)
ref










0.044
AC + AA vs. CC










0.740
AA vs. AC + CC



hCV1952126
1976
(0.56)
138
(0.53)
2258
(0.54)
0.019
AA vs. CC




1343
(0.38)
101
(0.39)
1598
(0.38)
0.018
AC vs. CC




236
(0.07)
19
(0.07)
338
(0.08)
ref










0.014
AC + AA vs. CC










0.507
AA vs. AC + CC



hCV22272267
1141
(0.32)
66
(0.26)
1092
(0.26)
0.141
AA vs. GG




1723
(0.49)
126
(0.49)
2112
(0.5)
0.793
AG vs. GG




680
(0.19)
64
(0.25)
985
(0.24)
ref










0.665
AG + AA vs. GG










0.045
AA vs. AG + GG



hCV2434510
46
(0.01)
2
(0.01)
44
(0.01)
0.804
CC vs. TT




699
(0.2)
55
(0.22)
797
(0.19)
0.047
CT vs. TT




2774
(0.79)
196
(0.77)
3324
(0.8)
ref










0.046
CT + CC vs. TT










0.872
CC vs. CT + TT



hCV25610857
31
(0.01)
1
(0)
28
(0.01)
0.307
TT vs. CC




604
(0.17)
34
(0.13)
546
(0.13)
0.081
TC vs. CC




2886
(0.82)
224
(0.86)
3629
(0.86)
ref










0.058
TC + TT vs. CC










0.349
TT vs. TC + CC



hCV25631989
23
(0.01)
2
(0.01)
37
(0.01)
0.659
TT vs. CC




505
(0.14)
37
(0.14)
604
(0.14)
0.007
TC vs. CC




2963
(0.85)
218
(0.85)
3552
(0.85)
ref










0.006
TC + TT vs. CC










0.749
TT vs. TC + CC



hCV26175114
83
(0.02)
2
(0.01)
73
(0.02)
0.414
GG vs. AA




638
(0.18)
44
(0.17)
749
(0.18)
0.024
GA vs. AA




2785
(0.79)
210
(0.82)
3336
(0.8)
ref










0.054
GA + GG vs. AA










0.351
GG vs. GA + AA



hCV27474984
773
(0.22)
50
(0.2)
876
(0.21)
0.134
AA vs. GG




1761
(0.5)
144
(0.57)
1977
(0.47)
0.002
AG vs. GG




985
(0.28)
60
(0.24)
1310
(0.31)
ref










0.003
AG + AA vs. GG










0.896
AA vs. AG + GG



hCV27502514
97
(0.03)
4
(0.02)
109
(0.03)
0.011
AA vs. GG




1005
(0.28)
69
(0.27)
1155
(0.28)
0.502
AG vs. GG




2450
(0.69)
185
(0.72)
2910
(0.7)
ref










0.162
AG + AA vs. GG










0.014
AA vs. AG + GG



hCV3054799
515
(0.14)
37
(0.14)
587
(0.14)
0.408
GG vs. AA




1581
(0.44)
96
(0.37)
1901
(0.45)
0.003
GA vs. AA




1462
(0.41)
125
(0.48)
1710
(0.41)
ref










0.006
GA + GG vs. AA










0.763
GG vs. GA + AA



hCV3054805
666
(0.19)
46
(0.18)
741
(0.18)
0.181
GG vs. CC




1621
(0.46)
104
(0.41)
2019
(0.48)
0.003
GC vs. CC




1204
(0.34)
106
(0.41)
1431
(0.34)
ref










0.005
GC + GG vs. CC










0.960
GG vs. GC + CC



hCV3054808
584
(0.17)
42
(0.16)
675
(0.16)
0.580
AA vs. CC




1598
(0.46)
99
(0.39)
1957
(0.47)
0.009
AC vs. CC




1313
(0.38)
116
(0.45)
1565
(0.37)
ref










0.024
AC + AA vs. CC










0.612
AA vs. AC + CC



hCV3054813
593
(0.17)
44
(0.17)
663
(0.16)
0.561
GG vs. AA




1606
(0.46)
98
(0.38)
1977
(0.47)
0.005
GA vs. AA




1294
(0.37)
115
(0.45)
1555
(0.37)
ref










0.015
GA + GG vs. AA










0.531
GG vs. GA + AA



hCV3054822
270
(0.08)
17
(0.07)
298
(0.07)
0.819
AA vs. TT




1362
(0.39)
89
(0.35)
1646
(0.39)
0.002
AT vs. TT




1852
(0.53)
151
(0.59)
2248
(0.54)
ref










0.004
AT + AA vs. TT










0.620
AA vs. AT + TT



hCV3230113
1041
(0.3)
67
(0.26)
990
(0.24)
0.060
TT vs. AA




1739
(0.5)
119
(0.46)
2132
(0.51)
0.937
TA vs. AA




732
(0.21)
73
(0.28)
1078
(0.26)
ref










0.464
TA + TT vs. AA










0.024
TT vs. TA + AA



hCV470708
373
(0.1)
27
(0.11)
400
(0.1)
0.878
TT vs. GG




1519
(0.43)
124
(0.48)
1823
(0.43)
0.021
TG vs. GG




1673
(0.47)
106
(0.41)
1982
(0.47)
ref










0.068
TG + TT vs. GG










0.338
TT vs. TG + GG



hCV491830
1167
(0.33)
81
(0.32)
1302
(0.31)
0.036
TT vs. CC




1700
(0.48)
136
(0.53)
2020
(0.48)
0.070
TC vs. CC




666
(0.19)
40
(0.16)
846
(0.2)
ref










0.035
TC + TT vs. CC










0.236
TT vs. TC + CC



hCV8241630
726
(0.21)
38
(0.15)
627
(0.15)
0.070
AA vs. GG




1729
(0.49)
125
(0.48)
1922
(0.46)
0.116
AG vs. GG




1079
(0.31)
95
(0.37)
1650
(0.39)
ref










0.052
AG + AA vs. GG










0.203
AA vs. AG + GG



hCV8919444
2176
(0.61)
135
(0.53)
2295
(0.55)
0.110
TT vs. CC




1189
(0.34)
104
(0.41)
1589
(0.38)
0.272
TC vs. CC




181
(0.05)
17
(0.07)
304
(0.07)
ref










0.150
TC + TT vs. CC










0.065
TT vs. TC + CC



hDV68530934
775
(0.22)
49
(0.19)
876
(0.21)
0.036
AA vs. CC




1777
(0.5)
127
(0.49)
2081
(0.5)
0.099
AC vs. CC




1004
(0.28)
83
(0.32)
1242
(0.3)
ref










0.046
AC + AA vs. CC










0.153
AA vs. AC + CC







27 SNPs (shown above in Table 4) had a p(int) statin*SNP < 0.05 (Wald test) in any model.



p(int) statin*SNP: P value < 0.05 (Wald test) for statin*SNP interaction term (ModelFormula: VTE~SNP + statin user or nonuser + SNP*statin + age + sex) is specific for the subgroup shown.



Endpoint: VT (including DVT and PE)



Parameter: statin use (statin users or statin nonusers)













TABLE 5





Table 5. Association of 75 SNPs with VT risk in statin usuer and statin nonuser subgroups in MEGA (additive P < 0.05).































Allele1



marker
Gene
Risk



P-
(allele



(hCV #)
(SNP rs #)
Allele
parameter
Strata
OR (95% CI)
value
freq)





p(int) statin*SNP


(additive)


0.034221851
hCV8919444
F5 (rs4524)
T
T_vs_C
statin_0
1.26 (1.17-1.36)
5E−10
C (0.26)







statin_1
1.95 (1.31-2.93)
0.001
C (0.27)


0.04127343
hCV11786258
KLKB1 (rs4253303)
A
A_vs_G
statin_0
1.23 (1.15-1.31)
3E−10
A (0.39)







statin_1
0.88 (0.64-1.2) 
0.41
A (0.4) 


0.046438831
hCV8241630
F11 (rs925451)
A
A_vs_G
statin_0
1.34 (1.26-1.43)
5E−19
A (0.38)







statin_1
0.96 (0.7-1.32) 
0.805
A (0.39)


0.047140799
hCV25610857
(rs8176693)
T
T_vs_C
statin_0
1.35 (1.2-1.51) 
3E−07
C (0.93)







statin_1
2.27 (1.37-3.77)
0.002
C (0.93)


0.048367213
hCV491830
EPS8L2
T
T_vs_C
statin_0
1.07 (1-1.14)  
0.046
C (0.45)




(rs3087546)


statin_1
0.76 (0.56-1.05)
0.095
C (0.42)


0.06328739
hCV3230113
CYP4V2
T
T_vs_A
statin_0
1.25 (1.17-1.33)
1E−11
A (0.51)




(rs1053094)


statin_1
0.93 (0.69-1.26)
0.641
A (0.51)


0.065533427
hCV15968043
CYP4V2
A
A_vs_T
statin_0
1.23 (1.16-1.32)
1E−10
A (0.41)




(rs2292423)


statin_1
0.91 (0.66-1.25)
0.547
A (0.41)


0.069827287
hCV27474984
PIK3R1
A
A_vs_G
statin_0
1.09 (1.02-1.16)
0.007
A (0.45)




(rs3756668)


statin_1
0.81 (0.59-1.11)
0.195
A (0.48)


0.078778864
hCV11633415
LOC730144
T
T_vs_C
statin_0
1.17 (1.04-1.32)
0.011
C (0.08)




(rs4262503)


statin_1
0.69 (0.38-1.22)
0.201
C (0.07)


0.09822195
hCV2442143
ASAH1
T
T_vs_C
statin_0
0.92 (0.87-0.98)
0.013
C (0.51)




(rs12544854)


statin_1
 1.2 (0.88-1.64)
0.242
C (0.54)


0.09898811
hCV12066124
F11 (rs2036914)
C
C_vs_T
statin_0
1.32 (1.24-1.41)
5E−18
C (0.52)







statin_1
  1 (0.73-1.37)
0.999
C (0.51)


0.10233127
hCV9102827
GPATCH4
C
C_vs_T
statin_0
1.09 (1.02-1.17)
0.015
C (0.26)




(rs3795733)


statin_1
1.45 (1.04-2.04)
0.031
C (0.22)


0.110882818
hCV1952126
(rs7223784)
A
A_vs_C
statin_0
1.08 (1.01-1.16)
0.027
A (0.73)







statin_1
0.83 (0.6-1.14) 
0.248
A (0.73)


0.121999557
hCV27859399
ABO (rs7853989)
C
C_vs_G
statin_0
1.28 (1.16-1.42)
3E−06
C (0.09)







statin_1
1.87 (1.17-2.99)
0.009
C (0.09)


0.122240353
hCV3230038
F11 (rs2289252)
T
T_vs_C
statin_0
1.36 (1.27-1.44)
1E−20
C (0.6) 







statin_1
1.05 (0.77-1.43)
0.757
C (0.61)


0.126690785
hCV22272267
KLKB1 (rs3733402)
A
A_vs_G
statin_0
1.23 (1.16-1.32)
9E−11
A (0.51)







statin_1
0.97 (0.71-1.31)
0.822
A (0.5) 


0.129651976
hCV27477533
(rs3756008)
T
T_vs_A
statin_0
1.32 (1.24-1.41)
9E−18
A (0.61)







statin_1
1.03 (0.76-1.41)
0.84
A (0.6) 


0.135285269
hCV16182835
PTPN21
G
G_vs_A
statin_0
1.11 (1.03-1.18)
0.003
A (0.68)




(rs2274736)


statin_1
0.85 (0.61-1.18)
0.336
A (0.63)


0.142757821
hCV15793897
KLKB1 (rs3087505)
G
G_vs_A
statin_0
1.26 (1.14-1.4) 
1E−05
A (0.11)







statin_1
0.91 (0.58-1.41)
0.674
A (0.12)


0.154022293
hCV916107
LOC729138
C
C_vs_T
statin_0
1.11 (1.04-1.19)
0.002
C (0.64)




(rs670659)


statin_1
0.87 (0.63-1.21)
0.417
C (0.68)


0.164073369
hCV27474895
F11 (rs3756011)
A
A_vs_C
statin_0
1.34 (1.26-1.43)
1E−19
A (0.4) 







statin_1
1.06 (0.78-1.45)
0.702
A (0.4) 


0.179080773
hCV25474413
F11 (rs3822057)
C
C_vs_A
statin_0
 1.3 (1.22-1.39)
3E−16
A (0.52)







statin_1
1.04 (0.76-1.42)
0.808
A (0.52)


0.213897396
hCV31523650
AKT3 (rs12048930)
T
T_vs_C
statin_0
1.12 (1.04-1.21)
0.003
C (0.8) 







statin_1
0.88 (0.61-1.28)
0.516
C (0.78)


0.224108979
hCV16180170
SERPINC1
T
T_vs_C
statin_0
1.24 (1.12-1.38)
3E−05
C (0.91)




(rs2227589)


statin_1
1.71 (1.06-2.76)
0.029
C (0.92)


0.229850466
hCV1859855
GOLGA3
C
C_vs_T
statin_0
1.12 (1.04-1.21)
0.004
C (0.22)




(rs2291260)


statin_1
0.88 (0.6-1.28) 
0.507
C (0.24)


0.278514601
hCV1376266
GP6 (rs1654413)
A
A_vs_T
statin_0
0.89 (0.83-0.97)
0.007
A (0.2) 







statin_1
1.11 (0.76-1.62)
0.591
A (0.19)


0.285044775
hCV3230096
CYP4V2
T
T_vs_C
statin_0
1.22 (1.14-1.3) 
1E−09
C (0.59)




(rs3817184)


statin_1
1.03 (0.76-1.39)
0.864
C (0.58)


0.288005598
hCV16170613
MET (rs2237712)
G
G_vs_A
statin_0
 1.2 (1.01-1.43)
0.037
A (0.97)







statin_1
0.81 (0.39-1.66)
0.559
A (0.95)


0.288035569
hCV2532034
F13B (rs6003)
G
G_vs_A
statin_0
1.13 (1.02-1.26)
0.022
A (0.91)







statin_1
1.53 (0.88-2.65)
0.133
A (0.94)


0.302357106
hCV2915511
OBSL1 (rs627530)
C
C_vs_T
statin_0
1.18 (1.01-1.38)
0.036
C (0.04)







statin_1
1.84 (0.8-4.25) 
0.15
C (0.03)


0.31836145
hCV8726802
F2 (rs1799953)
A
A_vs_G
statin_0
2.66 (2.05-3.44)
1E−13
A (0.01)







statin_1
1.23 (0.29-5.25)
0.784
A (0.01)


0.343434006
hCV2590858
ADCY9
C
C_vs_T
statin_0
1.08 (1-1.16)  
0.037
C (0.73)




(rs2230738)


statin_1
0.91 (0.64-1.29)
0.592
C (0.76)


0.345514722
hCV2303891
APOH (rs1801690)
C
C_vs_G
statin_0
1.26 (1.08-1.45)
0.002
C (0.94)







statin_1
0.89 (0.45-1.78)
0.743
C (0.95)


0.35994798
hCV8911768
SERPINC1
T
T_vs_C
statin_0
1.24 (1.12-1.38)
3E−05
C (0.91)




(rs941988)


statin_1
1.59 (0.97-2.62)
0.066
C (0.92)


0.367055136
hCV11503470
(rs1800788)
T
T_vs_C
statin_0
1.21 (1.13-1.31)
4E−07
C (0.79)







statin_1
1.02 (0.72-1.45)
0.889
C (0.76)


0.367169692
hCV22273419
GP6 (rs2304167)
C
C_vs_T
statin_0
0.89 (0.82-0.96)
0.004
C (0.2) 







statin_1
1.06 (0.73-1.54)
0.751
C (0.19)


0.371584665
hCV1202883
MTHFR
G
G_vs_A
statin_0
1.08 (1-1.17)  
0.038
A (0.3) 




(rs1801133)


statin_1
1.28 (0.9-1.82) 
0.177
A (0.32)


0.371786352
hCV1376342
GP6 (rs1654416)
C
C_vs_T
statin_0
0.88 (0.81-0.95)
0.002
C (0.2) 







statin_1
1.05 (0.72-1.51)
0.809
C (0.19)


0.406756226
hCV11975250
F5 (rs6025)
T
T_vs_C
statin_0
3.42 (2.92-4.01)
1E−51
C (0.97)







statin_1
4.78 (2.34-9.77)
2E−05
C (0.98)


0.407763342
hCV2103346
DKFZP564J102
C
C_vs_T
statin_0
1.07 (1.01-1.14)
0.03
C (0.44)




(rs11733307)


statin_1
1.22 (0.9-1.65) 
0.201
C (0.44)


0.410870664
hCV15860324
PROCR
C
C_vs_T
statin_0
1.33 (1.16-1.52)
4E−05
C (0.05)




(rs2069946)


statin_1
1.03 (0.56-1.87)
0.928
C (0.06)


0.412798308
hCV11503469
FGG (rs2066854)
A
A_vs_T
statin_0
1.37 (1.28-1.47)
5E−19
A (0.27)







statin_1
1.19 (0.86-1.64)
0.301
A (0.3) 


0.423539585
hCV30562347
F11 (rs4253418)
G
G_vs_A
statin_0
1.28 (1.09-1.51)
0.003
A (0.04)







statin_1
0.99 (0.5-1.95) 
0.972
A (0.04)


0.435904222
hCV263841
NR1I2 (rs1523127)
C
C_vs_A
statin_0
1.11 (1.04-1.18)
0.002
A (0.62)







statin_1
0.97 (0.71-1.33)
0.85
A (0.62)


0.43932399
hCV596331
F9 (rs6048)
A
A_vs_G
statin_0
 1.1 (1.04-1.17)
0.001
A (0.7) 







statin_1
1.22 (0.93-1.61)
0.148
A (0.69)


