Novel genes and markers in essential arterial hypertension

Information

  • Patent Application
  • 20090155230
  • Publication Number
    20090155230
  • Date Filed
    July 05, 2007
    17 years ago
  • Date Published
    June 18, 2009
    15 years ago
Abstract
The present invention relates to previously unknown disease associations between various genes, loci and biomarkers and essential hypertension. The detection of these biomarkers provides novel in vitro methods and test kits which can be used as an aid when making risk assessment, molecular diagnosis or prognosis of HT or a HT related condition. The disclosed methods and test kits do not require interaction with the body of a subject during the biomarker detection. Instead the methods and test kits are for in vitro use (e.g. in a clinical laboratory) and typically biological samples for the biomarker analyses using a method or a test kit of this invention have been collected earlier in a different place. In addition the biomarkers provide methods and systems for identifying novel agents for preventing, treating and/or reducing risk of HT or a HT related condition. The HT associated genes can be used to develop novel therapies for prevention and/or treatment of essential hypertension.
Description
BACKGROUND OF THE INVENTION

Cardiovascular Diseases (CVD) (ICD/10 codes I00-I99, Q20-Q28) include ischemic (coronary) heart disease (IHD, CHD), hypertensive diseases, cerebrovascular disease (stroke) and rheumatic fever/rheumatic heart disease, among others. Essential hypertension (HT; ICD/10 codes I10-I15) is defined as blood pressure measurements of 140/90 mmHg or greater without any obvious cause such as renal disease, adrenal tumor, or drug therapy constitutes about 95% of all hypertension cases. HT prevalence rises with age irrespective of the type of BP measurement and the operational thresholds used for diagnosis. The prevalence of elevated blood pressure is 20-30% of the adult population in most western countries. HT aggregates with other cardiovascular risk factors such as abdominal obesity, dyslipidaemia, glucose intolerance, hyperinsulinaemia and hyperuricaemia, possibly because of a common underlying cause. Apart from being a CVD itself, HT is a risk factor for other CVD, such as IHD, stroke and congestive heart failure (CHF). About half of people having their first heart attack and two thirds of people having their first stroke, have blood pressure (BP) higher than 160/95 mmHg. HT precedes the development of CHF in 91% of cases. (AHA, 2004).


The pressure required to move blood through the circulatory bed is provided by the pumping action of the heart [cardiac output (CO)] and the tone of the arteries [peripheral resistance (PR)]. Each of these primary determinants of BP is, in turn, determined by the interaction of a complex series of factors. Data generated from animal models, human twin and family studies suggest that approximately 30 to 60% of blood pressure arises from genetic factors according to recent review (Binder A, 2007). It seems that hypertension cannot be understood without appreciating the critical role of gene-environment interactions as evidenced by cross-cultural population studies (Weder A B, 2007). Nuclear family studies show greater similarity in BP within families than between families, with heritability estimates ranging between 0.20 and 0.46. Twin studies document greater concordance of BP in monozygotic than dizygotic twins, giving the highest heritability estimates between 0.48 and 0.64. Adoption studies demonstrate greater concordance of BP among biological siblings than adoptive siblings living in the same household, estimating heritability between 0.45 and 0.61. (Fuentes R M, 2003).


In the rare Mendelian forms of high and low BP single genes can have major effects on BP (Lifton R P et al, 2001, Luft F C, 2003). Although identifiable single-gene mutations account for only a small percentage of all HT cases, study of these rare Mendelian disorders has been used to elucidate pathophysiologic mechanisms that predispose to more common forms of HT and to suggest novel therapeutic approaches. Several mutations that cause Mendelian forms of human HT or hypotension have been described to date (Lifton R P et al, 2001, Luft F C, 2003). These mutations affect BP by altering renal salt handling, reinforcing the hypothesis that a major component in the development of HT depends on genetically determined renal dysfunction with resultant salt and water retention (Guyton A C, 1991). Importantly, all the monogenic HT syndromes identified were caused by defects resulting in renal salt retention, whereas all the low BP syndromes shared a common mechanism of excess renal sodium loss (Hopkins P N and Hunt S C, 2003). The best studied monogenic cause of HT is the Liddle syndrome, a rare but clinically important disorder in which constitutive activation of the epithelial sodium channel predisposes to severe, treatment-resistant HT (Shimkets R A et al, 1994). Epithelial sodium channel activation has been traced to mutations in the beta or gamma subunits of the channel, resulting in inappropriate sodium retention at the renal collecting duct level. Patients with the Liddle syndrome typically present with volume-dependent, low-renin, and low-aldosterone HT.


Candidate gene studies have concerned genes encoding components of the renin-angiotensin-aldosterone system, the epithelial sodium channel, adrenergic receptors, G protein subunits, oxidative stress and other cellular signaling mediators and modifiers. Thus far, the candidate gene approach has provided more examples than the linkage approach of gene variants that appear to affect BP. Reasonable candidate genes to consider include genes related to physiological systems known to be involved in the control of BP and genes known to affect BP in mouse models. To date more than 80 candidate genes have been evaluated for HT. However, the association with HT of only a few genes have been widely replicated: angiotensinogen precursor (AGT), adducin 1 (ADD1) and guanine nucleotide-binding protein, beta-3 subunit (GNB3) (Hopkins PN and Hunt S C, 2003). In addition recently the impact of endothelial NO synthase gene (NOS3) polymorphism on the development of HT was confirmed by a large meta-analysis which included 35 genetic association studies (Zintzaras E et al, 2006). New HT candidate genes, such as cytochrome b-245, alpha polypeptide (CYBA), emerge together with the growing amount of knowledge about HT pathophysiology (Kokubo Y et al, 2005; Moreno M U et al, 2006). Gene-environment interactions affecting HT treatment have been shown between AGT, ADD1 and salt intake reduction (Hunt S C et al, 1998; Hunt S C et al, 1999; Cusi D et al, 1997), and between ADD1, GNB3 and diuretic treatment (Cusi D et al, 1997; Turner S T et al, 2001). Gene-gene interactions affecting HT risk development have been shown between ADD1 and the ACE gene I/D polymorphisms and between serotonin 2 (5-HT2) and endothelin-1 (ET-1) genes (Staessen J A et al, 2001; Yamamoto M et al. 2006). Lessons teamed from the studies of candidate genes to date include the shortcomings that result from limited statistical power of many studies, expected variation from one population to another, the need for better phenotyping of study subjects, the relatively small effect of the genes studied on population prevalence of HT, and the lack of sufficient certainty of consequences of any genes studied thus far to make treatment recommendations based on genotype (Hopkins P N and Hunt S C, 2003).