0.45280106
hCV8718961
RDH13 (rs1654451)
A
A_vs_T
statin_0
0.89 (0.81-0.97)
0.009
A (0.16)







statin_1
1.04 (0.69-1.56)
0.853
A (0.15)


0.469253388
hCV30710896
F2 (rs3136520)
T
T_vs_C
statin_0
1.28 (1.06-1.56)
0.012
C (0.98)







statin_1
 0.9 (0.37-2.18)
0.808
C (0.97)


0.497858665
hCV8717873
GP6 (rs1613662)
A
A_vs_G
statin_0
1.17 (1.08-1.27)
2E−04
A (0.82)







statin_1
1.02 (0.69-1.5) 
0.922
A (0.82)


0.518388541
hCV2892877
FGA (rs6050)
C
C_vs_T
statin_0
1.38 (1.26-1.52)
4E−12
C (0.24)







statin_1
1.19 (0.76-1.85)
0.447
C (0.25)


0.525140093
hCV2499170
(rs169713)
C
C_vs_T
statin_0
 1.1 (1.02-1.19)
0.015
C (0.2) 







statin_1
0.96 (0.64-1.44)
0.847
C (0.2) 


0.541874674
hCV11503414
FGG (rs2066865)
A
A_vs_G
statin_0
1.37 (1.28-1.47)
4E−19
A (0.26)







statin_1
1.23 (0.88-1.71)
0.219
A (0.29)


0.546620019
hCV15949414
XYLB (rs2234628)
G
G_vs_A
statin_0
1.34 (1.15-1.56)
2E−04
A (0.05)







statin_1
1.07 (0.49-2.36)
0.862
A (0.04)


0.583697812
hCV25597241
AQP2 (rs3782320)
A
A_vs_G
statin_0
1.12 (1.01-1.25)
0.038
A (0.09)







statin_1
0.96 (0.56-1.66)
0.895
A (0.09)


0.619356604
hCV16177220
ODZ1 (rs2266911)
C
C_vs_T
statin_0
1.09 (1.02-1.17)
0.009
C (0.8) 







statin_1
  1 (0.72-1.39)
0.996
C (0.83)


0.621640282
hCV27902808
CYP4V2
T
T_vs_C
statin_0
0.85 (0.79-0.9) 
9E−07
C (0.64)




(rs4253236)


statin_1
0.92 (0.67-1.25)
0.587
C (0.61)


0.652386012
hCV11541681
LOC200420
C
C_vs_G
statin_0
1.07 (1.01-1.14)
0.032
C (0.37)




(rs2001490)


statin_1
0.99 (0.72-1.38)
0.969
C (0.35)


0.66407521
hDV71075942
(rs8176719)
G
G_vs_T
statin_0
1.67 (1.56-1.79)
6E−51
G (0.34)







statin_1
1.81 (1.29-2.54)
6E−04
G (0.35)


0.676672364
hCV30690780
AKT3 (rs10737888)
C
C_vs_A
statin_0
1.15 (1.07-1.24)
2E−04
A (0.77)







statin_1
1.07 (0.76-1.51)
0.702
A (0.76)


0.701926538
hCV1825046
PROCR
C
C_vs_T
statin_0
0.84 (0.78-0.89)
7E−08
C (0.41)




(rs2069952)


statin_1
0.79 (0.57-1.09)
0.145
C (0.4) 


0.713175712
hCV31523608
AKT3 (rs12744297)
G
G_vs_A
statin_0
1.13 (1.06-1.21)
4E−04
A (0.67)







statin_1
 1.2 (0.86-1.66)
0.287
A (0.66)


0.715483519
hCV15990789
OTOG (rs2355466)
G
G_vs_A
statin_0
1.07 (1-1.14)  
0.045
A (0.41)







statin_1
0.99 (0.72-1.38)
0.975
A (0.36)


0.737326509
hCV30690777
AKT3 (rs12045585)
A
A_vs_G
statin_0
1.14 (1.04-1.24)
0.004
A (0.14)







statin_1
1.07 (0.71-1.6) 
0.747
A (0.16)


0.738278618
hCV15860433
(rs2070006)
T
T_vs_C
statin_0
1.24 (1.16-1.32)
1E−10
C (0.61)







statin_1
 1.3 (0.96-1.75)
0.091
C (0.6) 


0.798652766
hCV25748719
NAP5 ( )
C
C_vs_T
statin_0
1.08 (1.01-1.17)
0.036
C (0.77)







statin_1
1.15 (0.78-1.68)
0.482
C (0.77)


0.804517403
hCV2986566
F9 (rs4149755)
A
A_vs_T
statin_0
1.15 (1.03-1.28)
0.015
A (0.06)







statin_1
1.07 (0.65-1.78)
0.783
A (0.06)


0.808271852
hCV32291301
KLKB1 (rs4253302)
A
A_vs_G
statin_0
1.2 (1.1-1.31)
6E−05
A (0.84)







statin_1
1.25 (0.83-1.87)
0.282
A (0.82)


0.841280102
hCV1841973
(rs1799808)
T
T_vs_C
statin_0
0.94 (0.88-1)  
0.049
C (0.65)







statin_1
 0.9 (0.67-1.23)
0.515
C (0.64)


0.86593208
hCV25990131
CYP4V2
A
A_vs_C
statin_0
 1.2 (1.12-1.28)
2E−07
A (0.64)




(rs13146272)


statin_1
1.16 (0.84-1.6) 
0.358
A (0.62)


0.87763198
hCV25620145
PROCR (rs867186)
G
G_vs_A
statin_0
1.18 (1.07-1.29)
5E−04
A (0.88)







statin_1
1.14 (0.73-1.77)
0.565
A (0.87)


0.918870113
hCV1841974
(rs1799809)
G
G_vs_A
statin_0
1.15 (1.08-1.22)
3E−05
A (0.57)







statin_1
1.17 (0.87-1.57)
0.298
A (0.56)


0.927314636
hCV233148
AKT3 (rs1417121)
C
C_vs_G
statin_0
1.15 (1.08-1.23)
6E−05
C (0.28)







statin_1
1.14 (0.82-1.59)
0.44
C (0.27)


0.928029357
hCV1841983
PROC (rs5937)
C
C_vs_T
statin_0
1.13 (1.06-1.21)
3E−04
C (0.34)







statin_1
1.12 (0.82-1.52)
0.484
C (0.36)


0.96355332
hCV30747430
NR1I2 (rs11712211)
T
T_vs_C
statin_0
1.14 (1.06-1.24)
8E−04
C (0.82)







statin_1
1.15 (0.78-1.69)
0.484
C (0.83)


0.970695776
hCV1841975
PROC (rs1799810)
T
T_vs_A
statin_0
1.13 (1.06-1.21)
1E−04
A (0.57)







statin_1
1.13 (0.85-1.52)
0.403
A (0.56)


additive Pint


statin * SNP


0.002528557
hCV2211618
DDT (rs12483950)
G
G_vs_C
statin_0
1.08 (1.02-1.15)
0.015
C (0.57)







statin_1
0.66 (0.48-0.91)
0.011
C (0.53)























Allele2













(allele
Geno-
Case
Control
Geno-
Case
Control
Geno-
Case
Control




freq)
type 1
1
1
type 2
2
2
type 3
3
3







p(int) statin*SNP



(additive)



0.034221851
T (0.74)
CC
181
304
CT
1189
1589
TT
2176
2295




T (0.73)
CC
2
17
CT
36
104
TT
86
135



0.04127343
G (0.61)
AA
700
642
AG
1742
2007
GG
1114
1552




G (0.6) 
AG
61
122
GG
48
94
AA
15
41



0.046438831
G (0.62)
AA
726
627
AG
1729
1922
GG
1079
1650




G (0.61)
AA
18
38
AG
58
125
GG
47
95



0.047140799
T (0.07)
CC
2886
3629
CT
604
546
TT
31
28




T (0.07)
CC
89
224
CT
31
34
TT
2
1



0.048367213
T (0.55)
CC
666
846
CT
1700
2020
TT
1167
1302




T (0.58)
CC
29
40
CT
62
136
TT
34
81



0.06328739
T (0.49)
AA
732
1078
AT
1739
2132
TT
1041
990




T (0.49)
AA
32
73
AT
64
119
TT
25
67



0.065533427
T (0.59)
AA
739
693
AT
1755
2021
TT
1021
1456




T (0.59)
AA
15
44
AT
64
122
TT
42
90



0.069827287
G (0.55)
AA
773
876
AG
1761
1977
GG
985
1310




G (0.52)
AA
26
50
AG
54
144
GG
43
60



0.078778864
T (0.92)
CC
25
21
CT
431
616
TT
3105
3561




T (0.93)
CT
23
35
TT
101
224
0
0
0



0.09822195
T (0.49)
CC
996
1106
CT
1707
2065
TT
791
1032




T (0.46)
CC
32
73
CT
57
134
TT
32
50



0.09898811
T (0.48)
CC
1245
1138
CT
1679
2066
TT
623
994




T (0.49)
CC
27
68
CT
72
130
TT
23
61



0.10233127
T (0.74)
CC
324
309
CT
1267
1318
TT
1857
2113




T (0.78)
CC
15
13
CT
43
74
TT
63
138



0.110882818
C (0.27)
AA
1976
2258
AC
1343
1598
CC
236
338




C (0.27)
AA
64
138
AC
43
101
CC
17
19



0.121999557
G (0.91)
CC
54
37
CG
690
683
GG
2780
3480




G (0.91)
CC
2
2
CG
34
43
GG
86
213



0.122240353
T (0.4) 
CC
958
1513
CT
1752
1986
TT
812
704




T (0.39)
CC
43
96
CT
59
123
TT
20
40



0.126690785
G (0.49)
AA
1141
1092
AG
1723
2112
GG
680
985




G (0.5) 
AA
27
66
AG
70
126
GG
28
64



0.129651976
T (0.39)
AA
1029
1560
AT
1755
1960
TT
773
677




T (0.4) 
AA
43
91
AT
61
126
TT
21
41



0.135285269
G (0.32)
AA
1501
1930
AG
1586
1846
GG
405
422




G (0.37)
AA
52
102
AG
59
121
GG
11
33



0.142757821
G (0.89)
AA
26
69
AG
590
800
GG
2943
3331




G (0.88)
AA
2
7
AG
28
46
GG
95
206



0.154022293
T (0.36)
CC
1540
1725
CT
1618
1904
TT
375
544




T (0.32)
CC
50
118
CT
60
111
TT
13
26



0.164073369
C (0.6) 
AA
824
711
AC
1743
1975
CC
977
1509




C (0.6) 
AA
21
40
AC
60
126
CC
42
93



0.179080773
C (0.48)
AA
729
1140
AC
1733
2072
CC
1078
995




C (0.48)
AA
27
69
AC
71
131
CC
25
59



0.213897396
T (0.2) 
CC
2198
2738
CT
1170
1277
TT
179
183




T (0.22)
CC
79
160
CT
41
83
TT
4
15



0.224108979
T (0.09)
CC
2791
3443
CT
697
698
TT
53
40




T (0.08)
CC
94
219
CT
29
36
TT
2
3



0.229850466
T (0.78)
CC
232
175
CT
1207
1453
TT
2088
2522




T (0.76)
CC
3
14
CT
48
96
TT
71
147



0.278514601
T (0.8) 
AA
122
165
AT
1043
1351
TT
2346
2678




T (0.81)
AA
5
11
AT
40
76
TT
77
172



0.285044775
T (0.41)
CC
1036
1442
CT
1750
2029
TT
774
724




T (0.42)
CC
40
88
CT
63
124
TT
22
47



0.288005598
G (0.03)
AA
3258
3822
AG
253
252
GG
7
3




G (0.05)
AA
113
222
AG
11
25
GG
0
1



0.288035569
G (0.09)
AA
2803
3455
AG
598
647
GG
51
51




G (0.06)
AA
101
225
AG
19
30
GG
2
1



0.302357106
T (0.96)
CC
28
11
CT
253
285
TT
3263
3897




T (0.97)
CT
11
13
TT
112
244
0
0
0



0.31836145
G (0.99)
AA
1
0
AG
186
86
GG
3344
4104




G (0.99)
AG
3
5
GG
120
252
0
0
0



0.343434006
T (0.27)
CC
1939
2199
CT
1319
1530
TT
217
317




T (0.24)
CC
69
145
CT
48
91
TT
8
14



0.345514722
G (0.06)
CC
3249
3730
CG
300
456
GG
10
5




G (0.05)
CC
112
235
CG
13
22
GG
0
1



0.35994798
T (0.09)
CC
2769
3458
CT
696
707
TT
55
42




T (0.08)
CC
93
220
CT
28
36
TT
1
3



0.367055136
T (0.21)
CC
2057
2674
CT
1291
1325
TT
211
205




T (0.24)
CC
70
149
CT
46
92
TT
8
17



0.367159592
T (0.8) 
CC
121
167
CT
1048
1338
TT
2372
2671




T (0.81)
CC
5
12
CT
40
73
TT
80
169



0.371584665
G (0.7) 
AA
172
269
AG
1695
1988
GG
1684
1934




G (0.68)
AA
5
23
AG
57
117
GG
61
116



0.371786352
T (0.8) 
CC
115
159
CT
1029
1342
TT
2386
2693




T (0.81)
CC
5
14
CT
39
71
TT
79
172



0.406756226
T (0.03)
CC
2934
3930
CT
556
207
TT
23
7




T (0.02)
CC
99
239
CT
22
12
TT
2
0



0.407763342
T (0.56)
CC
753
862
CT
1731
1988
TT
1029
1341




T (0.56)
CC
28
52
CT
62
122
TT
31
85



0.410870664
T (0.95)
CC
17
13
CT
431
398
TT
3073
3789




T (0.94)
CC
1
2
CT
14
29
TT
107
226



0.412798308
T (0.73)
AA
405
298
AT
1544
1623
TT
1600
2265




T (0.7) 
AA
16
21
AT
52
111
TT
57
125



0.423539585
G (0.96)
AA
7
9
AG
231
349
GG
3317
3824




G (0.96)
AA
2
2
AG
7
18
GG
114
237



0.435904222
C (0.38)
AA
1263
1578
AC
1667
2003
CC
617
608




C (0.38)
AA
46
97
AC
62
121
CC
16
38



0.43932399
G (0.3) 
AA
2171
2457
AG
766
906
GG
583
813




G (0.31)
AA
83
161
AG
21
33
GG
19
62



0.45280106
T (0.84)
AA
68
104
AT
866
1114
TT
2591
2986




T (0.85)
AA
3
9
AT
33
62
TT
86
188



0.469253388
T (0.02)
CC
3315
4011
CT
198
189
TT
7
4




T (0.03)
CC
114
244
CT
7
14
TT
0
1



0.497858665
G (0.18)
AA
2488
2783
AG
954
1265
GG
93
136




G (0.18)
AA
85
174
AG
34
73
GG
5
10



0.518388541
T (0.76)
CC
14
18
CT
1808
1810
TT
1485
2090




T (0.75)
CC
1
0
CT
61
121
TT
52
117



0.525140093
T (0.8) 
CC
175
200
CT
1185
1305
TT
2135
2694




T (0.8) 
CC
3
5
CT
41
92
TT
78
160



0.541874674
G (0.74)
AA
396
294
AG
1535
1623
GG
1584
2266




G (0.71)
AA
15
20
AG
52
111
GG
54
126



0.546620019
G (0.95)
AA
13
14
AG
257
418
GG
3266
3762




G (0.96)
AG
10
22
GG
112
237
0
0
0



0.583697812
G (0.91)
AA
33
32
AG
607
659
GG
2877
3513




G (0.91)
AA
0
3
AG
21
40
GG
101
216



0.619356604
T (0.2) 
CC
2613
2982
CT
593
737
TT
347
475




T (0.17)
CT
23
34
TT
10
27
CC
92
195



0.621640282
T (0.36)
CC
1597
1711
CT
1557
1935
TT
364
555




T (0.39)
CC
44
100
CT
65
114
TT
13
45



0.652386012
G (0.63)
CC
560
583
CG
1631
1949
GG
1351
1661




G (0.65)
CC
15
28
CG
57
125
GG
52
104



0.66407521
T (0.66)
GG
669
512
TG
1896
1840
TT
951
1849




T (0.65)
GG
18
31
TG
80
120
TT
24
108



0.676672364
C (0.23)
AA
2011
2515
AC
1236
1466
CC
268
212




C (0.24)
AA
70
151
AC
42
91
CC
10
17



0.701926538
T (0.59)
CC
494
706
CT
1572
2005
TT
1457
1494




T (0.6) 
CC
15
38
CT
53
130
TT
53
91



0.713175712
G (0.33)
AA
1482
1917
AG
1578
1823
GG
460
464




G (0.34)
AA
45
110
AG
62
123
GG
15
26



0.715483519
G (0.59)
AA
544
690
AG
1643
2001
GG
1320
1478




G (0.64)
AA
15
33
AG
58
117
GG
48
101



0.737326509
G (0.86)
AA
99
75
AG
911
1035
GG
2505
3085




G (0.84)
AA
5
7
AG
32
70
GG
85
180



0.738278618
T (0.39)
CC
1090
1550
CT
1748
1971
TT
713
669




T (0.4) 
CC
37
96
CT
60
119
TT
28
43



0.798652766
T (0.23)
CC
2163
2462
CT
1206
1490
TT
169
225




T (0.23)
CC
74
152
CT
50
91
TT
1
13



0.804517403
T (0.94)
AA
113
106
AT
258
268
TT
3152
3826




T (0.94)
AA
5
9
AT
5
11
TT
111
239



0.808271852
G (0.16)
AA
2649
2949
AG
835
1140
GG
79
114




G (0.18)
AA
93
178
AG
28
70
GG
4
11



0.841280102
T (0.35)
CC
1545
1756
CT
1565
1918
TT
405
525




T (0.36)
CC
57
111
CT
48
105
TT
17
40



0.86593208
C (0.36)
AA
1584
1665
AC
1430
1808
CC
351
527




C (0.38)
AA
51
97
AC
56
107
CC
13
38



0.87763198
G (0.12)
AA
2601
3203
AG
869
917
GG
74
62




G (0.13)
AA
91
194
AG
30
61
GG
3
3



0.918870113
G (0.43)
AA
1007
1362
AG
1741
2046
GG
770
794




G (0.44)
AA
38
82
AG
50
122
GG
34
53



0.927314636
G (0.72)
CC
378
318
CG
1434
1694
GG
1735
2171




G (0.73)
CC
11
21
CG
52
98
GG
61
138



0.928029357
T (0.66)
CC
501
504
CT
1610
1873
TT
1392
1808




T (0.64)
CC
22
34
CT
49
117
TT
50
107



0.96355332
T (0.18)
CC
2251
2803
CT
1095
1253
TT
179
148




T (0.17)
CC
80
177
CT
36
74
TT
6
8



0.970695776
T (0.43)
AA
1036
1374
AT
1748
2035
TT
765
789




T (0.44)
AA
40
82
AT
49
122
TT
34
53



additive Pint



statin * SNP



0.002528557
G (0.43)
CC
1088
1358
CG
1710
2002
GG
710
750




G (0.47)
CC
46
74
CG
66
118
GG
13
58







SNPs are ranked above in Table 5 by P(int) statin*SNP from the additive model.