So far 25 genome-wide scanning studies have reported significant or suggestive linkage for BP/IT (Binder A, 2007). Some scans have utilized families, others affected or dissimilar sibling pairs. Linked loci with at least suggestive LOD scores have been observed on every chromosome. Perhaps most striking is the lack of consistency among the linked loci. Koivukoski et al, 2004 applying the genome-search meta-analysis method (GSMA) to nine published genome-wide scans of BP (n=5) and HT (n=4) in Caucasian populations found evidence of susceptibility regions for BP/HT only on chromosomes 2p12-q22.1 and 3p14.1-q12.3, which had modest or non-significant linkage in each individual study. This may serve to illustrate the heterogeneity of human HT as well as the potential shortcomings of family-based linkage studies.


Essential hypertension (HT) affects over one billion people worldwide, 20-55% of middle age Americans (over 50 million people) and Europeans (over 200 million people) across various ethnic subgroups, making it a public health issue of considerable magnitude and the single greatest risk factor for diseases of the brain, heart, and kidneys. Hypertension is the number one reason adults go to the doctor. It is estimated that Americans spend more than $8 billion per year on blood pressure medications. Even so, only 27% of Americans with high blood pressure have adequate blood pressure control.


Death and illness from diseases associated with high blood pressure exceeds that from all other causes and costs more than $250 billion each year. It is known that essential HT aggregates with major cardiovascular risk factors such as abdominal obesity, dyslipidaemia, glucose intolerance, hyperinsulinaemia and hyperuricaemia, possibly because of a common underlying cause and is a risk factor for other CVD, such as stroke and congestive heart failure (CHF). In 2001 an estimated 16.6 million—or one-third of total global deaths—resulted from the various forms of CVD (7.2 million due to HT, 5.5 million to cerebrovascular disease, and an additional 3.9 million to hypertensive and other heart conditions). At least 20 million people survive heart attacks and strokes every year, a significant proportion of them requiring costly clinical care, putting a huge burden on long-term care resources.


The high prevalence of essential HT in adult population and it's significant contribution to morbidity and mortality from cardiovascular diseases shows unmet medical need both for diagnostic methods to identify subjects having increased risk essential hypertension and for better therapies to prevent and to treat HT. The present invention provides a number of new correlations between various polymorphic alleles and essential hypertension. The HT associated polymorphic alleles, genes and loci disclosed in this invention provide the basis for improved risk assessment, more detailed diagnosis and prognosis of essential HT, and for the development of novel therapies to prevent and treat essential hypertension or related condition.


SUMMARY OF THE INVENTION

The present invention relates to previously unknown disease associations between various genes, loci and biomarkers and essential hypertension. The detection of these biomarkers provides novel in vitro methods and test kits which can be used as an aid when making risk assessment, molecular diagnosis or prognosis of HT or a HT related condition. The disclosed methods and test kits do not require interaction with the body of a subject during the biomarker detection. Instead the methods and test kits are for in vitro use (e.g. in a clinical laboratory) and typically biological samples for the biomarker analyses using a method or a test kit of this invention have been collected earlier in a different place. In addition the biomarkers provide methods and systems for identifying novel agents for preventing, treating and/or reducing risk of HT or a HT related condition. The HT associated genes can be used to develop novel therapies for prevention and/or treatment of essential hypertension.


Accordingly in a first aspect, the present invention provides methods and kits for determining in vitro a susceptibility to HT or a HT related condition in an individual. The methods comprise the step of detecting from a biological sample one or more HT associated biomarkers, wherein the biomarkers are related either to one or more genes set forth in table 1, and/or are selected from the SNP markers listed in tables 2 to 10 The presence of HT associated biomarkers is indicative of a susceptibility to hypertension. The kits provided for diagnosing a susceptibility to hypertension in an individual comprise wholly or in part protocol and reagents for detecting one or more biomarkers and interpretation software for data analysis and risk assessment.


In one typical embodiment, the HT risk biomarker information obtained using the methods and test kits of this invention are combined with other information concerning the individual, e.g. results from blood measurements, clinical examination and questionnaires. The blood measurements include but are not restricted to the determination of plasma or serum cholesterol and high-density lipoprotein cholesterol. The information to be collected by questionnaire includes information concerning gender, age, family and medical history such as the family history of HT and diabetes. Clinical information collected by examination includes e.g. information concerning height, weight, hip and waist circumference, systolic and diastolic BP, and heart rate.


In one embodiment, the methods and kits of the invention are used in early detection of HT at or before disease onset, thus reducing or minimizing the debilitating effects of HT. In a preferred embodiment the methods and kits are applied in individuals who are free of clinical symptoms and signs of HT, but have family history of HT or in those who have multiple risk factors of HT.


In a second aspect, the present invention provides methods and kits for molecular diagnosis i.e. determining a molecular subtype of HT in an individual. In one preferred embodiment, molecular subtype of HT in an individual is determined to provide information of the molecular etiology of HT. When the molecular etiology is known, better diagnosis and prognosis of HT can be made and efficient and safe therapy for treating HT in an individual can be selected on the basis of the HT subtype data. For example, the drug that is likely to be effective, i.e. blood pressure lowering, can be selected without trial and error. In other embodiment, biomarker information obtained from methods and kits for determining molecular subtype of HT in an individual is for monitoring the effectiveness of their treatment. In one embodiment, methods and kits for determining molecular subtype of HT are used to select human subjects for clinical trials testing antihypertensive drugs and other therapies. The kits provided for detecting a molecular subtype of HT in an individual comprise wholly or in part protocol and reagents for detecting one or more biomarkers and interpretation software for data analysis and HT molecular subtype assessment.


In a third aspect, the present invention relates to methods and kits for identifying agents that modulate metabolic activity of a HT risk gene set forth in table 1. Such screening methods and kits are useful when developing drugs and other therapies having effect on a HT risk gene of table 1, or on a related metabolic pathway thereof. The methods and kits comprise exposing cells expressing one or more HT and/or obesity risk genes disclosed in table 1 to a potential modulator and measuring the effect of the potential modulator on activity or function of one or more HT risk genes or their encoded polypeptides, or on related metabolic pathways. Useful measurements include, but are not limited to expression and mRNA structure of a HT risk gene, concentration, structure, substrate specificity and biological activity of a HT risk gene encoded polypeptide, degradation rate of a HT risk gene encoded polypeptide or mRNA, and biological activity of a HT risk gene related metabolic pathway. Potential modulators include, but are not limited to, binding partners, agonists, antagonists and antibodies of a HT risk gene encoded polypeptides.


In a fourth aspect, the present invention relates to novel therapies, pharmaceutical or dietary compositions and kits for preventing and/or treating HT in an individual comprising administering, in a pharmaceutical or dietary composition, an agent, a recombinant protein or a nucleic acid modulating metabolic activity of a HT risk gene set forth in table 1. In a preferred embodiment, these compositions, methods or kits are used in an individual having HT or a susceptibility to HT to compensate altered expression of a HT risk gene, altered biological activity of HT risk gene encoded polypeptides or altered function of a HT risk gene related metabolic pathway when compared to healthy individuals of the same species.







DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to previously unknown associations between essential hypertension and various genes, loci and polymorphisms. These HT associated genes, loci and polymorphisms provide basis for novel methods and kits for risk assessment, diagnosis and prognosis of HT. In addition these genes, loci and markers provide basis for methods and kits for novel therapies to prevent, treat and/or reduce risk of HT in an individual.


A “biomarker” in the context of the present invention refers to a SNP marker disclosed in tables 2 to 10 or to a polymorphism of a gene disclosed in table 1 or at a locus closely linked thereto, or to an organic biomolecule which is related to a gene set forth in table 1 and which is differentially present in samples taken from subjects (patients) having HT compared to comparable samples taken from subjects who do not have HT. An “organic biomolecule” refers to an organic molecule of biological origin, e.g., steroids, amino acids, nucleotides, sugars, polypeptides, polynucleotides, complex carbohydrates or lipids. A biomarker is differentially present between two samples if the amount, structure, function or biological activity of the biomarker in one sample differs in a statistically significant way from the amount, structure, function or biological activity of the biomarker in the other sample.


A “haplotype,” as described herein, refers to any combination of genetic markers (“alleles”). A haplotype can comprise two or more alleles and the length of a genome region comprising a haplotype may vary from few hundred bases up to hundreds of kilobases. As it is recognized by those skilled in the art the same haplotype can be described differently by determining the haplotype defining alleles from different nucleic acid strands. E.g. the haplotype AGG defined by the SNP markers rs2202564, rs9564765 and rs803815 of this invention is the same as haplotype rs2202564, rs9564765 and rs803815 (TCC) in which the alleles are determined from the other strand, or haplotype rs2202564, rs9564765 and rs803815 (TGG), in which the first allele is determined from the other strand. The haplotypes described herein are differentially present in individuals with HT than in individuals without HT. Therefore, these haplotypes have diagnostic value for risk assessment, diagnosis and prognosis of HT in an individual. Detection of haplotypes can be accomplished by methods known in the art used for detecting nucleotides at polymorphic sites. The haplotypes described herein, e.g. having markers such as those shown in tables 4 and 10 are found more frequently in individuals with HT than in individuals without HT. Therefore, these haplotypes have predictive value for detecting HT or a susceptibility to HT in an individual. Some of the haplotypes shown in tables 4 and 10 are found less frequently in individuals with HT than in individuals without HT thus reducing the risk of HT.


A nucleotide position in genome at which more than one sequence is possible in a population, is referred to herein as a “polymorphic site” or “polymorphism”. Where a polymorphic site is a single nucleotide in length, the site is referred to as a SNP. For example, if at a particular chromosomal location, one member of a population has an adenine and another member of the population has a thymine at the same position, then this position is a polymorphic site, and, more specifically, the polymorphic site is a SNP. Polymorphic sites may be several nucleotides in length due to insertions, deletions, conversions or translocations. Each version of the sequence with respect to the polymorphic site is referred to herein as an “allele” of the polymorphic site. Thus, in the previous example, the SNP allows for both an adenine allele and a thymine allele.


Typically, a reference nucleotide sequence is referred to for a particular gene e.g. in NCBI databases (www.ncbi.nlm.nih.gov). Alleles that differ from the reference are referred to as “variant” alleles. The polypeptide encoded by the reference nucleotide sequence is the “reference” polypeptide with a particular reference amino acid sequence, and polypeptides encoded by variant alleles are referred to as “variant” polypeptides with variant amino acid sequences. Nucleotide sequence variants can result in changes affecting properties of a polypeptide. These sequence differences, when compared to a reference nucleotide sequence, include insertions, deletions, conversions and substitutions: e.g. an insertion, a deletion or a conversion may result in a frame shift generating an altered polypeptide; a substitution of at least one nucleotide may result in a premature stop codon, amino acid change or abnormal mRNA splicing; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of a reading frame; duplication of all or a part of a sequence; transposition; or a rearrangement of a nucleotide sequence, as described in detail above. Such sequence changes alter the polypeptide encoded by a HT susceptibility gene. For example, a nucleotide change resulting in a change in polypeptide sequence can alter the physiological properties of a polypeptide dramatically by resulting in altered activity, distribution and stability or otherwise affect on properties of a polypeptide. Alternatively, nucleotide sequence variants can result in changes affecting transcription of a gene or translation of its mRNA. A polymorphic site located in a regulatory region of a gene may result in altered transcription of a gene e.g. due to altered tissue specificity, altered transcription rate or altered response to transcription factors. A polymorphic site located in a region corresponding to the mRNA of a gene may result in altered translation of the mRNA e.g. by inducing stable secondary structures to the mRNA and affecting the stability of the mRNA. Such sequence changes may alter the expression of a HT susceptibility gene.


The SNP markers to which we have disclosed novel HT associations in tables 2 to 10 of this invention have been known in prior art with their official reference SNP (rs) ID identification tags assigned to each unique SNP by the National Center for Biotechnological Information (NCBI). Each rs ID has been linked to specific variable alleles present in a specific nucleotide position in the human genome, and the nucleotide position has been specified with the nucleotide sequences flanking each SNP. For example the SNP having rs ID rs2202564 is SNP is in chromosome 13, variable alleles are A and G, and the nucleotide sequence assigned to rs2202564 is (R denotes the variable base; Genomic build 127) (SEQ ID NO: 1):