p(int) statin*SNP: P value < 0.05 (Wald test) for statin*SNP interaction term (ModelFormula: VTE~SNP + statin user or nonuser + SNP*statin + age + sex) from an additive model



Endpoint: VT (including DVT and PE)



Strata: statin_0 (statin nonusers), statin_1 (statin users)



Model: additive













TABLE 6





Table 6. Association of statin use and VTE in SNP genotype subgroups in MEGA,


and VTE risk of that genotype in statin nonusers in MEGA (last 2 columns)

















Model: VTE~statin + age + sex






















reference group
statin






OR(95% CI) for

P(int
for P(int
users,


Gene (rs #)
Risk Allele
Strata
model
statin*VTE
P
statin*SNP)
statin*SNP)
cases





DDT (rs12483950)
G
GG

0.24 (0.13-0.44)
6E−06
0.001202
GG vs. CC
13 (0.1) 


DDT (rs12483950)
G
GC

0.67 (0.49-0.92)
0.013
0.494961
GC vs. CC
66 (0.53)


DDT (rs12483950)
G
CC

0.78 (0.53-1.14)
0.196
0.002529

46 (0.37)


DDT (rs12483950)
G
GC + CC
rec
0.71 (0.56-0.91)
0.006
0.001199
GG vs. GC + CC
13


DDT (rs12483950)
G
GC + GG
dom
0.52 (0.4-0.69) 
4E−06
0.077571
GC + GG vs. CC
79


DDT (rs12483950)
G

add


0.002529


F2RL1 (rs1529505)
T
TT

0.47 (0.31-0.73)
7E−04
0.067
TT vs. CC
31 (0.25)


F2RL1 (rs1529505)
T
TC

0.55 (0.4-0.75) 
2E−04
0.163
TC vs. CC
62 (0.5) 


F2RL1 (rs1529505)
T
CC

0.88 (0.55-1.41)
0.595


32 (0.26)


F2RL1 (rs1529505)
T
TT
rec
0.63 (0.49-0.82)
5E−04
0.220
TT vs. TT
31


F2RL1 (rs1529505)
T
TC + TT
dom
0.52 (0.4-0.67) 
4E−07
0.083
TC + TT vs. CC
93


LOC729672 (rs4334028)
T
TT

0.62 (0.31-1.23)
0.168
0.199
TT vs. CC
15 (0.12)


LOC729672 (rs4334028)
T
TC

0.69 (0.5-0.95) 
0.023
0.082
TC vs. CC
63 (0.51)


LOC729672 (rs4334028)
T
CC

0.46 (0.32-0.65)
1E−05


46 (0.37)


LOC729672 (rs4334028)
T
TT
rec
0.57 (0.45-0.72)
2E−06
0.446
TT vs. TT
15


LOC729672 (rs4334028)
T
TC + TT
dom
0.68 (0.51-0.91)
0.009
0.060
TC + TT vs. CC
78


ASAH1 (rs12544854)
T
TT

0.85 (0.54-1.35)
0.487
0.085
TT vs. CC
 32 (0.2645)


ASAH1 (rs12544854)
T
TC

0.53 (0.38-0.73)
1E−04
0.833
TC vs. CC
 57 (0.4711)


ASAH1 (rs12544854)
T
CC

 0.5 (0.32-0.77)
0.002


 32 (0.2645)


ASAH1 (rs12544854)
T
TT
rec
0.52 (0.4-0.67) 
6E−07
0.055
TT vs. TT
32


ASAH1 (rs12544854)
T
TC + TT
dom
0.61 (0.47-0.8) 
3E−04
0.404
TC + TT vs. CC
89


LOC730144 (rs4262503)
T
TC

  1 (0.58-1.73)
0.995
0.051
TC vs. TT
23 (0.19)


LOC730144 (rs4262503)
T
TT

0.52 (0.41-0.66)
2E−07


101 (0.81) 


LOC730144 (rs4262503)
T
TT
rec
0.98 (0.57-1.7) 
0.954
0.060
TC vs. TT
101 


LOC730144 (rs4262503)
T
TC + TT
dom
0.57 (0.46-0.72)
1E−06
n/a













Model: VTE~statin + age + sex
Model: SNP~VTE + age















statin
statin
statin

P for




nonusers,
users,
nonusers,
OR(95% CI)
VTE



Gene (rs #)
cases
controls
controls
for VTE risk
risk







DDT (rs12483950)
710 (0.2)
 58 (0.23)
 750 (0.18)
1.18 (1.03-1.34)
0.0134



DDT (rs12483950)
1710 (0.49)
118 (0.47)
2002 (0.49)
1.07 (0.96-1.18)
0.2276



DDT (rs12483950)
1088 (0.31)
74 (0.3)
1358 (0.33)
1.08 (1.02-1.15)
0.0148



DDT (rs12483950)
 710
 58
 750
1.13 (1.01-1.27)
0.0309



DDT (rs12483950)
2420
176
2752
 1.1 (0.99-1.21)
0.0633



DDT (rs12483950)



1.08 (1.02-1.15)
0.0148



F2RL1 (rs1529505)
1095 (0.31)
77 (0.3)
1248 (0.3) 
1.08 (0.95-1.23)
0.233



F2RL1 (rs1529505)
1722 (0.49)
131 (0.51)
2025 (0.49)
1.05 (0.93-1.18)
0.457



F2RL1 (rs1529505)
709 (0.2)
 48 (0.19)
 872 (0.21)
ref
ref



F2RL1 (rs1529505)
1095
 77
1248
1.05 (0.95-1.15)
0.350



F2RL1 (rs1529505)
2817
208
3273
1.06 (0.95-1.18)
0.310



LOC729672 (rs4334028)
 332 (0.09)
 22 (0.08)
 355 (0.08)
1.11 (0.95-1.31)
0.193



LOC729672 (rs4334028)
1521 (0.43)
113 (0.44)
1824 (0.43)
0.99 (0.9-1.09) 
0.889



LOC729672 (rs4334028)
1705 (0.48)
124 (0.48)
2030 (0.48)
ref
ref



LOC729672 (rs4334028)
 332
 22
 355
1.12 (0.96-1.31)
0.164



LOC729672 (rs4334028)
1853
135
2179
1.01 (0.93-1.11)
0.777



ASAH1 (rs12544854)
  791 (0.2264)
  50 (0.1946)
 1032 (0.2455)
0.85 (0.75-0.97)
0.013



ASAH1 (rs12544854)
 1707 (0.4886)
 134 (0.5214)
 2065 (0.4913)
0.92 (0.82-1.02)
0.113



ASAH1 (rs12544854)
  996 (0.2851)
 73 (0.284)
 1106 (0.2631)
ref
ref



ASAH1 (rs12544854)
 791
 50
1032
0.9 (0.81-1)
0.054



ASAH1 (rs12544854)
2498
184
3097
 0.9 (0.81-0.99)
0.032



LOC730144 (rs4262503)
 431 (0.12)
 35 (0.14)
 616 (0.15)
0.59 (0.33-1.06)
0.080



LOC730144 (rs4262503)
3105 (0.87)
224 (0.86)
3561 (0.85)
ref
ref



LOC730144 (rs4262503)
3105
224
3561
1.22 (1.07-1.39)
0.003



LOC730144 (rs4262503)







SNPs in Table 6 had additive P interaction < 0.1 in MEGA.



P(int) = P interaction from the Wald test for statin*SNP from the following model: VTE~SNP + statin user or nonuser + SNP*statin user or nonuser + age + sex.



OR (95% CI) and P value for VTE~SNP in last 2 columns calculated in statin nonusers.



VT is interchangeably referred to as VTE.