ACATATAGGT CAATCTGAAA AGGTGGAAGA GAAGTGAAAA








GCAATTCTTG TGCTCTAGTC AGTAGTGTGT TTATCTTTGA







CAGCCATTAC GTGTCAAAAA TTACTGACCC TTACTTAATG







ATATCTCTAT TGTTTTGGGA AGCCTAAGCA GTGGTAATAA







ATAGGCCCAA TAGGTATCAT GAATCCTACA TCATCGATGA







TCATTCTTGC TTGCTTCACC ACACAGGCAC GTGTTCCCAA







TTTGCAGCAA TTCTTTGCAG CTATTCCGGT GTCCATGCTT







CTTGCTTTTT GTAACCCTAC TATTTCTATA ATCCCTATAA







TCTGCACTCA TTCATAGGGG AGGAAAGAAG ACACAGACGG







GGCAAGGCCA CTTTTTGAAC GCCTCAGCCT AGAAATGCGC







TATGCCACTC ATTCTCACAT TCTTTCTTCT AGAAATGGCC







ACACCTAACA GCAAGGGAGG AAGGAACACA TAGTCTGGTA







TGTCCAGGAT GAAGAGAACA TAAATTTAAA TAAACAGTTT







GCAGTCTCCA TCACATTATT CR GAGATTAAAA ATATTTTTCT







CAAGTAAAGA TCTTTCTTAG AGATTAGCTT TGAAAATAAA







GATGGTACAA TATCCTAAAT TTATTTGCTG CAAGATAATT







TTACAATGTG GCCACATCTG ATCAGGCTTA ATAACCA






Although the numerical chromosomal position of a SNP may still change upon annotating the current human genome build the SNP identification information such as variable alleles and flanking nucleotide sequences assigned to a SNP will remain the same. Those skilled in the art will readily recognize that the analysis of the nucleotides present in one or more SNPs set forth in tables 2 to 10 of this invention in an individual's nucleic acid can be done by any method or technique capable of determining nucleotides present in a polymorphic site using the sequence information assigned in prior art to the rs IDs of the SNPs listed in tables 2 to 10 of this invention As it is obvious in the art the nucleotides present in polymorphisms can be determined from either nucleic acid strand or from both strands.


It is understood that the HT associated SNP markers and haplotypes described in tables 2 to 10 of this invention may be associated with other polymorphisms present in same HT associated genes and loci of this invention. This is because the SNP markers listed in tables 2 to 10 are so called tagging SNPs (tagSNPs). TagSNPs are loci that can serve as proxies for many other SNPs. The use of tagSNPs greatly improves the power of association studies as only a subset of loci needs to be genotyped while maintaining the same information and power as if one had genotyped a larger number of SNPs. These other polymorphic sites associated with the SNP markers listed in tables 2 to 10 of this invention may be either equally useful as biomarkers or even more useful as causative variations explaining the observed HT association of SNP markers and haplotypes of this invention.


The term “gene,” as used herein, refers to an entirety containing entire transcribed region and all regulatory regions of a gene. The transcribed region of a gene including all exon and intron sequences of a gene including alternatively spliced exons and introns so the transcribed region of a gene contains in addition to polypeptide encoding region of a gene also regulatory and 5′ and 3′ untranslated regions present in transcribed RNA. Each gene of the HT associated genes disclosed in table 1 of this invention has been assigned a specific and unique nucleotide sequence by the scientific community. By using the name of a HT associated gene provided in table 1 those skilled in the art will readily find the nucleotide sequences of a gene and it's encoded mRNAs as well as amino acid sequences of it's encoded polypeptides although some genes may have been known with other name(s) in the art.


In certain methods described herein, an individual who is at risk for hypertension is an individual in whom one or more HT associated polymorphisms selected from the tables 2 to 10 of this invention are identified. In other embodiment also polymorphisms associated to SNPs and haplotypes of the tables 2 to 10 may be used in risk assessment of HT. The significance associated with an allele or a haplotype is measured by an odds ratio. In a further embodiment, the significance is measured by a percentage. In one embodiment, a significant risk is measured as odds ratio of 0.8 or less or at least about 1.2, including by not limited to: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 4.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0 and 40.0. In a further embodiment, a significant increase or reduction in risk is at least about 20%, including but not limited to about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 98%. In a further embodiment, a significant increase in risk is at least about 50%. It is understood however, that identifying whether a risk is medically significant may also depend on a variety of factors such as family history of HT, central or other type of obesity, lack of physical activity, high sodium intake, high alcohol intake, high intake of saturated fats, low intake of potassium and/or magnesium, low HDL cholesterol, diabetes mellitus, glucose intolerance, insulin resistance, the metabolic syndrome, and inflammation.


“Probes” or “primers” are oligonucleotides that hybridize in a base-specific manner to a complementary strand of nucleic acid molecules. By “base specific manner” is meant that the two sequences must have a degree of nucleotide complementarity sufficient for the primer or probe to hybridize to its specific target. Accordingly, the primer or probe sequence is not required to be perfectly complementary to the sequence of the template. Non-complementary bases or modified bases can be interspersed into the primer or probe, provided that base substitutions do not inhibit hybridization. The nucleic acid template may also include “non-specific priming sequences” or “nonspecific sequences” to which the primer or probe has varying degrees of complementarity. Probes and primers may include modified bases as in polypeptide nucleic acids (Nielsen P E et al, 1991). Probes or primers typically comprise about 15, to 30 consecutive nucleotides present e.g. in human genome and they may further comprise a detectable label, e.g., radioisotope, fluorescent compound, enzyme, or enzyme co-factor. Probes and primers to a SNP marker disclosed in tables 2 to 10 are available in the art or can easily be designed using the flanking nucleotide sequences assigned to a SNP rs ID and standard probe and primer design tools. Primers and probes (publicly available or designed) for SNP markers disclosed in tables 2 to 10 can be used in risk assessment as well as molecular diagnostic methods and kits of this invention.


The invention comprises polyclonal and monoclonal antibodies that bind to a polypeptide encoded by a HT associated gene set forth in table 1 of the invention. The term “antibody” as used herein refers to immunoglobulin molecules or their immunologically active portions that specifically bind to an epitope (antigen, antigenic determinant) present in a polypeptide or a fragment thereof, but does not substantially bind other molecules in a sample, e.g., a biological sample, which contains the polypeptide. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab′).sub.2 fragments which can be generated by treating the antibody with an enzyme such as pepsin. The term “monoclonal antibody” as used herein refers to a population of antibody molecules that are directed against a specific epitope and are produced either by a single clone of B cells or a single hybridoma cell line. Polyclonal and monoclonal antibodies can be prepared by various methods known in the art. Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be produced by recombinant DNA techniques known in the art. Antibodies can be coupled to various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, or radioactive materials to enhance detection.


An antibody specific for a polypeptide encoded by a HT associated gene set forth in table 1 of the invention can be used to detect the polypeptide in a biological sample in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor protein levels in tissue such as blood as part of a test predicting the susceptibility to HT or as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Highly purified antibodies (e.g. monoclonal humanized antibodies specific to a polypeptide encoded by a HT associated gene of this invention) may be produced using GMP-compliant manufacturing processes known in the art. These “pharmaceutical grade” antibodies can be used in novel therapies modulating activity and/or function of a polypeptide encoded by a HT associated gene disclosed in table 1 of this invention to treat HT.


“A HT related condition” in the context of this invention refers to cerebrovascular disease, arterial aneurysm, left ventricular hypertrophy, congestive heart failure, other congestive heart disease, coronary heart disease, other ischemic arterial disease, other arteriosclerotic disease, hypertensive renal disease or hypertensive retinal disease.


In Vitro Methods and Test Kits

The HT associated biomarkers of this invention provide novel in vitro methods and test kits, which can be used when making risk assessment, molecular diagnosis or prognosis of HT or a HT related condition for an individual. The disclosed methods and test kits do not require interaction with the body of a subject during the biomarker detection, instead only a test sample containing the biomarkers and representing the subject is needed. In practice to make risk assessment, molecular diagnosis or prognosis of HT or a HT related condition for an individual the methods and test kits are used in vitro e.g. in a clinical laboratory (i) to determine the presence of one or more HT associated biomarkers of this invention in a biological sample representing said individual and (ii) to compare the biomarker data of the subject to the biomarker data of healthy and hypertensive. The biomarker data of a subject obtained using the in vitro methods and test kits of this invention may be combined with non-genetic data of the subject to make risk assessment, molecular diagnosis or prognosis of HT or a HT related condition.


The methods and test kits provided for risk assessment, molecular diagnosis or prognosis of HT or a HT related condition of an individual comprise wholly or in part protocol and reagents for detecting one or more HT associated biomarkers and interpretation software for data analysis and risk assessment. Prior using the disclosed methods and test kits of this invention a biological sample is needed from a subject to be tested. Any biological sample representing the subject and containing the biomarkers, which are to be detected from the subject can be used. Typically a biological sample is taken by a health care professional e.g. by a MD or by a nurse and it comprises blood, saliva, buccal cells or urine. In some cases a subject may collect a biological sample (e.g. a saliva sample) himself or herself. To minimize degradation of the HT associated biomarkers during the sample collection, storage and transportation a biological sample may be collected to a tube or to a vial containing stabilizers and chemicals inactivating interfering agents from the collected sample. Prior to biomarker analyses in a test laboratory biological samples to be tested typically need processing, e.g. if the biomarkers are SNP-markers processing may comprise genomic DNA extraction and DNA quality (integrity) assessment.


One major application of the current invention is detecting a susceptibility to HT or a HT related condition. The risk assessment methods and test kits of this invention can be applied to any healthy person as a screening or predisposition test, although the methods and test kits are preferably applied to high-risk individuals (who have e.g. family history of HT, central or other type of obesity, lack of physical activity, high sodium intake, high alcohol intake, high intake of saturated fats, low intake of potassium and/or magnesium, low HDL cholesterol, diabetes mellitus, glucose intolerance, insulin resistance and the metabolic syndrome, elevated inflammatory marker, or any combination of these or an elevated level of any other risk factor for HT). Molecular tests that define genetic factors contributing to HT might be used together with or independent of the known clinical risk factors to define an individual's risk relative to the general population. Better means for identifying those individuals susceptible for HT should lead to better preventive and treatment regimens, including more aggressive management of the risk factors for HT such as central or other type of obesity, lack of physical activity, high sodium intake, high alcohol intake, high intake of saturated fats, low intake of potassium and/or magnesium, low HDL cholesterol, elevated blood glucose, glucose intolerance, insulin resistance, the metabolic syndrome and inflammatory components as reflected by increased C-reactive protein levels or other inflammatory markers. Physicians may use the information on genetic risk factors to convince particular patients to adjust their life style e.g. to stop smoking, to change their diet or to increase exercise. A detected high risk of HT may also motivate the HT patients to improved compliance to antihypertensive treatments such as drugs and functional food products. The latter include antihypertensive peptides.


In one embodiment of the invention, detection of a susceptibility to HT in a subject, is made by determining one or more SNP markers and haplotypes disclosed in tables 2 to 10 of this invention in the subject's nucleic acid. The presence of HT associated alleles of the assessed SNP markers and haplotypes in individual's genome indicates subject's increased risk for HT. The invention also pertains to methods of diagnosing a susceptibility to HT in an individual comprising detection of a haplotype in a HT risk gene that is more frequently present in an individual having HT (affected), compared to the frequency of its presence in a healthy individual (control), wherein the presence of the haplotype is indicative of a susceptibility to HT. A haplotype may be associated with a reduced rather than increased risk of HT, wherein the presence of the haplotype is indicative of a reduced risk of HT. In other embodiment of the invention, diagnosis of susceptibility to HT, is done by detecting in the subject's nucleic acid one or more polymorphic sites which are in linkage disequilibrium with one or more SNP markers and haplotypes disclosed in tables 2 to 10 of this invention. The most useful polymorphic sites for in vitro methods and test kits are those altering the biological activity of a polypeptide encoded by a HT associated gene set forth in table 1. Examples of such functional polymorphisms include, but are not limited to frame shifts, premature stop codons, amino acid changing polymorphisms and polymorphisms inducing abnormal mRNA splicing. Nucleotide changes resulting in a change in polypeptide sequence in many cases alter the physiological properties of a polypeptide by resulting in altered activity, distribution and stability or otherwise affect on properties of a polypeptide. Other useful polymorphic sites are those affecting transcription of a HT associated gene set forth in table 1, or translation of it's mRNA due to altered tissue specificity, due to altered transcription rate, due to altered response to physiological status, due to altered translation efficiency of the mRNA and/or due to altered stability of the mRNA. The presence of nucleotide sequence variants altering the polypeptide structure and/or expression in HT associated genes of this invention in individual's nucleic acid is indicative for susceptibility to HT.


In biomarker assays determination of the nucleotides present in one or more HT associated SNP markers of this invention, as well as polymorphic sites associated with HT associated SNP markers of this invention, in an individual's nucleic acid can be done by any method or technique which can accurately determine nucleotides present in a polymorphic site. Numerous suitable methods have been described in the art (see e.g. Kwok P-Y, 2001; Syvänen A-C, 2001), these methods include, but are not limited to, hybridization assays, ligation assays, primer extension assays, enzymatic cleavage assays, chemical cleavage assays and any combinations of these assays. The assays may or may not include PCR, solid phase step, a microarray, modified oligonucleotides, labeled probes or labeled nucleotides and the assay may be multiplex or singleplex. As it is obvious in the art the nucleotides present in a polymorphic site can be determined from either nucleic acid strand or from both strands.


In another embodiment of the invention, a susceptibility to HT is assessed from transcription products of one or more HT associated genes. Qualitative or quantitative alterations in transcription products can be assessed by a variety of methods described in the art, including e.g. hybridization methods, enzymatic cleavage assays, RT-PCR assays and microarrays. A test sample from an individual is collected and the alterations in the transcription of HT associated genes are assessed from the RNA molecules present in the sample. Altered transcription is diagnostic for a susceptibility to HT.