TABLE 7









Statin response by genotype group






















HR 95% CI
HR 95% CI


SNP
MODE
GENO_RESP
STATIN_USE
EVENTS_RESP
TOTAL_RESP
HR_RESP
lower_RESP
upper_RESP





hCV7543812
GEN
TT
statin
40
51
1.04
0.631
1.7243


hCV7543812
GEN
TT
no statin
136
195
ref




hCV7543812
GEN
TC
statin
65
134
0.56
0.389
0.7992


hCV7543812
GEN
TC
no statin
276
283
ref




hCV7543812
GEN
CC
statin
20
72
0.28
0.156
0.5093


hCV7543812
GEN
CC
no statin
126
129
ref




hCV7543812
REC
TC + CC
statin
85
206
0.46
0.337
0.6217


hCV7543812
REC
TC + CC
no statin
402
412
ref




hCV2690378
GEN
GG
statin
51
71
0.82
0.53 
1.2743


hCV2690378
GEN
GG
no statin
187
203
ref




hCV2690378
GEN
GT
statin
47
140
0.37
0.248
0.5445


hCV2690378
GEN
GT
no statin
272
287
ref




hCV2690378
GEN
TT
statin
27
46
0.89
0.494
1.6077


hCV2690378
GEN
TT
no statin
79
117
ref




hCV7543812
DOM
TC + TT
statin
105
185
0.69
0.519
0.9287


hCV7543812
DOM
TC + TT
no statin
412
478
ref




hCV931685
GEN
GG
statin
90
205
0.48
0.356
0.6484


hCV931685
GEN
GG
no statin
413
431
ref




hCV931685
GEN
GT
statin
29
48
0.86
0.492
1.5118


hCV931685
GEN
GT
no statin
120
161
ref




hCV931685
GEN
TT
statin
6
4
2.76
0.489
15.611 


hCV931685
GEN
TT
no statin
6
15
ref




hCV11686277
GEN
CC
statin
51
70
0.82
0.531
1.2762


hCV11686277
GEN
CC
no statin
190
207
ref




hCV11686277
GEN
CG
statin
48
140
0.39
0.264
0.5766


hCV11686277
GEN
CG
no statin
271
292
ref




hCV11686277
GEN
GG
statin
26
47
0.77
0.426
1.4035


hCV11686277
GEN
GG
no statin
78
108
ref




hCV29260019
REC
GA + AA
statin
81
138
0.77
0.553
1.0792


hCV29260019
REC
GA + AA
no statin
319
378
ref




hDV70820190
DOM
GA + GG
statin
116
252
0.54
0.416
0.7072


hDV70820190
DOM
GA + GG
no statin
525
584
ref




hCV931685
REC
GT + TT
statin
35
52
0.98
0.579
1.6589


hCV931685
REC
GT + TT
no statin
126
176
ref




hDV70437895
DOM
CT + CC
statin
108
237
0.52
0.397
0.6865


hDV70437895
DOM
CT + CC
no statin
505
550
ref




hCV931685
DOM
GT + GG
statin
119
253
0.55
0.422
0.7148


hCV931685
DOM
GT + GG
no statin
533
592
ref




hCV29245634
GEN
CC
statin
104
227
0.5 
0.38 
0.6657


hCV29245634
GEN
CC
no statin
471
509
ref




hCV29245634
GEN
CT
statin
21
28
1.45
0.707
2.9636


hCV29245634
GEN
CT
no statin
64
96
ref




hCV29245634
GEN
TT
statin
0
2
0  
0   
2E+158


hCV29245634
GEN
TT
no statin
4
1
ref




hDV70437895
GEN
CC
statin
65
148
0.49
0.346
0.7051


hDV70437895
GEN
CC
no statin
293
285
ref




hDV70437895
GEN
CT
statin
43
89
0.56
0.364
0.8634


hDV70437895
GEN
CT
no statin
212
265
ref




hDV70437895
GEN
TT
statin
17
20
1.48
0.602
3.6304


hDV70437895
GEN
TT
no statin
34
57
ref




hDV72050312
REC
GA + AA
statin
63
98
0.83
0.562
1.2327


hDV72050312
REC
GA + AA
no statin
201
239
ref




hCV29948033
DOM
TC + TT
statin
116
251
0.53
0.409
0.6979


hCV29948033
DOM
TC + TT
no statin
511
572
ref




hDV70794769
REC
CT + TT
statin
63
99
0.83
0.562
1.2319


hDV70794769
REC
CT + TT
no statin
204
243
ref




hCV12066124
REC
CT + TT
statin
95
189
0.66
0.485
0.896 


hCV12066124
REC
CT + TT
no statin
341
435
ref




hCV3054799
REC
AG + GG
statin
83
132
0.7 
0.503
0.9774


hCV3054799
REC
AG + GG
no statin
328
360
ref




hDV70820190
GEN
GG
statin
79
178
0.49
0.354
0.6732


hDV70820190
GEN
GG
no statin
367
389
ref




hDV70820190
GEN
GA
statin
37
74
0.68
0.421
1.0862


hDV70820190
GEN
GA
no statin
158
195
ref




hDV70820190
GEN
AA
statin
8
5
2.05
0.506
8.3068


hDV70820190
GEN
AA
no statin
14
23
ref




hCV1396435
REC
GT + TT
statin
95
172
0.68
0.501
0.9275


hCV1396435
REC
GT + TT
no statin
351
416
ref




hDV70437895
REC
CT + TT
statin
60
109
0.68
0.461
0.9886


hDV70437895
REC
CT + TT
no statin
246
322
ref




hCV11686277
REC
CG + GG
statin
74
187
0.47
0.342
0.6558


hCV11686277
REC
CG + GG
no statin
349
400
ref




hCV11778561
DOM
AT + AA
statin
92
210
0.49
0.369
0.6625


hCV11778561
DOM
AT + AA
no statin
458
501
ref




hCV2690378
REC
GT + TT
statin
74
186
0.47
0.343
0.6562


hCV2690378
REC
GT + TT
no statin
351
404
ref




hDV70830411
REC
TG + GG
statin
77
179
0.47
0.339
0.6482


hDV70830411
REC
TG + GG
no statin
353
376
ref




hCV7422169
DOM
GA + GG
statin
118
253
0.54
0.417
0.708 


hCV7422169
DOM
GA + GG
no statin
515
581
ref




hCV29260019
GEN
GG
statin
42
119
0.36
0.234
0.5439


hCV29260019
GEN
GG
no statin
219
229
ref




hCV29260019
GEN
GA
statin
65
106
0.75
0.513
1.0947


hCV29260019
GEN
GA
no statin
254
292
ref




hCV29260019
GEN
AA
statin
16
32
0.86
0.419
1.7833


hCV29260019
GEN
AA
no statin
65
86
ref




hCV29245634
REC
CT + TT
statin
21
30
1.32
0.651
2.6788


hCV29245634
REC
CT + TT
no statin
68
97
ref




hCV29948033
GEN
TT
statin
66
153
0.5 
0.353
0.7033


hCV29948033
GEN
TT
no statin
338
383
ref




hCV29948033
GEN
TC
statin
50
98
0.58
0.382
0.8933


hCV29948033
GEN
TC
no statin
173
189
ref




hCV29948033
GEN
CC
statin
9
6
2.72
0.715
10.345 


hCV29948033
GEN
CC
no statin
27
34
ref




hCV3054799
GEN
AA
statin
41
125
0.42
0.273
0.6386


hCV3054799
GEN
AA
no statin
211
247
ref




hCV3054799
GEN
AG
statin
66
95
0.74
0.509
1.0894


hCV3054799
GEN
AG
no statin
255
272
ref




hCV3054799
GEN
GG
statin
17
37
0.57
0.284
1.1433


hCV3054799
GEN
GG
no statin
73
88
ref




hCV31671070
DOM
AG + AA
statin
125
251
0.59
0.451
0.7603


hCV31671070
DOM
AG + AA
no statin
528
591
ref




hCV12066124
GEN
CC
statin
27
68
0.38
0.225
0.625 


hCV12066124
GEN
CC
no statin
193
169
ref




hCV12066124
GEN
CT
statin
72
129
0.68
0.475
0.9711


hCV12066124
GEN
CT
no statin
254
296
ref




hCV12066124
GEN
TT
statin
23
60
0.6 
0.328
1.1042


hCV12066124
GEN
TT
no statin
87
139
ref




hCV1772768
REC
GA + AA
statin
84
146
0.64
0.463
0.8972


hCV1772768
REC
GA + AA
no statin
308
351
ref




hDV72050312
GEN
GG
statin
62
159
0.43
0.305
0.6143


hDV72050312
GEN
GG
no statin
337
368
ref




hDV72050312
GEN
GA
statin
50
83
0.81
0.528
1.2483


hDV72050312
GEN
GA
no statin
172
215
ref




hDV72050312
GEN
AA
statin
13
15
0.79
0.285
2.1974


hDV72050312
GEN
AA
no statin
29
24
ref




hCV9540478
REC
TC + CC
statin
38
94
0.44
0.282
0.6919


hCV9540478
REC
TC + CC
no statin
201
204
ref




hCV2690378
DOM
GT + GG
statin
98
211
0.52
0.389
0.6943


hCV2690378
DOM
GT + GG
no statin
459
490
ref




hCV29245634
DOM
CT + CC
statin
125
255
0.58
0.446
0.7496


hCV29245634
DOM
CT + CC
no statin
535
605
ref




hCV16233239
REC
AG + GG
statin
48
86
0.8 
0.522
1.2301


hCV16233239
REC
AG + GG
no statin
196
251
ref




hCV3286482
DOM
TC + TT
statin
116
245
0.55
0.419
0.7162


hCV3286482
DOM
TC + TT
no statin
517
572
ref




hDV70794769
GEN
CC
statin
62
158
0.43
0.306
0.6163


hDV70794769
GEN
CC
no statin
334
364
ref




hDV70794769
GEN
CT
statin
50
84
0.82
0.534
1.2614


hDV70794769
GEN
CT
no statin
174
220
ref




hDV70794769
GEN
TT
statin
13
15
0.69
0.246
1.9396


hDV70794769
GEN
TT
no statin
30
23
ref




hDV77026147
DOM
CT + CC
statin
124
257
0.56
0.435
0.7324


hDV77026147
DOM
CT + CC
no statin
535
602
ref




hCV1396435
GEN
GG
statin
30
85
0.38
0.235
0.627 


hCV1396435
GEN
GG
no statin
187
191
ref




hCV1396435
GEN
GT
statin
75
134
0.67
0.473
0.9506


hCV1396435
GEN
GT
no statin
258
305
ref




hCV1396435
GEN
TT
statin
20
38
0.75
0.386
1.4425


hCV1396435
GEN
TT
no statin
93
111
ref




hDV70820190
REC
GA + AA
statin
45
79
0.77
0.491
1.1912


hDV70820190
REC
GA + AA
no statin
172
218
ref















Statin response by genotype group












P-

Risk of VT in no statin use group













SNP
value_RESP
P(INT)_RESP
GENO_PLACEBO
EVENTS_PLACEBO
TOTAL_PLACEBO
HR_PLACEBO





hCV7543812
0.8698
0.00045
TT
136
195
0.71


hCV7543812

0.00045






hCV7543812
0.0015
0.00045
TC
276
283
1  


hCV7543812

0.00045






hCV7543812
<.0001
0.00045
CC
126
129
ref


hCV7543812

0.00045






hCV7543812
<.0001
0.00046
TT
136
195
0.71


hCV7543812

0.00046






hCV2690378
0.3805
0.00439
GG
187
203
1.35


hCV2690378

0.00439






hCV2690378
<.0001
0.00439
GT
272
287
1.39


hCV2690378

0.00439






hCV2690378
0.7017
0.00439
TT
 79
117
ref


hCV2690378

0.00439






hCV7543812
0.014 
0.0048
TC + TT
412
478
0.88


hCV7543812

0.0048






hCV931685
<.0001
0.00984
GG
413
431
2.26


hCV931685

0.00984






hCV931685
0.6056
0.00984
GT
120
161
1.76


hCV931685

0.00984






hCV931685
0.25 
0.00984
TT
 6
 15
ref


hCV931685

0.00984






hCV11686277
0.3845
0.01246
CC
190
207
1.25


hCV11686277

0.01246






hCV11686277
<.0001
0.01246
CG
271
292
1.27


hCV11686277

0.01246






hCV11686277
0.3976
0.01246
GG
 78
108
ref


hCV11686277

0.01246






hCV29260019
0.1302
0.01356
GG
219
229
1.14


hCV29260019

0.01356






hDV70820190
<.0001
0.01407
GA + GG
525
584
1.43


hDV70820190

0.01407






hCV931685
0.9396
0.01448
GG
413
431
1.33


hCV931685

0.01448






hDV70437895
<.0001
0.01491
CT + CC
505
550
1.53


hDV70437895

0.01491






hCV931685
<.0001
0.01611
GT + GG
533
592
2.12


hCV931685

0.01611






hCV29245634
<.0001
0.01659
CC
471
509
0.26


hCV29245634

0.01659






hCV29245634
0.3114
0.01659
CT
 64
 96
0.18


hCV29245634

0.01659






hCV29245634
0.9403
0.01659
TT
 4
 1
ref


hCV29245634

0.01659






hDV70437895
0.0001
0.01843
CC
293
285
1.71


hDV70437895

0.01843






hDV70437895
0.0086
0.01843
CT
212
265
1.34


hDV70437895

0.01843






hDV70437895
0.3932
0.01843
TT
 34
 57
ref


hDV70437895

0.01843






hDV72050312
0.3593
0.01937
GG
337
368
1.1 


hDV72050312

0.01937






hCV29948033
<.0001
0.02073
TC + TT
511
572
1.16


hCV29948033

0.02073






hDV70794769
0.358 
0.02149
CC
334
364
1.1 


hDV70794769

0.02149






hCV12066124
0.0078
0.02348
CC
193
169
1.49


hCV12066124

0.02348






hCV3054799
0.0362
0.02372
AA
211
247
0.94


hCV3054799

0.02372






hDV70820190
<.0001
0.02944
GG
367
389
1.5 


hDV70820190

0.02944






hDV70820190
0.1057
0.02944
GA
158
195
1.29


hDV70820190

0.02944






hDV70820190
0.3149
0.02944
AA
 14
 23
ref


hDV70820190

0.02944






hCV1396435
0.0147
0.02966
GG
187
191
1.16


hCV1396435

0.02966






hDV70437895
0.0435
0.03119
CC
293
285
1.34


hDV70437895

0.03119






hCV11686277
<.0001
0.03337
CC
190
207
1.04


hCV11686277

0.03337






hCV11778561
<.0001
0.03501
AT + AA
458
501
1.22


hCV11778561

0.03501






hCV2690378
<.0001
0.04169
GG
187
203
1.05


hCV2690378

0.04169






hDV70830411
<.0001
0.04469
TT
186
231
0.85


hDV70830411

0.04469






hCV7422169
<.0001
0.04504
GA + GG
515
581
0.99


hCV7422169

0.04504






hCV29260019
<.0001
0.04625
GG
219
229
1.28


hCV29260019

0.04625






hCV29260019
0.1357
0.04625
GA
254
292
1.16


hCV29260019

0.04625






hCV29260019
0.6933
0.04625
AA
 65
 86
ref


hCV29260019

0.04625






hCV29245634
0.4409
0.04661
CC
471
509
1.34


hCV29245634

0.04661






hCV29948033
<.0001
0.05902
TT
338
383
1.14


hCV29948033

0.05902






hCV29948033
0.0131
0.05902
TC
173
189
1.19


hCV29948033

0.05902






hCV29948033
0.1423
0.05902
CC
 27
 34
ref


hCV29948033

0.05902






hCV3054799
<.0001
0.06051
AA
211
247
1.04


hCV3054799

0.06051






hCV3054799
0.1288
0.06051
AG
255
272
1.14


hCV3054799

0.06051






hCV3054799
0.1135
0.06051
GG
 73
 88
ref


hCV3054799

0.06051






hCV31671070
<.0001
0.07368
AG + AA
528
591
1.43


hCV31671070

0.07368






hCV12066124
0.0002
0.07542
CC
193
169
1.87


hCV12066124

0.07542






hCV12066124
0.0339
0.07542
CT
254
296
1.38


hCV12066124

0.07542






hCV12066124
0.101 
0.07542
TT
 87
139
ref


hCV12066124

0.07542






hCV1772768
0.0093
0.0798
GG
230
256
1.03


hCV1772768

0.0798






hDV72050312
<.0001
0.08047
GG
337
368
0.79


hDV72050312

0.08047






hDV72050312
0.3424
0.08047
GA
172
215
0.69


hDV72050312

0.08047






hDV72050312
0.6528
0.08047
AA
 29
 24
ref


hDV72050312

0.08047






hCV9540478
0.0004
0.08096
TT
335
402
0.84


hCV9540478

0.08096






hCV2690378
<.0001
0.08114
GT + GG
459
490
1.37


hCV2690378

0.08114






hCV29245634
<.0001
0.08203
CT + CC
535
605
0.25


hCV29245634

0.08203






hCV16233239
0.3111
0.0829
AA
342
356
1.25


hCV16233239

0.0829






hCV3286482
<.0001
0.08603
TC + TT
517
572
1.49


hCV3286482

0.08603






hDV70794769
<.0001
0.0899
CC
334
364
0.73


hDV70794769

0.0899






hDV70794769
0.3676
0.0899
CT
174
220
0.63


hDV70794769

0.0899






hDV70794769
0.4823
0.0899
TT
 30
 23
ref


hDV70794769

0.0899






hDV77026147
<.0001
0.09216
CT + CC
535
602
2.24


hDV77026147

0.09216






hCV1396435
0.0001
0.09466
GG
187
191
1.17


hCV1396435

0.09466






hCV1396435
0.0248
0.09466
GT
258
305
1.01


hCV1396435

0.09466






hCV1396435
0.384 
0.09466
TT
 93
111
ref


hCV1396435

0.09466






hDV70820190
0.2358
0.09992
GG
367
389
1.19


hDV70820190

0.09992

















Risk of VT in no statin use group














HR 95% CI
HR 95%CI
P-

Risk of VT in statin use group













SNP
lower_PLACEBO
upper_PLACEBO
value_PLACEBO
P_DF2_PLACEBO
GENO_statin
EVENTS_statin





hCV7543812
0.5117
0.989
0.043 
0.0373
TT
40


hCV7543812








hCV7543812
0.7414
1.343
0.9893
0.0373
TC
65


hCV7543812








hCV7543812



0.0373
CC
20


hCV7543812








hCV7543812
0.5499
0.923
0.0103

TT
40


hCV7543812








hCV2690378
0.9508
1.91 
0.0936
0.133 
GG
51


hCV2690378








hCV2690378
1.0016
1.941
0.0489
0.133 
GT
47


hCV2690378








hCV2690378



0.133 
TT
27


hCV2690378








hCV7543812
0.666 
1.165
0.3726

TC + TT
105 


hCV7543812








hCV931685
0.8633
5.895
0.0969
0.0639
GG
90


hCV931685








hCV931685
0.6621
4.696
0.2564
0.0639
GT
29


hCV931685








hCV931685



0.0639
TT
 6


hCV931685








hCV11686277
0.8787
1.779
0.2145
0.357 
CC
51


hCV11686277








hCV11686277
0.9077
1.776
0.1632
0.357 
CG
48


hCV11686277








hCV11686277



0.357 
GG
26


hCV11686277








hCV29260019
0.8974
1.446
0.2846

GG
42


hCV29260019








hDV70820190
0.7288
2.82 
0.2967

GA + GG
116 


hDV70820190








hCV931685
1.0163
1.731
0.0376

GG
90


hCV931685








hDV70437895
0.9848
2.388
0.0585

CT + CC
108 


hDV70437895








hCV931685
0.8129
5.524
0.1245

GT + GG
119 


hCV931685








hCV29245634
0.0288
2.338
0.2291
0.066 
CC
104 


hCV29245634








hCV29245634
0.0201
1.691
0.1347
0.066 
CT
21


hCV29245634








hCV29245634



0.066 
TT
 0


hCV29245634








hDV70437895
1.086 
2.706
0.0206
0.0234
CC
65


hDV70437895








hDV70437895
0.8434
2.128
0.2155
0.0234
CT
43


hDV70437895








hDV70437895



0.0234
TT
17


hDV70437895








hDV72050312
0.8637
1.394
0.4473

GG
62


hDV72050312








hCV29948033
0.6865
1.945
0.5864

TC + TT
116 


hCV29948033








hDV70794769
0.8686
1.4 
0.422 

CC
62


hDV70794769








hCV12066124
1.1552
1.911
0.002 

CC
27


hCV12066124








hCV3054799
0.7447
1.198
0.6363

AA
41


hCV3054799








hDV70820190
0.7614
2.974
0.2398
0.2887
GG
79


hDV70820190








hDV70820190
0.642 
2.597
0.4736
0.2887
GA
37


hDV70820190








hDV70820190



0.2887
AA
 8


hDV70820190








hCV1396435
0.905 
1.485
0.242 

GG
30


hCV1396435








hDV70437895
1.0607
1.691
0.0141

CC
65


hDV70437895








hCV11686277
0.8177
1.333
0.7295

CC
51


hCV11686277








hCV11778561
0.8884
1.675
0.2194

AT + AA
92


hCV11778561








hCV2690378
0.8232
1.345
0.6842

GG
51


hCV2690378








hDV70830411
0.6685
1.085
0.1942

TT
48


hDV70830411








hCV7422169
0.5617
1.754
0.9792

GA + GG
118 


hCV7422169








hCV29260019
0.8796
1.853
0.1987
0.416 
GG
42


hCV29260019








hCV29260019
0.8036
1.665
0.4335
0.416 
GA
65


hCV29260019








hCV29260019



0.416 
AA
16


hCV29260019








hCV29245634
0.9614
1.881
0.0836

CC
104 


hCV29245634








hCV29948033
0.6725
1.931
0.6271
0.8191
TT
66


hCV29948033








hCV29948033
0.6871
2.054
0.5374
0.8191
TC
50


hCV29948033








hCV29948033



0.8191
CC
 9


hCV29948033








hCV3054799
0.7272
1.499
0.8157
0.6888
AA
41


hCV3054799








hCV3054799
0.7991
1.626
0.4703
0.6888
AG
66


hCV3054799








hCV3054799



0.6888
GG
17


hCV3054799








hCV31671070
0.6402
3.173
0.3855

AG + AA
125 


hCV31671070








hCV12066124
1.3346
2.634
0.0003
0.0012
CC
27


hCV12066124








hCV12066124
1.0085
1.901
0.0442
0.0012
CT
72


hCV12066124








hCV12066124



0.0012
TT
23


hCV12066124








hCV1772768
0.8109
1.298
0.8305

GG
41


hCV1772768








hDV72050312
0.4485
1.382
0.405 
0.3308
GG
62


hDV72050312








hDV72050312
0.3843
1.223
0.2011
0.3308
GA
50


hDV72050312








hDV72050312



0.3308
AA
13


hDV72050312








hCV9540478
0.6583
1.072
0.1604

TT
87


hCV9540478








hCV2690378
1.0052
1.881
0.0463

GT + GG
98


hCV2690378








hCV29245634
0.0274
2.218
0.2115

CT + CC
125 


hCV29245634








hCV16233239
0.9806
1.583
0.0719

AA
77


hCV16233239








hCV3286482
0.8535
2.591
0.1613

TC + TT
116 


hCV3286482








hDV70794769
0.4152
1.286
0.2765
0.2084
CC
62


hDV70794769








hDV70794769
0.3509
1.12 
0.1148
0.2084
CT
50


hDV70794769








hDV70794769



0.2084
TT
13


hDV70794769








hDV77026147
0.4312
11.62 
0.3376

CT + CC
124 


hDV77026147








hCV1396435
0.8309
1.648
0.3681
0.5028
GG
30


hCV1396435








hCV1396435
0.734 
1.398
0.9373
0.5028
GT
75


hCV1396435








hCV1396435



0.5028
TT
20


hCV1396435








hDV70820190
0.9331
1.527
0.1589

GG
79


hDV70820190


















Ris of VT in statin use group


















HR 95% CI
HR 95% CI
P-




SNP
TOTAL_statin
HR_statin
lower_statin
upper_statin
value_statin
P_DF2_statin







hCV7543812
 51
2.85
1.4892
5.4472
0.0016
0.0065



hCV7543812









hCV7543812
134
1.76
0.9862
3.1463
0.0557
0.0065



hCV7543812









hCV7543812
 72
ref



0.0065



hCV7543812









hCV7543812
 51
1.9 
1.1708
3.0924
0.0094




hCV7543812









hCV2690378
 71
1.22
0.6713
2.2133
0.5154
0.0078



hCV2690378









hCV2690378
140
0.57
0.3215
1.0235
0.0599
0.0078



hCV2690378









hCV2690378
 46
ref



0.0078



hCV2690378









hCV7543812
185
2.06
1.1851
3.5833
0.0104




hCV7543812









hCV931685
205
0.3 
0.0821
1.0866
0.0667
0.104 



hCV931685









hCV931685
 48
0.42
0.1077
1.6061
0.2031
0.104 



hCV931685









hCV931685
 4
ref



0.104 



hCV931685









hCV11686277
 70
1.31
0.7207
2.3934
0.3734
0.0098



hCV11686277









hCV11686277
140
0.62
0.3476
1.1112
0.1086
0.0098



hCV11686277









hCV11686277
 47
ref



0.0098



hCV11686277









hCV29260019
119
0.6 
0.3805
0.9313
0.0231




hCV29260019









hDV70820190
252
0.29
0.0922
0.903 
0.0327




hDV70820190









hCV931685
205
0.65
0.3932
1.0614
0.0846




hCV931685









hDV70437895
237
0.53
0.2635
1.0523
0.0694




hDV70437895









hCV931685
253
0.32
0.0884
1.1575
0.0824




hCV931685









hCV29245634
227
43000    
0   
1E+182
0.9592
0.2804



hCV29245634









hCV29245634
 28
71000    
0   
2E+182
0.9573
0.2804



hCV29245634









hCV29245634
 2
ref



0.2804



hCV29245634









hDV70437895
148
0.51
0.25 
1.0405
0.0642
0.1798



hDV70437895









hDV70437895
 89
0.56
0.2621
1.1868
0.1297
0.1798



hDV70437895









hDV70437895
 20
ref



0.1798



hDV70437895









hDV72050312
159
0.61
0.3943
0.9355
0.0237




hDV72050312









hCV29948033
251
0.3 
0.1035
0.8704
0.0267




hCV29948033









hDV70794769
158
0.62
0.4006
0.9498
0.0282




hDV70794769









hCV12066124
 68
0.77
0.4624
1.29 
0.3237




hCV12066124









hCV3054799
125
0.52
0.3344
0.8198
0.0047




hCV3054799









hDV70820190
178
0.28
0.088 
0.8787
0.0292
0.0908



hDV70820190









hDV70820190
 74
0.31
0.0957
1.0268
0.0553
0.0908



hDV70820190









hDV70820190
 5
ref



0.0908



hDV70820190









hCV1396435
 85
0.63
0.3882
1.0284
0.0647




hCV1396435









hDV70437895
148
0.79
0.5162
1.2238
0.297 




hDV70437895









hCV11686277
 70
1.83
1.1658
2.8751
0.0086




hCV11686277









hCV11778561
210
0.61
0.3675
1.0239
0.0615




hCV11778561









hCV2690378
 71
1.79
1.1434
2.8144
0.011 




hCV2690378









hDV70830411
 77
1.45
0.9242
2.2691
0.1061




hDV70830411









hCV7422169
253
0.26
0.0748
0.9243
0.0373




hCV7422169









hCV29260019
119
0.71
0.3538
1.4308
0.3395
0.0605



hCV29260019









hCV29260019
106
1.26
0.6363
2.4766
0.5118
0.0605



hCV29260019









hCV29260019
 32
ref



0.0605



hCV29260019









hCV29245634
227
0.65
0.3571
1.1968
0.1683




hCV29245634









hCV29948033
153
0.28
0.0951
0.8275
0.0213
0.0674



hCV29948033









hCV29948033
 98
0.33
0.1102
0.9849
0.0469
0.0674



hCV29948033









hCV29948033
 6
ref



0.0674



hCV29948033









hCV3054799
125
0.72
0.3683
1.4234
0.3491
0.0078



hCV3054799









hCV3054799
 95
1.54
0.7943
2.9729
0.202 
0.0078



hCV3054799









hCV3054799
 37
ref



0.0078



hCV3054799









hCV31671070
251
2E+06
0   

0.9868




hCV31671070









hCV12066124
 68
1.01
0.5219
1.9537
0.977 
0.2627



hCV12066124









hCV12066124
129
1.45
0.8244
2.5485
0.1973
0.2627



hCV12066124









hCV12066124
 60
ref



0.2627



hCV12066124









hCV1772768
110
0.65
0.4134
1.0147
0.0579




hCV1772768









hDV72050312
159
0.45
0.2043
1.0116
0.0534
0.054 



hDV72050312









hDV72050312
 83
0.7 
0.3087
1.6002
0.4009
0.054 



hDV72050312









hDV72050312
 15
ref



0.054 



hDV72050312









hCV9540478
163
1.33
0.8381
2.0967
0.2282




hCV9540478









hCV2690378
211
0.79
0.4646
1.3477
0.3888




hCV2690378









hCV29245634
255
9E+05
0   

0.9883




hCV29245634









hCV16233239
171
0.8 
0.5152
1.2554
0.3376




hCV16233239









hCV3286482
245
0.59
0.2377
1.4739
0.2599




hCV3286482









hDV70794769
158
0.46
0.2056
1.0179
0.0553
0.0614



hDV70794769









hDV70794769
 84
0.7 
0.3054
1.5824
0.3862
0.0614



hDV70794769









hDV70794769
 15
ref



0.0614



hDV70794769









hDV77026147
257
0  
0   

0.9867




hDV77026147









hCV1396435
 85
0.66
0.3299
1.3053
0.2299
0.1794



hCV1396435









hCV1396435
134
1.05
0.567 
1.942 
0.8783
0.1794



hCV1396435









hCV1396435
 38
ref



0.1794



hCV1396435









hDV70820190
178
0.78
0.4957
1.2255
0.2805




hDV70820190













Above analysis adjusted for sex and age.