In another embodiment of the invention, detection of a susceptibility to HT is made by examining expression, abundance, biological activities, structures and/or functions of polypeptides encoded by one or more HT related genes disclosed in table 1. A test sample from an individual is assessed for the presence of alterations in the expression, biological activities, structures and/or functions of the polypeptides, or for the presence of a particular polypeptide variant (e.g., an isoform) encoded by a HT risk gene. An alteration can be, for example, quantitative (an alteration in the quantity of the expressed polypeptide, i.e., the amount of polypeptide produced) or qualitative (an alteration in the structure and/or function of a polypeptide encoded by a HT risk gene, i.e. expression of a mutant polypeptide or of a different splicing variant or isoform). Alterations in expression, abundance, biological activity, structure and/or function of a HT susceptibility polypeptide can be determined by various methods known in the art e.g. by assays based on chromatography, spectroscopy, colorimetry, electrophoresis, isoelectric focusing, specific cleavage, immunologic techniques and measurement of biological activity as well as combinations of different assays. An “alteration” in the polypeptide expression or composition, as used herein, refers to an alteration in expression or composition in a test sample, as compared with the expression or composition in a control sample and an alteration can be assessed either directly from the HT susceptibility polypeptide itself or it's fragment or from substrates and reaction products of said polypeptide. A control sample is a sample that corresponds to the test sample (e.g., is from the same type of cells), and is from an individual who is not affected by HT. An alteration in the expression, abundance, biological activity, function or composition of a polypeptide encoded by a HT susceptibility gene of the invention in the test sample, as compared with the control sample, is indicative of a susceptibility to HT. In another embodiment, assessment of the splicing variant or isoform(s) of a polypeptide encoded by a polymorphic or mutant HT risk gene can be performed directly (e.g., by examining the polypeptide itself, or indirectly (e.g., by examining the mRNA encoding the polypeptide, such as through mRNA profiling).


Yet in another embodiment, a susceptibility to HT can be detected by assessing the status and/or function of biological networks and/or metabolic pathways related to one or more polypeptides encoded by HT risk genes of this invention. Status and/or function of a biological network and/or a metabolic pathway can be assessed e.g. by measuring amount or composition of one or several polypeptides or metabolites belonging to the biological network and/or to the metabolic pathway from a biological sample taken from a subject. Risk to develop HT is evaluated by comparing observed status and/or function of biological networks and or metabolic pathways of a subject to the status and/or function of biological networks and or metabolic pathways of healthy controls.


Another major application of the current invention is determination of a molecular subtype of HT in a subject. In vitro methods and kits of this invention can be applied to a person having HT, although the methods and test kits are preferably applied to persons having familial essential hypertension (who have family members with HT). In one preferred embodiment, molecular subtype of HT in an individual is determined to provide information of the molecular etiology of HT. When the molecular etiology is known, better diagnosis and prognosis of HT can be made and efficient and safe therapy for treating HT in an individual can be selected on the basis of this HT subtype. For example, the drug that is likely to be effective, i.e. blood pressure lowering, can be selected without trial and error. Physicians may use the information on genetic risk factors with or without known clinical risk factors to convince particular patients to adjust their life style and manage HT risk factors and select intensified preventive and curative interventions for them. In other embodiment, biomarker information obtained from methods and kits for determining molecular subtype of HT in an individual is for monitoring the effectiveness of their treatment. In one embodiment, methods and kits for determining molecular subtype of HT are used to select human subjects for clinical trials testing antihypertensive drugs or other therapies. The kits provided for determination of a molecular subtype of HT in an individual comprise wholly or in part protocol and reagents for detecting one or more biomarkers and interpretation software for data analysis and HT molecular subtype assessment.


The methods and test kits of the invention may further comprise a step of combining non-genetic information with the biomarker data to make risk assessment, molecular diagnosis or prognosis of HT or a HT related condition. Useful non-genetic information comprises age, gender, ethnicity, the family history of HT, CVD, obesity, diabetes and hypercholesterolemia, and the medical history concerning CVD, obesity, diabetes and hypercholesterolemia of the subject. The detection method of the invention may also further comprise a step determining blood, serum or plasma cholesterol, HDL cholesterol, LDL cholesterol, triglyceride, apolipoprotein B and AI, fibrinogen, ferritin, transferrin receptor, C-reactive protein, serum or plasma insulin concentration, vasoactive peptides and dietary intake of relevant nutrients such as sodium, other minerals such as potassium, magnesium, calcium, selenium, and alcohol, saturated and unsaturated fatty acids, amino acids, and dietary antioxidants such as vitamin C and E.


The score that predicts the probability of HT may be calculated e.g. using a multivariate failure time model or a logistic regression equation. The results from the further steps of the method as described above render possible a step of calculating the probability of HT using a logistic regression equation as follows. Probability of HT=1/[1+e (−(−a+Σ(bi*Xi))], where e is Napier's constant, Xi are variables related to the HT, bi are coefficients of these variables in the logistic function, and a is the constant term in the logistic function, and wherein a and bi are preferably determined in the population in which the method is to be used, and Xi are preferably selected among the variables that have been measured in the population in which the method is to be used. Preferable values for bi are between −20 and 20; and for i between 0 (none) and 100,000. A negative coefficient bi implies that the marker is risk-reducing and a positive that the marker is risk-increasing. Xi are binary variables that can have values or are coded as 0 (zero) or 1 (one) such as SNP markers. The model may additionally include any interaction (product) or terms of any variables Xi, e.g. biXi. An algorithm is developed for combining the information to yield a simple prediction of HT as percentage of risk in one year, two years, five years, 10 years or 20 years. Alternative statistical models are failure-time models such as the Cox's proportional hazards' model, other iterative models and neural networking models.


In vitro test kits (e.g. reagent kits) of this invention comprise reagents, materials and protocols for assessing one or more biomarkers, and instructions and software for comparing the biomarker data from a subject to biomarker data from healthy and diseased people to make risk assessment, diagnosis or prognosis of HT. Useful reagents and materials for kits include, but are not limited to PCR primers, hybridization probes and primers as described herein (e.g., labeled probes or primers), allele-specific oligonucleotides, reagents for genotyping SNP markers, reagents for detection of labeled molecules, restriction enzymes (e.g., for RFLP analysis), DNA polymerases, RNA polymerases, DNA ligases, marker enzymes, antibodies which bind to altered or to non-altered (native) HT risk gene encoded polypeptide, means for amplification of nucleic acids fragments from one or more HT risk genes selected from the table 1, means for analyzing the nucleic acid sequence of one or more HT risk genes or fragments thereof, or means for analyzing the sequence of one or more amino acid residues of HT risk gene encoded polypeptides, etc. In one embodiment, a kit for diagnosing susceptibility to HT comprises primers and reagents for detecting the nucleotides present in one or more SNP markers selected from the tables 2 to 10 in individual's nucleic acid.