TABLE 8









Primary VT























OR
OR








GENO-

Odds
95% CI
95% CI
EFFECT


SNP rs #
Gene
MODE
TYPE
Strata
Ratio
lower
upper
LABEL
Variable
ProbChiSq





rs3820059
C1orf114
GEN
AG
All
1.127
1.027
1.237
GEN
GEN
0.0119










HET


rs3820059
C1orf114
GEN
AA
All
1.228
1.072
1.408
GEN
GEN
0.0031










HOM


rs3820059
C1orf114
ADD
A
All
1.113
1.045
1.186
ADD
ADD
0.0009


rs3820059
C1orf114
DOM
AG + AA
All
1.149
1.053
1.255
DOM
DOM
0.0019


rs3820059
C1orf114
REC
AA
All
1.155
1.017
1.313
REC
REC
0.0264


rs6025
F5
GEN
AG
All
3.567
3.047
4.176
GEN
GEN
<.0001










HET


rs6025
F5
GEN
AA
All
5.412
2.353
12.446
GEN
GEN
<.0001










HOM


rs6025
F5
ADD
A
All
3.423
2.944
3.98
ADD
ADD
<.0001


rs6025
F5
DOM
AG + AA
All
3.62
3.1
4.228
DOM
DOM
<.0001


rs6025
F5
REC
AA
All
4.768
2.074
10.963
REC
REC
0.0002


rs4262503
LOC730144/
GEN
CT
All
0.817
0.718
0.928
GEN
GEN
0.0019



LOC100505872






HET


rs4262503
LOC730144/
GEN
CC
All
1.468
0.834
2.582
GEN
GEN
0.1832



LOC100505872






HOM


rs4262503
LOC730144/
ADD
C
All
0.87
0.774
0.979
ADD
ADD
0.0209



LOC100505872


rs4262503
LOC730144/
DOM
CT + CC
All
0.837
0.739
0.949
DOM
DOM
0.0055



LOC100505872


rs4262503
LOC730144/
REC
CC
All
1.508
0.858
2.653
REC
REC
0.1537



LOC100505872


rs627530
STK11IP/OBSL1
GEN
CT
All
1.094
0.924
1.295
GEN
GEN
0.2963










HET


rs627530
STK11IP/OBSL1
GEN
CC
All
2.998
1.527
5.885
GEN
GEN
0.0014










HOM


rs627530
STK11IP/OBSL1
ADD
C
All
1.207
1.04
1.401
ADD
ADD
0.0133


rs627530
STK11IP/OBSL1
DOM
CT + CC
All
1.165
0.99
1.372
DOM
DOM
0.0667


rs627530
STK11IP/OBSL1
REC
CC
All
2.979
1.518
5.847
REC
REC
0.0015


rs1800788

GEN
TC
All
1.231
1.121
1.351
GEN
GEN
<.0001










HET


rs1800788

GEN
TT
All
1.307
1.076
1.589
GEN
GEN
0.007










HOM


rs1800788

ADD
T
All
1.189
1.105
1.278
ADD
ADD
<.0001


rs1800788

DOM
TC + TT
All
1.241
1.135
1.356
DOM
DOM
<.0001


rs1800788

REC
TT
All
1.214
1.002
1.471
REC
REC
0.048


rs2066865
FGG
GEN
AG
All
1.327
1.21
1.456
GEN
GEN
<.0001










HET


rs2066865
FGG
GEN
AA
All
1.939
1.655
2.271
GEN
GEN
<.0001










HOM


rs2066865
FGG
ADD
A
All
1.366
1.277
1.462
ADD
ADD
<.0001


rs2066865
FGG
DOM
AG + AA
All
1.421
1.302
1.551
DOM
DOM
<.0001


rs2066865
FGG
REC
AA
All
1.704
1.464
1.985
REC
REC
<.0001


rs2066854
FGG
GEN
AT
All
1.314
1.199
1.441
GEN
GEN
<.0001










HET


rs2066854
FGG
GEN
AA
All
1.927
1.647
2.254
GEN
GEN
<.0001










HOM


rs2066854
FGG
ADD
A
All
1.359
1.271
1.453
ADD
ADD
<.0001


rs2066854
FGG
DOM
AT + AA
All
1.41
1.292
1.538
DOM
DOM
<.0001


rs2066854
FGG
REC
AA
All
1.702
1.463
1.979
REC
REC
<.0001


rs3756008

GEN
TA
All
1.349
1.222
1.489
GEN
GEN
<.0001










HET


rs3756008

GEN
TT
All
1.721
1.517
1.952
GEN
GEN
<.0001










HOM


rs3756008

ADD
T
All
1.317
1.238
1.401
ADD
ADD
<.0001


rs3756008

DOM
TA + TT
All
1.444
1.316
1.585
DOM
DOM
<.0001


rs3756008

REC
TT
All
1.44
1.288
1.609
REC
REC
<.0001


rs925451
F11
GEN
AG
All
1.36
1.233
1.5
GEN
GEN
<.0001










HET


rs925451
F11
GEN
AA
All
1.747
1.537
1.985
GEN
GEN
<.0001










HOM


rs925451
F11
ADD
A
All
1.328
1.248
1.413
ADD
ADD
<.0001


rs925451
F11
DOM
AG + AA
All
1.455
1.327
1.596
DOM
DOM
<.0001


rs925451
F11
REC
AA
All
1.462
1.304
1.64
REC
REC
<.0001


rs3822057
F11
GEN
AC
All
0.785
0.707
0.871
GEN
GEN
<.0001










HET


rs3822057
F11
GEN
AA
All
0.6
0.53
0.679
GEN
GEN
<.0001










HOM


rs3822057
F11
ADD
A
All
0.775
0.729
0.824
ADD
ADD
<.0001


rs3822057
F11
DOM
AC + AA
All
0.72
0.652
0.794
DOM
DOM
<.0001


rs3822057
F11
REC
AA
All
0.703
0.633
0.779
REC
REC
<.0001


rs2036914
F11
GEN
TC
All
0.755
0.683
0.835
GEN
GEN
<.0001










HET


rs2036914
F11
GEN
TT
All
0.586
0.517
0.664
GEN
GEN
<.0001










HOM


rs2036914
F11
ADD
T
All
0.764
0.719
0.813
ADD
ADD
<.0001


rs2036914
F11
DOM
TC + TT
All
0.701
0.638
0.77
DOM
DOM
<.0001


rs2036914
F11
REC
TT
All
0.696
0.624
0.776
REC
REC
<.0001


rs3756011
F11
GEN
AC
All
1.347
1.218
1.489
GEN
GEN
<.0001










HET


rs3756011
F11
GEN
AA
All
1.775
1.566
2.011
GEN
GEN
<.0001










HOM


rs3756011
F11
ADD
A
All
1.334
1.254
1.419
ADD
ADD
<.0001


rs3756011
F11
DOM
AC + AA
All
1.459
1.328
1.604
DOM
DOM
<.0001


rs3756011
F11
REC
AA
All
1.482
1.329
1.653
REC
REC
<.0001


rs2289252
F11
GEN
TC
All
1.381
1.249
1.527
GEN
GEN
<.0001










HET


rs2289252
F11
GEN
TT
All
1.807
1.593
2.049
GEN
GEN
<.0001










HOM


rs2289252
F11
ADD
T
All
1.348
1.267
1.435
ADD
ADD
<.0001


rs2289252
F11
DOM
TC + TT
All
1.492
1.357
1.64
DOM
DOM
<.0001


rs2289252
F11
REC
TT
All
1.485
1.331
1.657
REC
REC
<.0001


rs2281390
LOC642074/
GEN
TG
All
1.132
1.028
1.245
GEN
GEN
0.0113



LOC642043






HET


rs2281390
LOC642074/
GEN
TT
All
0.931
0.729
1.187
GEN
GEN
0.5621



LOC642043






HOM


rs2281390
LOC642074/
ADD
T
All
1.067
0.986
1.155
ADD
ADD
0.1086



LOC642043


rs2281390
LOC642074/
DOM
TG + TT
All
1.109
1.011
1.216
DOM
DOM
0.0277



LOC642043


rs2281390
LOC642074/
REC
TT
All
0.898
0.705
1.143
REC
REC
0.382



LOC642043


rs2274736
PTPN21
GEN
GA
All
1.098
1
1.204
GEN
GEN
0.0489










HET


rs2274736
PTPN21
GEN
GG
All
1.207
1.041
1.399
GEN
GEN
0.0126










HOM


rs2274736
PTPN21
ADD
G
All
1.098
1.028
1.173
ADD
ADD
0.0053


rs2274736
PTPN21
DOM
GA + GG
All
1.118
1.024
1.221
DOM
DOM
0.013


rs2274736
PTPN21
REC
GG
All
1.151
1.001
1.324
REC
REC
0.0485


rs2266911
STAG2/ODZ1
GEN
TC
Female
0.928
0.815
1.057
GEN
GEN
0.2614










HET


rs2266911
STAG2/ODZ1
GEN
TT
Female
0.931
0.687
1.263
GEN
GEN
0.647






adj age



HOM


rs2266911
STAG2/ODZ1
ADD
T
Female
0.943
0.848
1.048
ADD
ADD
0.2766






adj age


rs2266911
STAG2/ODZ1
DOM
TC + TT
Female
0.928
0.819
1.052
DOM
DOM
0.2447






adj age


rs2266911
STAG2/ODZ1
REC
TT
Female
0.954
0.706
1.291
REC
REC
0.7616






adj age


rs3765407
LUZP1
GEN
GT
All
0.958
0.869
1.055
GEN
GEN
0.3815










HET


rs3765407
LUZP1
GEN
GG
All
1.392
1.08
1.794
GEN
GEN
0.0106










HOM


rs3765407
LUZP1
ADD
G
All
1.031
0.951
1.118
ADD
ADD
0.4595


rs3765407
LUZP1
DOM
GT + GG
All
0.994
0.905
1.091
DOM
DOM
0.8922


rs3765407
LUZP1
REC
GG
All
1.409
1.095
1.814
REC
REC
0.0077


rs4524
F5
GEN
CT
All
0.77
0.701
0.844
GEN
GEN
<.0001










HET


rs4524
F5
GEN
CC
All
0.613
0.507
0.741
GEN
GEN
<.0001










HOM


rs4524
F5
ADD
C
All
0.776
0.722
0.834
ADD
ADD
<.0001


rs4524
F5
DOM
CT + CC
All
0.745
0.682
0.814
DOM
DOM
<.0001


rs4524
F5
REC
CC
All
0.677
0.562
0.816
REC
REC
<.0001


rs2070006

GEN
TC
All
1.271
1.152
1.402
GEN
GEN
<.0001










HET


rs2070006

GEN
TT
All
1.531
1.348
1.738
GEN
GEN
<.0001










HOM


rs2070006

ADD
T
All
1.242
1.167
1.322
ADD
ADD
<.0001


rs2070006

DOM
TC + TT
All
1.337
1.219
1.467
DOM
DOM
<.0001


rs2070006

REC
TT
All
1.329
1.187
1.487
REC
REC
<.0001


rs4253418
F11
GEN
AG
All
0.773
0.653
0.915
GEN
GEN
0.0028










HET


rs4253418
F11
GEN
AA
All
0.87
0.349
2.165
GEN
GEN
0.7643










HOM


rs4253418
F11
ADD
A
All
0.789
0.673
0.926
ADD
ADD
0.0036


rs4253418
F11
DOM
AG + AA
All
0.776
0.657
0.916
DOM
DOM
0.0027


rs4253418
F11
REC
AA
All
0.887
0.356
2.208
REC
REC
0.7968


rs169713

GEN
CT
All
1.145
1.042
1.258
GEN
GEN
0.0048










HET


rs169713

GEN
CC
All
1.129
0.917
1.389
GEN
GEN
0.2521










HOM


rs169713

ADD
C
All
1.108
1.028
1.194
ADD
ADD
0.0075


rs169713

DOM
CT + CC
All
1.143
1.044
1.251
DOM
DOM
0.0037


rs169713

REC
CC
All
1.078
0.878
1.323
REC
REC
0.4732


rs8176750
ABO
GEN
AC
All
0.93
0.815
1.061
GEN
GEN
0.281










HET


rs8176750
ABO
GEN
AA
All
0.813
0.413
1.602
GEN
GEN
0.55










HOM


rs8176750
ABO
ADD
A
All
0.926
0.818
1.049
ADD
ADD
0.2264


rs8176750
ABO
DOM
AC + AA
All
0.926
0.813
1.055
DOM
DOM
0.2462


rs8176750
ABO
REC
AA
All
0.821
0.417
1.616
REC
REC
0.5677


rs8176750
ABO
GEN
AC
age sex among
0.659
0.574
0.757
GEN
GEN
<.0001






Dom (GG



HET






or GT) of






rs8176719


rs8176750
ABO
GEN
AA
age sex among
0.582
0.295
1.148
GEN
GEN
0.1183






Dom (GG



HOM






or GT) of






rs8176719


rs8176750
ABO
ADD
A
age sex among
0.672
0.59
0.765
ADD
ADD
<.0001






Dom (GG






or GT) of






rs8176719


rs8176750
ABO
DOM
AC + AA
age sex among
0.657
0.573
0.752
DOM
DOM
<.0001






Dom (GG






or GT) of






rs8176719


rs8176750
ABO
REC
AA
age sex among
0.632
0.321
1.246
REC
REC
0.1851






Dom (GG






or GT) of






rs8176719


rs8176719
ABO
GEN
GT
All
2.023
1.833
2.232
GEN
GEN
<.0001










HET


rs8176719
ABO
GEN
GG
All
2.491
2.174
2.853
GEN
GEN
<.0001










HOM


rs8176719
ABO
ADD
G
All
1.662
1.556
1.774
ADD
ADD
<.0001


rs8176719
ABO
DOM
GT + GG
All
2.124
1.934
2.333
DOM
DOM
<.0001


rs8176719
ABO
REC
GG
All
1.646
1.457
1.86
REC
REC
<.0001


rs2069946
PROCR
GEN
CT
All
1.304
1.133
1.5
GEN
GEN
0.0002










HET


rs2069946
PROCR
GEN
CC
All
1.344
0.691
2.613
GEN
GEN
0.3835










HOM


rs2069946
PROCR
ADD
C
All
1.282
1.125
1.46
ADD
ADD
0.0002


rs2069946
PROCR
DOM
CT + CC
All
1.305
1.137
1.498
DOM
DOM
0.0002


rs2069946
PROCR
REC
CC
All
1.305
0.672
2.538
REC
REC
0.4319


rs2266911
STAG2/ODZ1
GEN
TC
male age
2.868
1.089
7.553
GEN
GEN
0.0329






among



HET


rs2266911
STAG2/ODZ1
GEN
TT
male age
0.815
0.688
0.967
GEN
GEN
0.0189






among



HOM


rs2266911
STAG2/ODZ1
ADD
T
male age
0.909
0.835
0.99
ADD
ADD
0.0276






among


rs2266911
STAG2/ODZ1
DOM
TC + TT
male age
0.845
0.714
0.999
DOM
DOM
0.0493






among


rs2266911
STAG2/ODZ1
REC
TT
male age
0.81
0.683
0.961
REC
REC
0.0154






among


rs6003
F13B
GEN
GA
All
1.181
1.049
1.33
GEN
GEN
0.0059










HET


rs6003
F13B
GEN
GG
All
1.315
0.904
1.914
GEN
GEN
0.1523










HOM


rs6003
F13B
ADD
G
All
1.172
1.057
1.298
ADD
ADD
0.0025


rs6003
F13B
DOM
GA + GG
All
1.191
1.062
1.335
DOM
DOM
0.0028


rs6003
F13B
REC
GG
All
1.279
0.88
1.861
REC
REC
0.1976


rs1417121
SDCCAG8/
GEN
CG
All
1.072
0.978
1.175
GEN
GEN
0.1388



AKT3






HET


rs1417121
SDCCAG8/
GEN
CC
All
1.47
1.256
1.72
GEN
GEN
<.0001



AKT3






HOM


rs1417121
SDCCAG8/
ADD
C
All
1.155
1.08
1.235
ADD
ADD
<.0001



AKT3


rs1417121
SDCCAG8/
DOM
CG + CC
All
1.135
1.041
1.239
DOM
DOM
0.0043



AKT3


rs1417121
SDCCAG8/
REC
CC
All
1.425
1.224
1.659
REC
REC
<.0001



AKT3


rs12744297
AKT3
GEN
GA
All
1.107
1.009
1.215
GEN
GEN
0.0324










HET


rs12744297
AKT3
GEN
GG
All
1.311
1.138
1.511
GEN
GEN
0.0002










HOM


rs12744297
AKT3
ADD
G
All
1.133
1.063
1.209
ADD
ADD
0.0001


rs12744297
AKT3
DOM
GA + GG
All
1.148
1.051
1.253
DOM
DOM
0.0021


rs12744297
AKT3
REC
GG
All
1.246
1.09
1.424
REC
REC
0.0012


rs3733402
KLKB1
GEN
GA
All
0.798
0.721
0.883
GEN
GEN
<.0001










HET


rs3733402
KLKB1
GEN
GG
All
0.674
0.595
0.763
GEN
GEN
<.0001










HOM


rs3733402
KLKB1
ADD
G
All
0.819
0.77
0.871
ADD
ADD
<.0001


rs3733402
KLKB1
DOM
GA + GG
All
0.758
0.689
0.835
DOM
DOM
<.0001


rs3733402
KLKB1
REC
GG
All
0.777
0.698
0.865
REC
REC
<.0001


rs3087505
KLKB1
GEN
AG
All
0.85
0.758
0.952
GEN
GEN
0.005










HET


rs3087505
KLKB1
GEN
AA
All
0.483
0.317
0.736
GEN
GEN
0.0007










HOM


rs3087505
KLKB1
ADD
A
All
0.812
0.734
0.898
ADD
ADD
<.0001


rs3087505
KLKB1
DOM
AG + AA
All
0.82
0.734
0.916
DOM
DOM
0.0005


rs3087505
KLKB1
REC
AA
All
0.498
0.327
0.757
REC
REC
0.0011


rs2480089
KIF6
GEN
CA
All
0.89
0.811
0.976
GEN
GEN
0.0135










HET


rs2480089
KIF6
GEN
CC
All
1.054
0.912
1.217
GEN
GEN
0.4768










HOM


rs2480089
KIF6
ADD
C
All
0.98
0.918
1.046
ADD
ADD
0.5491


rs2480089
KIF6
DOM
CA + CC
All
0.921
0.844
1.006
DOM
DOM
0.0671


rs2480089
KIF6
REC
CC
All
1.117
0.975
1.281
REC
REC
0.1111


rs8176750
ABO
GEN
AC
age sex among
0.659
0.574
0.757
GEN
GEN
<.0001






Dom (GG



HET






or GT) of






rs8176719


rs8176750
ABO
GEN
AA
age sex among
0.582
0.295
1.148
GEN
GEN
0.1183






Dom (GG



HOM






or GT) of






rs8176719


rs8176750
ABO
ADD
A
age sex among
0.672
0.59
0.765
ADD
ADD
<.0001






Dom (GG






or GT) of






rs8176719


rs8176750
ABO
DOM
AC + AA
age sex among
0.657
0.573
0.752
DOM
DOM
<.0001






Dom (GG






or GT) of






rs8176719


rs8176750
ABO
REC
AA
age sex among
0.632
0.321
1.246
REC
REC
0.1851






Dom (GG






or GT) of






rs8176719


rs8176719
ABO
GEN
GT
All
2.023
1.833
2.232
GEN
GEN
<.0001










HET


rs8176719
ABO
GEN
GG
All
2.491
2.174
2.853
GEN
GEN
<.0001










HOM


rs8176719
ABO
ADD
G
All
1.662
1.556
1.774
ADD
ADD
<.0001


rs8176719
ABO
DOM
GT + GG
All
2.124
1.934
2.333
DOM
DOM
<.0001


rs8176719
ABO
REC
GG
All
1.646
1.457
1.86
REC
REC
<.0001


rs3730055
AKT2
GEN
TC
All
0.981
0.868
1.11
GEN
GEN
0.7646










HET


rs3730055
AKT2
GEN
TT
All
1.878
1.161
3.037
GEN
GEN
0.0102










HOM


rs3730055
AKT2
ADD
T
All
1.05
0.94
1.173
ADD
ADD
0.387


rs3730055
AKT2
DOM
TC + TT
All
1.017
0.902
1.146
DOM
DOM
0.7853


rs3730055
AKT2
REC
TT
All
1.883
1.165
3.044
REC
REC
0.0098


rs2304167
GP6
GEN
CT
All
0.907
0.825
0.997
GEN
GEN
0.0442










HET


rs2304167
GP6
GEN
CC
All
0.818
0.648
1.032
GEN
GEN
0.0901










HOM


rs2304167
GP6
ADD
C
All
0.906
0.838
0.98
ADD
ADD
0.0133


rs2304167
GP6
DOM
CT + CC
All
0.897
0.818
0.983
DOM
DOM
0.0198


rs2304167
GP6
REC
CC
All
0.844
0.67
1.063
REC
REC
0.1489


rs1654416
RDH13/GP6
GEN
CT
All
0.888
0.807
0.976
GEN
GEN
0.0143










HET


rs1654416
RDH13/GP6
GEN
CC
All
0.798
0.629
1.013
GEN
GEN
0.0641










HOM


rs1654416
RDH13/GP6
ADD
C
All
0.89
0.822
0.963
ADD
ADD
0.0037


rs1654416
RDH13/GP6
DOM
CT + CC
All
0.878
0.801
0.962
DOM
DOM
0.0055


rs1654416
RDH13/GP6
REC
CC
All
0.829
0.654
1.05
REC
REC
0.1203













Primary VT
Recurrent VT
















HW




HR




(control)