Yet another application of the current invention is related to methods and test kits for monitoring the effectiveness of a treatment for HT. The disclosed methods and kits comprise taking a tissue sample (e.g. peripheral blood sample or adipose tissue biopsy) from a subject before starting a treatment, taking one or more comparable samples from the same tissue of the subject during the therapy, assessing expression (e.g., relative or absolute expression) of one or more HT risk genes set forth in table 1 in the collected samples of the subject and detecting differences in expression related to the treatment. Differences in expression can be assessed from mRNAs and/or polypeptides encoded by one or more HT risk genes of the invention and an alteration in the expression towards the expression observed in the same tissue in healthy individuals indicates the treatment is efficient. In a preferred embodiment the differences in expression related to a treatment are detected by assessing biological activities of one or more polypeptides encoded by HT risk genes set forth in table 1.


Alternatively the effectiveness of a treatment for HT can be followed by assessing the status and/or function of metabolic pathways related to one or more polypeptides encoded by HT risk genes set forth in table 1. Status and/or function of a metabolic pathway can be assessed e.g. by measuring amount or composition of one or morel polypeptides, belonging to the metabolic pathway, from a biological sample taken from a subject before and during a treatment. Alternatively status and/or function of a metabolic pathway can be assessed by measuring one or more metabolites belonging to the metabolic pathway, from a biological sample before and during a treatment. Effectiveness of a treatment is evaluated by comparing observed changes in status and/or function of metabolic pathways following treatment with HT therapeutic agents to the data available from healthy subjects.


Methods of Therapy

The present invention discloses novel methods for the prevention and treatment of HT. In particular, the invention relates to methods of treatment for HT or susceptibility to HT as well as to methods of treatment for manifestations and subtypes of HT.


The term “treatment” as used herein, refers not only to ameliorating symptoms associated with the disease, but also preventing or delaying the onset of the disease, and also lessening the severity or frequency of symptoms of the disease, preventing or delaying the occurrence of a second episode of the disease or condition; and/or also lessening the severity or frequency of symptoms of the disease or condition.


The present invention encompasses methods of treatment (prophylactic and/or therapeutic) for HT using a HT therapeutic agent. A “HT therapeutic agent” is an agent that alters (e.g., enhances or inhibits) enzymatic activity or function of a HT risk affecting polypeptide, and/or expression of a HT risk gene disclosed in table 1. Useful therapeutic agents can alter biological activity or function of a HT susceptibility polypeptide and/or expression of related gene by a variety of means, for example, by altering translation rate of a HT susceptibility polypeptide encoding mRNA; by altering transcription rate of a HT risk gene; by altering posttranslational processing rate of a HT susceptibility polypeptide; by interfering with a HT susceptibility polypeptide biological activity and/or function (e.g., by binding to a HT susceptibility polypeptide); by altering stability of a HT susceptibility polypeptide; by altering the transcription rate of splice variants of a HT risk gene or by inhibiting or enhancing the elimination of a HT susceptibility polypeptide from target cells, organs and/or tissues.


Representative therapeutic agents of the invention comprise the following: (a) nucleic acids, fragments, variants or derivatives of the HT associated genes disclosed in table 1 of this invention, nucleic acids encoding a HT susceptibility polypeptide or an active fragment or a derivative thereof and nucleic acids modifying the expression of said HT associated genes (e.g. antisense polynucleotides, catalytically active polynucleotides (e.g. ribozymes and DNAzymes), molecules inducing RNA interference (RNAi) and micro RNA), and vectors comprising said nucleic acids; (b) HT susceptibility polypeptides encoded by genes set forth in table 1, active fragments, variants or derivatives thereof, binding agents of HT susceptibility polypeptides; peptidomimetics; fusion proteins or prodrugs thereof, antibodies (e.g., an antibody to a mutant HT susceptibility polypeptide, or an antibody to a non-mutant HT susceptibility polypeptide, or an antibody to a particular variant encoded by a HT risk gene, as described above) and other polypeptides (e.g., HT susceptibility polypeptide receptors, active fragments, variants or derivatives thereof); (c) metabolites of HT susceptibility polypeptides or derivatives thereof; (d) small molecules and compounds that alter (e.g., inhibit or antagonize) a HT risk gene expression, activity and/or function of a HT risk gene encoded polypeptide, or activity and/or function of a HT gene related metabolic pathway and; (e) small molecules and compounds that alter (e.g. induce, agonize or modulate) a HT risk gene expression, activity and/or function of a HT risk gene encoded polypeptide, or activity and/or function of a HT gene related metabolic pathway.


The nucleic acid sequences assigned in the art to the HT associated genes provided in table 1 of this invention are publicly available and can be used to design and develop therapeutic nucleic acid molecules and recombinant DNA molecules for the prevention and treatment of HT. For example antisense nucleic acid molecules targeted to a gene listed in table 1 can be designed using tools and the nucleotide sequence of the gene available in the art and constructed using chemical synthesis and/or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid molecule (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense oligonucleotide and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Alternatively, the antisense nucleic acid molecule can be produced biologically using an expression vector into which a nucleic acid molecule encoding a HT risk gene, a fragment or a variant thereof has been cloned in antisense orientation (i.e., RNA transcribed from the expression vector will be complementary to the transcribed RNA of a HT risk gene of interest).


More than one HT therapeutic agent can be used concurrently, if desired. The therapy is designed to alter (e.g., inhibit or enhance), replace or supplement activity and/or function of one or more HT polypeptides or related metabolic pathways in an individual. For example, a HT therapeutic agent can be administered in order to upregulate or increase the expression or availability of a HT risk gene encoded polypeptide or it's specific variant or, conversely, to downregulate or decrease the expression or availability of a HT risk gene encoded polypeptide or a specific variant thereof. Upregulation or increasing expression or availability of a native HT risk gene encoded polypeptide or it's particular variant in an individual could e.g. compensate for the low or altered biological activity of a defective gene or variant; whereas downregulation or decreasing expression or availability of a defective HT risk gene encoded polypeptide or it's particular splicing variant in an individual could minimize the impact of the defective gene or the particular variant.


The HT therapeutic agent(s) are administered in a therapeutically effective amount (i.e., an amount that is sufficient to treat the disease, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and/or also lessening the severity or frequency of symptoms of the disease). The amount which will be therapeutically effective in the treatment of a particular individual's disorder or condition will depend on the symptoms and severity of the disease, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of a practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.