95% CI


SNP rs #
P_DF2
pExact
GENO_ALL
EVENTS_ALL
TOTAL_ALL
HR_ALL
lower_ALL





rs3820059
0.00364
0.0353
AG
248
1633
1.11
0.919


rs3820059
0.00364
0.0353
AA
101
508
1.45
1.141


rs3820059

0.0353


rs3820059

0.0353
AG + AA
349
2141
1.19
0.998


rs3820059

0.0353
AA
101
508
1.45
1.141


rs6025
0
0.0475
AG
127
580
1.53
1.258


rs6025
0
0.0475
AA
7
27
1.73
0.817


rs6025

0.0475


rs6025

0.0475
AG + AA
134
607
1.54
1.27


rs6025

0.0475
AA
7
27
1.73
0.817


rs4262503
0.00294
0.258
CT
73
437
1.14
0.892


rs4262503
0.00294
0.258
CC
8
27
2.93
1.454


rs4262503

0.258


rs4262503

0.258
CT + CC
81
464
1.22
0.959


rs4262503

0.258
CC
8
27
2.93
1.454


rs627530
0.00378
3.57E−11
CT
44
260
1.21
0.891


rs627530
0.00378
3.57E−11
CC
8
26
2.4
1.192


rs627530

3.57E−11


rs627530

3.57E−11
CT + CC
52
286
1.31
0.987


rs627530

3.57E−11
CC
8
26
2.4
1.192


rs1800788
0.00001
0.0217
TC
199
1284
1.09
0.911


rs1800788
0.00001
0.0217
TT
48
207
1.61
1.187


rs1800788

0.0217


rs1800788

0.217
TC + TT
247
1491
1.16
0.983


rs1800788

0.0217
TT
48
207
1.61
1.187


rs2066865
0
0.97
AG
229
1528
1.05
0.872


rs2066865
0
0.97
AA
85
406
1.53
1.194


rs2066865

0.97


rs2066865

0.97
AG + AA
314
1934
1.15
0.966


rs2066865

0.97
AA
85
406
1.53
1.194


rs2066854
0
0.849
AT
228
1537
1.03
0.855


rs2066854
0
0.849
AA
87
415
1.53
1.196


rs2066854

0.849


rs2066854

0.849
AT + AA
315
1952
1.13
0.953


rs2066854

0.849
AA
87
415
1.53
1.196


rs3756008
0
0.644
TA
257
1751
0.95
0.778


rs3756008
0
0.644
TT
137
774
1.25
0.993


rs3756008

0.644


rs3756008

0.644
TA + TT
394
2525
1.04
0.86


rs3756008

0.644
TT
137
774
1.25
0.993


rs925451
0
0.0947
AG
259
1719
1.02
0.838


rs925451
0
0.0947
AA
129
725
1.33
1.05


rs925451

0.0947


rs925451

0.0947
AG + AA
388
2444
1.11
0.918


rs925451

0.0947
AA
129
725
1.33
1.05


rs3822057
0
0.514
AC
269
1740
0.84
0.694


rs3822057
0
0.514
AA
86
734
0.65
0.505


rs3822057

0.514


rs3822057

0.514
AC + AA
355
2474
0.78
0.656


rs3822057

0.514
AA
86
734
0.65
0.505


rs2036914
0
0.476
TC
262
1684
0.9
0.747


rs2036914
0
0.476
TT
77
631
0.71
0.544


rs2036914

0.476


rs2036914

0.476
TC + TT
339
2315
0.85
0.711


rs2036914

0.476
TT
77
631
0.71
0.544


rs3756011
0
0.391
AC
258
1730
1.01
0.823


rs3756011
0
0.391
AA
147
827
1.3
1.026


rs3756011

0.391


rs3756011

0.391
AC + AA
405
2557
1.1
0.906


rs3756011

0.391
AA
147
827
1.3
1.026


rs2289252
0
0.817
TC
257
1739
1
0.807


rs2289252
0
0.817
TT
144
814
1.29
1.017


rs2289252

0.817


rs2289252

0.817
TC + TT
401
2553
1.08
0.891


rs2289252

0.817
TT
144
814
1.29
1.017


rs2281390
0.02735
0.0129
TG
154
1100
0.89
0.742


rs2281390
0.02735
0.0129
TT
27
112
1.54
1.043


rs2281390

0.0129


rs2281390

0.0129
TG + TT
181
1212
0.95
0.8


rs2281390

0.0129
TT
27
112
1.54
1.043


rs2274736
0.02063
0.455
GA
245
1597
1.13
0.94


rs2274736
0.02063
0.455
GG
77
402
1.42
1.092


rs2274736

0.455


rs2274736

0.455
GA + GG
322
1999
1.19
0.998


rs2274736

0.455
GG
77
402
1.42
1.092


rs2266911
0.50818

TC
5
13
2.74
1.13


rs2266911
0.50818

TT
67
261
1.3
0.996


rs2266911



rs2266911


TC + TT
72
274
1.35
1.042


rs2266911


TT
67
261
1.29
0.986


rs3765407
0.01959
0.338
GT
165
981
1.2
0.998


rs3765407
0.01959
0.338
GG
18
128
1.07
0.661


rs3765407

0.338


rs3765407

0.338
GT + GG
183
1109
1.19
0.993


rs3765407

0.338
GG
18
128
1.07
0.661


rs4524
0
0.3
CT
159
1185
0.82
0.681


rs4524
0
0.3
CC
28
175
0.98
0.666


rs4524

0.3


rs4524

0.3
CT + CC
187
1360
0.84
0.705


rs4524

0.3
CC
28
175
0.98
0.666


rs2070006
0
0.251
TC
265
1756
1.1
0.903


rs2070006
0
0.251
TT
124
720
1.31
1.036


rs2070006

0.251


rs2070006

0.251
TC + TT
389
2476
1.16
0.963


rs2070006

0.251
TT
124
720
1.31
1.036


rs4253418
0.01096
0.0809
AG
33
233
0.9
0.633


rs4253418
0.01096
0.0809
AA
3
8
3.29
1.058


rs4253418

0.0809


rs4253418

0.0809
AG + AA
36
241
0.96
0.683


rs4253418

0.0809
AA
3
8
3.29
1.058


rs169713
0.01464
0.0383
CT
165
1186
0.85
0.709


rs169713
0.01464
0.0383
CC
29
171
1.15
0.789


rs169713

0.0383


rs169713

0.0383
CT + CC
194
1357
0.89
0.745


rs169713

0.0383
CC
29
171
1.15
0.789


rs8176750
0.47492
1
AC
62
425
0.95
0.727


rs8176750
0.47492
1
AA
4
14
2.94
1.094


rs8176750

1


rs8176750

1
AC + AA
66
439
0.99
0.764


rs8176750

1
AA
4
14
2.94
1.094


rs8176750
1.032E−08

AC
61
421
0.88
0.672


rs8176750
1.032E−08

AA
4
14
2.87
1.063


rs8176750



rs8176750


AC + AA
65
435
0.92
0.707


rs8176750


AA
4
14
2.92
1.086


rs8176719
0
0.156
GT
301
1928
1.21
0.984


rs8176719
0
0.156
GG
111
642
1.36
1.052


rs8176719

0.156


rs8176719

0.156
GT + GG
412
2570
1.25
1.022


rs8176719

0.156
GG
111
642
1.36
1.052


rs2069946
0.00076
0.131
CT
55
429
0.79
0.599


rs2069946
0.00076
0.131
CC
1
16
0.36
0.05


rs2069946

0.131


rs2069946

0.131
CT + CC
56
445
0.78
0.588


rs2069946

0.131
CC
1
16
0.36
0.05


rs2266911
0.00558

TC
51
590
0.75
0.542


rs2266911
0.00558

TT
4
77
0.47
0.175


rs2266911



rs2266911


TC + TT
55
667
0.72
0.524


rs2266911


TT
4
77
0.52
0.192


rs6003
0.0099
0.00061
GA
94
605
1.01
0.81


rs6003
0.0099
0.00061
GG
12
53
1.62
0.913


rs6003

0.00061


rs6003

0.00061
GA + GG
106
658
1.06
0.855


rs6003

0.00061
GG
12
53
1.62
0.913


rs1417121
0.00001
0.795
CG
219
1447
1.02
0.854


rs1417121
0.00001
0.795
CC
64
377
1.27
0.967


rs1417121

0.795


rs1417121

0.795
CG + CC
283
1824
1.07
0.904


rs1417121

0.795
CC
64
377
1.27
0.967


rs12744297
0.00055
0.14
GA
259
1577
1.12
0.934


rs12744297
0.00055
0.14
GG
59
469
0.89
0.67


rs12744297

0.14


rs12744297

0.14
GA + GG
318
2046
1.07
0.899


rs12744297

0.14
GG
59
469
0.89
0.67


rs3733402
0
0.592
GA
252
1736
0.88
0.725


rs3733402
0
0.592
GG
97
685
0.82
0.644


rs3733402

0.592


rs3733402

0.592
GA + GG
349
2421
0.86
0.721


rs3733402

0.592
GG
97
685
0.82
0.644


rs3087505
0.0001
0.00568
AG
84
595
0.89
0.705


rs3087505
0.0001
0.00568
AA
7
31
1.58
0.75


rs3087505

0.00568


rs3087505

0.00568
AG + AA
91
626
0.92
0.735


rs3087505

0.00568
AA
7
31
1.58
0.75


rs2480089
0.01339
0.0209
CA
236
1500
1.12
0.932


rs2480089
0.01339
0.0209
CC
71
424
1.22
0.931


rs2480089

0.0209


rs2480089

0.0209
CA + CC
307
1924
1.14
0.96


rs2480089

0.0209
CC
71
424
1.22
0.931


rs8176750
1.032E−08

AC
61
421
0.88
0.672


rs8176750
1.032E−08

AA
4
14
2.87
1.063


rs8176750



rs8176750


AC + AA
65
435
0.92
0.707


rs8176750


AA
4
14
2.92
1.086


rs8176719
0
0.156
GT
301
1928
1.21
0.984


rs8176719
0
0.156
GG
111
642
1.36
1.052


rs8176719

0.156


rs8176719

0.156
GT + GG
412
2570
1.25
1.022


rs8176719

0.156
GG
111
642
1.36
1.052


rs3730055
0.03411
0.766
TC
86
516
1.22
0.967


rs3730055
0.03411
0.766
TT
6
42
0.88
0.394


rs3730055

0.766


rs3730055

0.766
TC + TT
92
558
1.19
0.95


rs3730055

0.766
TT
6
42
0.88
0.394


rs2304167
0.04653
0.744
CT
176
1065
1.18
0.98


rs2304167
0.04653
0.744
CC
20
123
1.09
0.688


rs2304167

0.744


rs2304167

0.744
CT + CC
196
1188
1.17
0.978


rs2304167

0.744
CC
20
123
1.09
0.688


rs1654416
0.01484
1
CT
172
1042
1.17
0.975


rs1654416
0.01484
1
CC
18
115
1.01
0.623


rs1654416

1


rs1654416

1
CT + CC
190
1157
1.15
0.966


rs1654416

1
CC
18
115
1.01
0.623












Recurrent VT
















HR









95% CI
P-

Ref



SNP rs #
upper_ALL
value_ALL
P_DF2_ALL
geno
EVENTS_ALL
TOTAL_ALL







rs3820059
1.335
0.2836
0.0095
GG
199
1459



rs3820059
1.843
0.0024
0.0095
GG
199
1459



rs3820059


0.0095
GG
199
1459



rs3820059
1.415
0.0521
0.0095
GG
199
1459



rs3820059
1.843
0.0024
0.0095
GG
199
1459



rs6025
1.871
<.0001
<.0001
GG
429
3072



rs6025
3.647
0.1522
<.0001
GG
429
3072



rs6025


<.0001
GG
429
3072



rs6025
1.874
<.0001
<.0001
GG
429
3072



rs6025
3.647
0.1522
<.0001
GG
429
3072



rs4262503
1.462
0.2913
0.0072
TT
462
3106



rs4262503
5.891
0.0026
0.0072
TT
462
3106



rs4262503


0.0072
TT
462
3106



rs4262503
1.539
0.1059
0.0072
TT
462
3106



rs4262503
5.891
0.0026
0.0072
TT
462
3106



rs627530
1.65
0.2195
0.0259
TT
510
3372



rs627530
4.831
0.0143
0.0259
TT
510
3372



rs627530


0.0259
TT
510
3372



rs627530
1.747
0.0615
0.0259
TT
510
3372



rs627530
4.831
0.0143
0.0259
TT
510
3372



rs1800788
1.306
0.3433
0.009
CC
293
2076



rs1800788
2.186
0.0022
0.009
CC
293
2076



rs1800788


0.009
CC
293
2076



rs1800788
1.379
0.0788
0.009
CC
293
2076



rs1800788
2.186
0.0022
0.009
CC
293
2076



rs2066865
1.263
0.6081
0.0027
GG
221
1585



rs2066865
1.971
0.0008
0.0027
GG
221
1585



rs2066865


0.0027
GG
221
1585



rs2066865
1.363
0.1174
0.0027
GG
221
1585



rs2066865
1.971
0.0008
0.0027
GG
221
1585



rs2066854
1.236
0.7678
0.002
TT
225
1607



rs2066854
1.964
0.0007
0.002
TT
225
1607



rs2066854


0.002
TT
225
1607



rs2066854
1.342
0.1595
0.002
TT
225
1607



rs2066854
1.964
0.0007
0.002
TT
225
1607



rs3756008
1.165
0.635
0.0316
AA
149
1042



rs3756008
1.58
0.0578
0.0316
AA
149
1042



rs3756008


0.0316
AA
149
1042



rs3756008
1.254
0.6945
0.0316
AA
149
1042



rs3756008
1.58
0.0578
0.0316
AA
149
1042



rs925451
1.252
0.815
0.0283
GG
151
1096



rs925451
1.681
0.0179
0.0283
GG
151
1096



rs925451


0.0283
GG
151
1096



rs925451
1.338
0.2834
0.0283
GG
151
1096



rs925451
1.681
0.0179
0.0283
GG
151
1096



rs3822057
1.011
0.0646
0.0042
CC
184
1072



rs3822057
0.842
0.0011
0.0042
CC
184
1072



rs3822057


0.0042
CC
184
1072



rs3822057
0.937
0.0073
0.0042
CC
184
1072



rs3822057
0.842
0.0011
0.0042
CC
184
1072



rs2036914
1.079
0.252
0.0359
CC
201
1238



rs2036914
0.921
0.01
0.0359
CC
201
1238



rs2036914


0.0359
CC
201
1238



rs2036914
1.008
0.0611
0.0359
CC
201
1238



rs2036914
0.921
0.01
0.0359
CC
201
1238



rs3756011
1.247
0.9046
0.0344
CC
136
994



rs3756011
1.637
0.0295
0.0344
CC
136
994



rs3756011


0.0344
CC
136
994



rs3756011
1.336
0.3371
0.0344
CC
136
994



rs3756011
1.637
0.0295
0.0344
CC
136
994



rs2289252
1.226
0.9634
0.032
CC
134
974



rs2289252
1.63
0.0354
0.032
CC
134
974



rs2289252


0.032
CC
134
974



rs2289252
1.318
0.4225
0.032
CC
134
974



rs2289252
1.63
0.0354
0.032
CC
134
974



rs2281390
1.079
0.2445
0.0318
GG
383
2448



rs2281390
2.278
0.0298
0.0318
GG
383
2448



rs2281390


0.0318
GG
383
2448



rs2281390
1.139
0.6074
0.0318
GG
383
2448



rs2281390
2.278
0.0298
0.0318
GG
383
2448



rs2274736
1.361
0.1919
0.0308
AA
208
1498



rs2274736
1.842
0.0088
0.0308
AA
208
1498



rs2274736


0.0308
AA
208
1498



rs2274736
1.415
0.0522
0.0308
AA
208
1498



rs2274736
1.842
0.0088
0.0308
AA
208
1498



rs2266911
6.635
0.0257
0.0163
CC
278
1332



rs2266911
1.699
0.0533
0.0163
CC
278
1332



rs2266911


0.0163
CC
278
1332



rs2266911
1.751
0.0232
0.0163
CC
278
1332



rs2266911
1.679
0.0639
0.0163
CC
278
1332



rs3765407
1.441
0.0521
0.1515
TT
372
2519



rs3765407
1.725
0.7881
0.1515
TT
372
2519



rs3765407


0.1515
TT
372
2519



rs3765407
1.415
0.06
0.1515
TT
372
2519



rs3765407
1.725
0.7881
0.1515
TT
372
2519



rs4524
0.991
0.0404
0.1197
TT
350
2195



rs4524
1.439
0.9138
0.1197
TT
350
2195



rs4524


0.1197
TT
350
2195



rs4524
1.006
0.058
0.1197
TT
350
2195



rs4524
1.439
0.9138
0.1197
TT
350
2195



rs2070006
1.348
0.3359
0.0761
CC
150
1084



rs2070006
1.669
0.0244
0.0761
CC
150
1084



rs2070006


0.0761
CC
150
1084



rs2070006
1.404
0.1168
0.0761
CC
150
1084



rs2070006
1.669
0.0244
0.0761
CC
150
1084



rs4253418
1.281
0.5596
0.0992
GG
506
3321



rs4253418
10.254
0.0397
0.0992
GG
506
3321



rs4253418


0.0992
GG
506
3321



rs4253418
1.344
0.8053
0.0992
GG
506
3321



rs4253418
10.254
0.0397
0.0992
GG
506
3321



rs169713
1.029
0.0975
0.1511
TT
338
2143



rs169713
1.685
0.4617
0.1511
TT
338
2143



rs169713


0.1511
TT
338
2143



rs169713
1.06
0.1906
0.1511
TT
338
2143



rs169713
1.685
0.4617
0.1511
TT
338
2143



rs8176750
1.235
0.6915
0.0912
CC
469
3083



rs8176750
7.894
0.0325
0.0912
CC
469
3083



rs8176750


0.0912
CC
469
3083



rs8176750
1.279
0.9286
0.0912
CC
469
3083



rs8176750
7.894
0.0325
0.0912
CC
469
3083



rs8176750
1.159
0.3685
0.0704
CC
345
2125



rs8176750
7.725
0.0374
0.0704
CC
345
2125



rs8176750


0.0704
CC
345
2125



rs8176750
1.201
0.5458
0.0704
CC
345
2125



rs8176750
7.876
0.0337
0.0704
CC
345
2125



rs8176719
1.498
0.0704
0.0549
TT
123
952



rs8176719
1.759
0.019
0.0549
TT
123
952



rs8176719


0.0549
TT
123
952



rs8176719
1.529
0.0301
0.0549
TT
123
952



rs8176719
1.759
0.019
0.0549
TT
123
952



rs2069946
1.047
0.1017
0.1585
TT
482
3081



rs2069946
2.545
0.3048
0.1585
TT
482
3081



rs2069946


0.1585
TT
482
3081



rs2069946
1.023
0.0718
0.1585
TT
482
3081



rs2069946
2.545
0.3048
0.1585
TT
482
3081



rs2266911
1.033
0.0784
0.0881
CC
136
1292



rs2266911
1.278
0.1399
0.0881
CC
136
1292



rs2266911


0.0881
CC
136
1292



rs2266911
0.982
0.0384
0.0881
CC
136
1292



rs2266911
1.389
0.1901
0.0881
CC
136
1292



rs6003
1.267
0.9087
0.256
AA
421
2802



rs6003
2.88
0.0988
0.256
AA
421
2802



rs6003


0.256
AA
421
2802



rs6003
1.31
0.6027
0.256
AA
421
2802



rs6003
2.88
0.0988
0.256
AA
421
2802



rs1417121
1.224
0.8117
0.2183
GG
259
1733



rs1417121
1.672
0.0854
0.2183
GG
259
1733



rs1417121


0.2183
GG
259
1733



rs1417121
1.266
0.4343
0.2183
GG
259
1733



rs1417121
1.672
0.0854
0.2183
GG
259
1733



rs12744297
1.34
0.2246
0.2172
AA
217
1479



rs12744297
1.191
0.4428
0.2172
AA
217
1479



rs12744297


0.2172
AA
217
1479



rs12744297
1.27
0.4531
0.2172
AA
217
1479



rs12744297
1.191
0.4428
0.2172
AA
217
1479



rs3733402
1.058
0.1696
0.2211
AA
189
1133



rs3733402
1.051
0.1189
0.2211
AA
189
1133



rs3733402


0.2211
AA
189
1133



rs3733402
1.027
0.0967
0.2211
AA
189
1133



rs3733402
1.051
0.1189
0.2211
AA
189
1133



rs3087505
1.123
0.3252
0.2805
GG
450
2940



rs3087505
3.339
0.2284
0.2805
GG
450
2940



rs3087505


0.2805
GG
450
2940



rs3087505
1.153
0.4718
0.2805
GG
450
2940



rs3087505
3.339
0.2284
0.2805
GG
450
2940



rs2480089
1.344
0.2266
0.2685
AA
225
1576



rs2480089
1.588
0.151
0.2685
AA
225
1576



rs2480089


0.2685
AA
225
1576



rs2480089
1.354
0.135
0.2685
AA
225
1576



rs2480089
1.588
0.151
0.2685
AA
225
1576



rs8176750
1.159
0.3685
0.0704
CC
345
2125



rs8176750
7.725
0.0374
0.0704
CC
345
2125



rs8176750


0.0704
CC
345
2125



rs8176750
1.201
0.5458
0.0704
CC
345
2125



rs8176750
7.876
0.0337
0.0704
CC
345
2125



rs8176719
1.498
0.0704
0.0549
TT
123
952



rs8176719
1.759
0.019
0.0549
TT
123
952



rs8176719


0.0549
TT
123
952



rs8176719
1.529
0.0301
0.0549
TT
123
952



rs8176719
1.759
0.019
0.0549
TT
123
952



rs3730055
1.537
0.0934
0.2272
CC
436
2935



rs3730055
1.974
0.7595
0.2272
CC
436
2935



rs3730055


0.2272
CC
436
2935



rs3730055
1.489
0.1309
0.2272
CC
436
2935



rs3730055
1.974
0.7595
0.2272
CC
436
2935



rs2304167
1.41
0.081
0.2165
TT
345
2364



rs2304167
1.714
0.7231
0.2165
TT
345
2364



rs2304167


0.2165
TT
345
2364



rs2304167
1.39
0.0864
0.2165
TT
345
2364



rs2304167
1.714
0.7231
0.2165
TT
345
2364



rs1654416
1.405
0.0912
0.2362
TT
348
2379



rs1654416
1.627
0.9773
0.2362
TT
348
2379



rs1654416


0.2362
TT
348
2379



rs1654416
1.377
0.1144
0.2362
TT
348
2379



rs1654416
1.627
0.9773
0.2362
TT
348
2379

























TABLE 9














OR
OR






GENO-


95% CI
95% CI


SNP hCV #
SNP rs #
Gene
MODE
TYPE
ADJUST
OR
lower
upper





hCV16282389
rs2726953
SCARA5
GEN
AG
sex age
1.049
0.913
1.205


hCV16282389
rs2726953
SCARA5
GEN
AA
sex age
1.34
1.063
1.689


hCV16282389
rs2726953
SCARA5
ADD
A
sex age
1.115
1.01
1.232


hCV16282389
rs2726953
SCARA5
DOM
AG or AA
sex age
1.1
0.964
1.254


hCV16282389
rs2726953
SCARA5
REC
AA
sex age
1.312
1.049
1.639


hCV16282389
rs2726953
SCARA5
GEN
AG

1.046
0.91
1.201


hCV16282389
rs2726953
SCARA5
GEN
AA

1.337
1.061
1.685


hCV16282389
rs2726953
SCARA5
ADD
A

1.113
1.008
1.23


hCV16282389
rs2726953
SCARA5
DOM
AG or AA

1.097
0.962
1.25


hCV16282389
rs2726953
SCARA5
REC
AA

1.31
1.049
1.637


hCV9326428
rs687289
ABO
GEN
AG
sex age
2.188
1.891
2.532


hCV9326428
rs687289
ABO
GEN
AA
sex age
2.867
2.318
3.546


hCV9326428
rs687289
ABO
ADD
A
sex age
1.813
1.639
2.006


hCV9326428
rs687289
ABO
DOM
AG or AA
sex age
2.322
2.021
2.668


hCV9326428
rs687289
ABO
REC
AA
sex age
1.834
1.509
2.228


hCV9326428
rs687289
ABO
GEN
AG

2.18
1.885
2.521


hCV9326428
rs687289
ABO
GEN
AA

2.851
2.307
3.524


hCV9326428
rs687289
ABO
ADD
A

1.807
1.634
1.999


hCV9326428
rs687289
ABO
DOM
AG or AA

2.313
2.014
2.657


hCV9326428
rs687289
ABO
REC
AA

1.829
1.506
2.221


hCV15887091
rs2519093
ABO
GEN
TC
sex age
2.135
1.852
2.462


hCV15887091
rs2519093
ABO
GEN
TT
sex age
1.962
1.457
2.642


hCV15887091
rs2519093
ABO
ADD
T
sex age
1.766
1.576
1.979


hCV15887091
rs2519093
ABO
DOM
TC or TT
sex age
2.111
1.843
2.419


hCV15887091
rs2519093
ABO
REC
TT
sex age
1.475
1.101
1.975


hCV15887091
rs2519093
ABO
GEN
TC

2.123
1.842
2.447


hCV15887091
rs2519093
ABO
GEN
TT

1.964
1.46
2.641


hCV15887091
rs2519093
ABO
ADD
T

1.76
1.571
1.972


hCV15887091
rs2519093
ABO
DOM
TC or TT

2.101
1.834
2.406


hCV15887091
rs2519093
ABO
REC
TT

1.48
1.106
1.981


hCV3188439
rs4981022
STAB2
GEN
GA
sex age
0.852
0.741
0.979


hCV3188439
rs4981022
STAB2
GEN
GG
sex age
0.799
0.642
0.995


hCV3188439
rs4981022
STAB2
ADD
G
sex age
0.88
0.798
0.97


hCV3188439
rs4981022
STAB2
DOM
GA or GG
sex age
0.841
0.737
0.959


hCV3188439
rs4981022
STAB2
REC
GG
sex age
0.861
0.699
1.062


hCV3188439
rs4981022
STAB2
GEN
GA

0.851
0.741
0.978


hCV3188439
rs4981022
STAB2
GEN
GG

0.799
0.642
0.994


hCV3188439
rs4981022
STAB2
ADD
G

0.879
0.798
0.969


hCV3188439
rs4981022
STAB2
DOM
GA or GG

0.84
0.737
0.958


hCV3188439
rs4981022
STAB2
REC
GG

0.861
0.699
1.061


hCV3188431
rs12229292
STAB2
GEN
TG
sex age
0.994
0.867
1.14


hCV3188431
rs12229292
STAB2
GEN
TT
sex age
1.563
1.196
2.042


hCV3188431
rs12229292
STAB2
ADD
T
sex age
1.121
1.009
1.245


hCV3188431
rs12229292
STAB2
DOM
TG or TT
sex age
1.063
0.933
1.212


hCV3188431
rs12229292
STAB2
REC
TT
sex age
1.567
1.207
2.034


hCV3188431
rs12229292
STAB2
GEN
TG

1.004
0.875
1.151


hCV3188431
rs12229292
STAB2
GEN
TT

1.564
1.198
2.043


hCV3188431
rs12229292
STAB2
ADD
T

1.126
1.014
1.25


hCV3188431
rs12229292
STAB2
DOM
TG or TT

1.072
0.94
1.222


hCV3188431
rs12229292
STAB2
REC
TT

1.562
1.204
2.026


hCV2485050
rs6575009

GEN
GA
sex age
1.226
1.003
1.499


hCV2485050
rs6575009

GEN
GG
sex age
1.412
0.601
3.319


hCV2485050
rs6575009

ADD
G
sex age
1.22
1.015
1.466


hCV2485050
rs6575009

DOM
GA or GG
sex age
1.234
1.014
1.503


hCV2485050
rs6575009

REC
GG
sex age
1.378
0.587
3.236


hCV2485050
rs6575009

GEN
GA

1.23
1.006
1.503


hCV2485050
rs6575009

GEN
GG

1.408
0.6
3.304


hCV2485050
rs6575009

ADD
G

1.222
1.017
1.468


hCV2485050
rs6575009

DOM
GA or GG

1.238
1.017
1.506


hCV2485050
rs6575009

REC
GG

1.373
0.585
3.22


hCV27960688
rs4900088
TC2N
GEN
AG
sex age
1.131
0.973
1.314


hCV27960688
rs4900088
TC2N
GEN
AA
sex age
1.387
1.147
1.677


hCV27960688
rs4900088
TC2N
ADD
A
sex age
1.172
1.067
1.287


hCV27960688
rs4900088
TC2N
DOM
AG or AA
sex age
1.198
1.039
1.38


hCV27960688
rs4900088
TC2N
REC
AA
sex age
1.286
1.089
1.518


hCV27960688
rs4900088
TC2N
GEN
AG

1.136
0.978
1.32


hCV27960688
rs4900088
TC2N
GEN
AA

1.396
1.155
1.688


hCV27960688
rs4900088
TC2N
ADD
A

1.176
1.071
1.291


hCV27960688
rs4900088
TC2N
DOM
AG or AA

1.204
1.045
1.387


hCV27960688
rs4900088
TC2N
REC
AA

1.291
1.094
1.524


hCV2889230
rs11686314

GEN
AG
sex age
0.943
0.807
1.103


hCV2889230
rs11686314

GEN
AA
sex age
0.511
0.308
0.847


hCV2889230
rs11686314

ADD
A
sex age
0.875
0.764
1.003


hCV2889230
rs11686314

DOM
AG or AA
sex age
0.902
0.775
1.049


hCV2889230
rs11686314

REC
AA
sex age
0.518
0.313
0.857


hCV2889230
rs11686314

GEN
AG

0.941
0.805
1.1


hCV2889230
rs11686314

GEN
AA

0.517
0.312
0.856


hCV2889230
rs11686314

ADD
A

0.875
0.764
1.002


hCV2889230
rs11686314

DOM
AG or AA

0.901
0.774
1.048


hCV2889230
rs11686314

REC
AA

0.524
0.317
0.867


hCV31716902
rs12999640

GEN
TC
sex age
0.938
0.806
1.091


hCV31716902
rs12999640

GEN
TT
sex age
0.619
0.398
0.964


hCV31716902
rs12999640

ADD
T
sex age
0.889
0.781
1.012


hCV31716902
rs12999640

DOM
TC or TT
sex age
0.906
0.782
1.049


hCV31716902
rs12999640

REC
TT
sex age
0.63
0.405
0.979


hCV31716902
rs12999640

GEN
TC

0.934
0.803
1.087


hCV31716902
rs12999640

GEN
TT

0.627
0.403
0.976


hCV31716902
rs12999640

ADD
T

0.888
0.78
1.011


hCV31716902
rs12999640

DOM
TC or TT

0.903
0.78
1.046


hCV31716902
rs12999640

REC
TT

0.638
0.411
0.991


hCV27484761
rs3783886
PTPN21
GEN
GA
sex age
1.317
1.074
1.615


hCV27484761
rs3783886
PTPN21
GEN
GG
sex age
1.566
0.708
3.467


hCV27484761
rs3783886
PTPN21
ADD
G
sex age
1.304
1.085
1.567


hCV27484761
rs3783886
PTPN21
DOM
GA or GG
sex age
1.33
1.09
1.623


hCV27484761
rs3783886
PTPN21
REC
GG
sex age
1.515
0.685
3.353


hCV27484761
rs3783886
PTPN21
GEN
GA

1.323
1.079
1.622


hCV27484761
rs3783886
PTPN21
GEN
GG

1.575
0.712
3.481


hCV27484761
rs3783886
PTPN21
ADD
G

1.309
1.089
1.573


hCV27484761
rs3783886
PTPN21
DOM
GA or GG

1.336
1.095
1.63


hCV27484761
rs3783886
PTPN21
REC
GG

1.523
0.689
3.365






















HW







Risk
Ref
(CONTROL)

CASE


SNP hCV #
ProbChiSq
P_DF2
allele
allele
pExact
Geno t
cnt





hCV16282389
0.5017
0.0467
A
G
0.6
AA
201


hCV16282389
0.0133
0.0467
A
G
0.6
AA
201


hCV16282389
0.0318

A
G
0.6
AA
201


hCV16282389
0.1567

A
G
0.6
AA
201


hCV16282389
0.0172

A
G
0.6
AA
201


hCV16282389
0.5266
0.0485
A
G
0.6
AA
201


hCV16282389
0.0139
0.0485
A
G
0.6
AA
201


hCV16282389
0.0347

A
G
0.6
AA
201


hCV16282389
0.1682

A
G
0.6
AA
201


hCV16282389
0.0174

A
G
0.6
AA
201


hCV9326428
<.0001
0   
A
G
0.377
AA
326


hCV9326428
<.0001
0   
A
G
0.377
AA
326


hCV9326428
<.0001

A
G
0.377
AA
326


hCV9326428
<.0001

A
G
0.377
AA
326


hCV9326428
<.0001

A
G
0.377
AA
326


hCV9326428
<.0001
0   
A
G
0.377
AA
326


hCV9326428
<.0001
0   
A
G
0.377
AA
326


hCV9326428
<.0001

A
G
0.377
AA
326


hCV9326428
<.0001

A
G
0.377
AA
326


hCV9326428
<.0001

A
G
0.377
AA
326


hCV15887091
<.0001
0   
T
C
0.0024
TT
121


hCV15887091
<.0001
0   
T
C
0.0024
TT
121


hCV15887091
<.0001

T
C
0.0024
TT
121


hCV15887091
<.0001

T
C
0.0024
TT
121


hCV15887091
0.0092

T
C
0.0024
TT
121


hCV15887091
<.0001
0   
T
C
0.0024
TT
121


hCV15887091
<.0001
0   
T
C
0.0024
TT
121


hCV15887091
<.0001

T
C
0.0024
TT
121


hCV15887091
<.0001

T
C
0.0024
TT
121


hCV15887091
0.0084

T
C
0.0024
TT
121


hCV3188439
0.0242
0.0298
G
A
0.161
GG
190


hCV3188439
0.0453
0.0298
G
A
0.161
GG
190


hCV3188439
0.0101

G
A
0.161
GG
190


hCV3188439
0.0096

G
A
0.161
GG
190


hCV3188439
0.1623

G
A
0.161
GG
190


hCV3188439
0.0232
0.0285
G
A
0.161
GG
190


hCV3188439
0.0444
0.0285
G
A
0.161
GG
190


hCV3188439
0.0096

G
A
0.161
GG
190


hCV3188439
0.0091

G
A
0.161
GG
190


hCV3188439
0.1606

G
A
0.161
GG
190


hCV3188431
0.9337
0.0033
T
G
0.0155
TT
158


hCV3188431
0.0011
0.0033
T
G
0.0155
TT
158


hCV3188431
0.0332

T
G
0.0155
TT
158


hCV3188431
0.3598

T
G
0.0155
TT
158


hCV3188431
0.0007

T
G
0.0155
TT
158


hCV3188431
0.9597
0.0035
T
G
0.0155
TT
158


hCV3188431
0.001
0.0035
T
G
0.0155
TT
158


hCV3188431
0.0264

T
G
0.0155
TT
158


hCV3188431
0.2992

T
G
0.0155
TT
158


hCV3188431
0.0008

T
G
0.0155
TT
158


hCV2485050
0.0465
0.1052
G
A
0.29
GG
13


hCV2485050
0.4282
0.1052
G
A
0.29
GG
13


hCV2485050
0.0342

G
A
0.29
GG
13


hCV2485050
0.0358

G
A
0.29
GG
13


hCV2485050
0.4621

G
A
0.29
GG
13


hCV2485050
0.0432
0.0993
G
A
0.29
GG
13


hCV2485050
0.4315
0.0993
G
A
0.29
GG
13


hCV2485050
0.0321

G
A
0.29
GG
13


hCV2485050
0.0333

G
A
0.29
GG
13


hCV2485050
0.4662

G
A
0.29
GG
13


hCV27960688
0.1087
0.0034
A
G
0.59
AA
397


hCV27960688
0.0008
0.0034
A
G
0.59
AA
397


hCV27960688
0.0009

A
G
0.59
AA
397


hCV27960688
0.0127

A
G
0.59
AA
397


hCV27960688
0.003

A
G
0.59
AA
397


hCV27960688
0.0951
0.0026
A
G
0.59
AA
397


hCV27960688
0.0006
0.0026
A
G
0.59
AA
397


hCV27960688
0.0007

A
G
0.59
AA
397


hCV27960688
0.0101

A
G
0.59
AA
397


hCV27960688
0.0025

A
G
0.59
AA
397


hCV2889230
0.4629
0.029 
A
G
0.116
AA
24


hCV2889230
0.0092
0.029 
A
G
0.116
AA
24


hCV2889230
0.0545

A
G
0.116
AA
24


hCV2889230
0.1817

A
G
0.116
AA
24


hCV2889230
0.0105

A
G
0.116
AA
24


hCV2889230
0.4459
0.0316
A
G
0.116
AA
24


hCV2889230
0.0104
0.0316
A
G
0.116
AA
24


hCV2889230
0.0542

A
G
0.116
AA
24


hCV2889230
0.1761

A
G
0.116
AA
24


hCV2889230
0.0119

A
G
0.116
AA
24


hCV31716902
0.408
0.086 
T
C
0.207
TT
34


hCV31716902
0.034
0.086 
T
C
0.207
TT
34


hCV31716902
0.0746

T
C
0.207
TT
34


hCV31716902
0.1866

T
C
0.207
TT
34


hCV31716902
0.0399

T
C
0.207
TT
34


hCV31716902
0.3778
0.092 
T
C
0.207
TT
34


hCV31716902
0.0386
0.092 
T
C
0.207
TT
34


hCV31716902
0.072

T
C
0.207
TT
34


hCV31716902
0.1741

T
C
0.207
TT
34


hCV31716902
0.0456

T
C
0.207
TT
34


hCV27484761
0.0081
0.0178
G
A
0.0779
0.17


hCV27484761
0.2683
0.0178
G
A
0.0779
0.17


hCV27484761
0.0047

G
A
0.0779
0.17


hCV27484761
0.005

G
A
0.0779
0.17


hCV27484761
0.3049

G
A
0.0779
0.17


hCV27484761
0.0071
0.0155
G
A
0.0779
0.17


hCV27484761
0.2619
0.0155
G
A
0.0779
0.17


hCV27484761
0.004

G
A
0.0779
0.17


hCV27484761
0.0043

G
A
0.0779
0.17


hCV27484761
0.2984

G
A
0.0779
0.17




















CONTROL

CASE
CONTROL

CASE
CONTROL



SNP hCV #
cnt
Geno t
cnt
cnt
Geno t
cnt
cnt







hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV16282389
149
AG
745
706
GG
895
887



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV9326428
184
AG
1005
742
GG
512
824



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV15887091
79
TC
803
485
CC
921
1181



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188439
206
GA
738
751
AA
919
796



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV3188431
99
TG
732
715
GG
961
942



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV2485050
9
GA
246
195
AA
1591
1551



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV27960688
306
AG
913
865
GG
537
578



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV2889230
43
AG
417
410
GG
1408
1303



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV31716902
50
TC
456
450
CC
1358
1252



hCV27484761



hCV27484761



hCV27484761



hCV27484761



hCV27484761



hCV27484761



hCV27484761



hCV27484761



hCV27484761



hCV27484761









Claims
  • 1. A method for determining whether a human's risk for venous thrombosis (VT) is reduced by treatment with an HMG-CoA reductase inhibitor, the method comprising testing nucleic acid from said human for the presence or absence of an allele at a polymorphism represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:713, 711, 501-710, 712, and 714-3098 or its complement, wherein the presence of said allele indicates said human's risk for VT is reduced by treatment with said HMG-CoA reductase inhibitor.
  • 2. The method of claim 1, further comprising correlating the presence of said allele with a reduction of said risk for VT by an HMG-CoA reductase inhibitor.
  • 3. The method of claim 2, wherein said correlating is performed by computer software.
  • 4. The method of claim 1, wherein said HMG-CoA reductase inhibitor is a hydrophilic statin.
  • 5. The method of claim 1, wherein said HMG-CoA reductase inhibitor is a hydrophobic statin.
  • 6. The method of claim 1, wherein said HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin (Lipitor®), rosuvastatin (Crestor®), pravastatin (Pravachol®), simvastatin (Zocor®), fluvastatin (Lescol®), and lovastatin (Mevacor®), or any combination thereof.
  • 7. The method of claim 1, wherein said HMG-CoA reductase inhibitor comprises an HMG-CoA reductase inhibitor in combination with at least one additional therapeutic agent.
  • 8. The method of claim 7, wherein said HMG-CoA reductase inhibitor is selected from the group consisting of: simvastatin in combination with ezetimibe (Vytorin®);lovastatin in combination with niacin (Advicor®);atorvastatin in combination with amlodipine besylate (Caduet®); andsimvastatin in combination with niacin (Simcor®).
  • 9. The method of claim 1, wherein said nucleic acid is a nucleic acid extract from a biological sample from said human.
  • 10. The method of claim 9, wherein said biological sample is blood, saliva, or buccal cells.
  • 11. The method of claim 9, further comprising preparing said nucleic acid extract from said biological sample prior to said testing.
  • 12. The method of claim 11, further comprising obtaining said biological sample from said human prior to said preparing.
  • 13. The method of claim 1, wherein said testing comprises nucleic acid amplification.
  • 14. The method of claim 13, wherein said nucleic acid amplification is carried out by polymerase chain reaction.
  • 15. 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).
  • 16. The method of claim 1, wherein said testing is performed using an allele-specific method.
  • 17. The method of claim 16, wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification.
  • 18. The method of claim 1 which is an automated method.
  • 19. The method of claim 1, wherein said human is homozygous for said allele.
  • 20. The method of claim 1, wherein said human is heterozygous for said allele.
  • 21. The method of claim 1, wherein said VT is deep vein thrombosis (DVT).
  • 22. The method of claim 1, wherein said VT is pulmonary embolism (PE).
  • 23. The method of claim 1, wherein said human did not have VT prior to said testing.
  • 24. The method of claim 1, wherein said human had VT prior to said testing and said risk is for recurrent VT.
  • 25. (canceled)
  • 26. A method for determining whether a human has an increased risk for venous thrombosis (VT), comprising testing nucleic acid from said human for the presence or absence of an allele at a polymorphism represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:713, 711, 501-710, 712, and 714-3098 or its complement, wherein the presence of said allele indicates said human has an increased risk for VT.
  • 27. The method of claim 26, wherein said human had VT prior to said testing and said risk is for recurrent VT.
  • 28. (canceled)
  • 29. The method of claim 1, further comprising administering an HMG-CoA reductase inhibitor to said human who has said allele.
  • 30. The method of claim 1, further comprising administering a therapeutic agent that is not an HMG-CoA reductase inhibitor to said human who does not have said allele.
  • 31. The method of claim 30, said therapeutic agent that is not an HMG-CoA reductase inhibitor is selected from the group consisting of anticoagulants such as warfarin, direct thrombin inhibitors such as dabigatran, and direct factor Xa inhibitors such as rivaroxaban or apixaban.
  • 32. The method of claim 26, further comprising administering a therapeutic agent for treating VT to said human who has said allele.
  • 33. The method of claim 32, wherein said therapeutic agent is selected from the group consisting of HMG-CoA reductase inhibitors, anticoagulants such as warfarin, direct thrombin inhibitors such as dabigatran, and direct factor Xa inhibitors such as rivaroxaban or apixaban.
  • 34. A method for reducing risk of venous thrombosis (VT) in a human, comprising administering to said human an effective amount of an HMG-CoA reductase inhibitor, wherein said human has been identified as having an allele at a polymorphism represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:713, 711, 501-710, 712, and 714-3098 or its complement, wherein the presence of said allele indicates said human's risk for VT is reduced by treatment with said HMG-CoA reductase inhibitor.
  • 35. The method of claim 34, wherein said method comprises testing nucleic acid from said human for the presence or absence of said allele.
  • 36-37. (canceled)
  • 38. A detection reagent for carrying out the method of claim 1, wherein said detection reagent is an allele-specific probe or an allele-specific primer.
  • 39. A test kit comprising one or more containers containing the detection reagent of claim 38 and one or more components selected from the group consisting of an enzyme, polymerase enzyme, ligase enzyme, buffer, amplification primer pair, dNTPs, ddNTPs, positive control nucleic acid, negative control, nucleic acid extraction reagent, and instructions for using said test kit which instruct that the presence of said allele indicates that said risk for VT is reduced by treatment with said HMG-CoA reductase inhibitor.
  • 40-42. (canceled)
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. non-provisional application Ser. No. 13/286,934, filed Nov. 1, 2011, which is a non-provisional application of U.S. provisional application Ser. No. 61/409,434, filed Nov. 2, 2010, the contents of which is hereby incorporated by reference in its entirety into this application.

Provisional Applications (1)
Number Date Country
61409434 Nov 2010 US
Continuations (1)
Number Date Country
Parent 13286934 Nov 2011 US
Child 13847750 US