In one embodiment, a nucleic acid encoding a HT susceptibility polypeptide, fragment, variant or derivative thereof, either by itself or included within a vector, can be introduced into cells of an individual affected by HT using variety of experimental methods described in the art, so that the treated cells start to produce native HT susceptibility polypeptide. Thus, cells which, in nature, lack of a native HT risk gene expression and activity, or have abnormal HT risk gene expression and activity, can be engineered to express a HT susceptibility polypeptide or an active fragment or a different variant of said HT susceptibility polypeptide. Genetic engineering of cells may be done either “ex vivo” (i.e. suitable cells are isolated and purified from a patient and re-infused back to the patient after genetic engineering) or “in vivo” (i.e. genetic engineering is done directly to a tissue of a patient using a vehicle). Alternatively, in another embodiment of the invention, a nucleic acid (e.g. a polynucleotide) which specifically hybridizes to the mRNA and/or genomic DNA of a HT risk gene is administered in a pharmaceutical composition to the target cells or said nucleic acid is generated “in vivo”. The antisense nucleic acid that specifically hybridizes to the mRNA and/or DNA inhibits expression of the HT susceptibility polypeptide, e.g., by inhibiting translation and/or transcription. Binding of the antisense nucleic acid can be due to conventional base pairing, or, for example, in the case of binding to DNA duplexes, through specific interaction in the major groove of the double helix. In a preferred embodiment nucleic acid therapeutic agents of the invention are delivered into cells that express one or more HT risk genes. A number of methods including, but not limited to, the methods known in the art can be used for delivering a nucleic acid to said cells. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of a RNA molecule, which induces RNA interference in the cell. Such a vector can remain episomal or become chromosomally integrated, and as long as it can be transcribed to produce the desired RNA molecules it will modify the expression of a HT risk gene. Such vectors can be constructed by various recombinant DNA technology methods standard in the art.


The expression of a HT risk gene disclosed in table 1 may be reduced e.g. by inactivating or “knocking out” it or its promoter using targeted homologous recombination methods described in the art. Alternatively, expression of a functional, non-mutant HT risk gene can be increased using a similar method: targeted homologous recombination can be used to replace a non-functional HT risk gene with a functional form of the said gene in a cell. In yet another embodiment of the invention, other HT therapeutic agents as described herein can also be used in the treatment or prevention of HT. The therapeutic agents can be delivered in a pharmaceutical composition they can be administered systemically, or can be targeted to a particular tissue. The therapeutic agents can be produced by a variety of means, including chemical synthesis, cell culture and recombinant techniques (e.g. with transgenic cells and animals). Therapeutic agents can be isolated and purified to meet pharmaceutical requirements using standard methods described in the art. A combination of any of the above methods of treatment (e.g., administration of non-mutant HT susceptibility polypeptide in conjunction with RNA molecules inducing RNA interference targeted to the mutant HT susceptibility mRNA) can also be used.


In the case of pharmaceutical therapy, the invention comprises compounds, which enhance or reduce the activity and/or function of at least one polypeptide encoded by HT susceptibility genes set forth in table 1. The treatment may also enhance or reduce the expression of one or more genes selected from HT susceptibility genes set forth in table 1. In another embodiment of the invention, pharmaceutical therapy of the invention comprises compounds, which enhance or reduce the activity and/or function of one or more metabolic pathways related to HT susceptibility genes, proteins or polypeptides. The treatment may also enhance or reduce the expression of one or more genes in metabolic pathways related to HT susceptibility genes, proteins or polypeptides.


Furthermore, a disclosed method or a test based on HT susceptibility gene specific biomarkers (e.g. polymorphic sites, expression or polypeptides) is useful in selecting drug therapy for patients with HT. For example when the less frequent, i.e. the minor, assumable mutated allele in the HT susceptibility gene is risk-reducing, and if said mutation is a gene function reducing mutation, one can deduce that the gene function and/or activity would increase the risk of HT. On that basis, drugs and other therapies such as gene therapies that reduce or inhibit the function or activity of the HT susceptibility gene or the encoded protein would reduce the risk of the said disease and could be used to both prevent and treat the said disease in subjects having said mutated allele.


In another embodiment of the invention a HT therapeutic agent comprises a know therapeutic agent related to a HT associated gene listed in table 1 of this invention but which is not used to treat HT. Such agents are useful for developing new therapies for HT as they probably are agonizing, modulating, binding, inhibiting and/or antagonizing (i) expression of a HT risk gene, (ii) biological activity and/or function of a HT risk gene encoded polypeptide, or (iii) biological activity and/or function of a HT risk gene related metabolic pathway. These agents may be used alone or with combination with other treatments and agents used for prevention or treatment of HT.


Pharmaceutical Compositions

The present invention also pertains to pharmaceutical compositions comprising agents described herein, particularly polynucleotides, polypeptides and any fractions, variants or derivatives of HT susceptibility genes, and/or agents that alter (e.g., enhance or inhibit) expression of a HT risk gene or genes, or activity of one or more polypeptides encoded by HT susceptibility genes as described herein. For instance, an agent that alters expression of a HT risk gene, or activity of one or more polypeptides encoded by HT susceptibility genes or a HT susceptibility polypeptide binding agent, binding partner, fragment, fusion protein or prodrug thereof, or polynucleotides of the present invention, can be formulated with a physiologically acceptable carrier or excipient to prepare a pharmaceutical composition. The carrier and composition can be sterile. The formulation should suit the mode of administration. In a preferred embodiment pharmaceutical compositions comprise agent or agents reversing, at least partially, HT associated changes in metabolic pathways related to the HT associated genes disclosed in table 1 of this invention.


Agents described herein can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions (e.g., NaCl), saline, buffered saline, alcohols, glycerol, ethanol, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, dextrose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrolidone, etc., as well as combinations thereof. The pharmaceutical preparations can, if desired, be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active agents. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrolidone, sodium saccharine, cellulose, magnesium carbonate, etc.


Methods of introduction of these compositions include, but are not limited to, intradermal, intramuscular, intraperitoneal, intraocular, intravenous, subcutaneous, topical, oral and intranasal. Other suitable methods of introduction can also include gene therapy (as described below), rechargeable or biodegradable devices, particle acceleration devises (“gene guns”) and slow release polymeric devices. The pharmaceutical compositions of this invention can also be administered as part of a combinatorial therapy with other agents. The composition can be formulated in accordance with the routine procedures as a pharmaceutical composition adapted for administration to human beings. For example, compositions for intravenous administration typically are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. Where the composition is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. For topical application, non-sprayable forms, viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water, can be employed. Suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, enemas, lotions, sols, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc. The agent may be incorporated into a cosmetic formulation. For topical application, also suitable are sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier material, is packaged in a squeeze bottle or in admixture with a pressurized volatile, normally gaseous propellant, e.g., pressurized air.


The agents are administered in a therapeutically effective amount. The amount of agents which will be therapeutically effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the symptoms of HT, and should be decided according to the judgment of a practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.


Functional Foods

By definition “functional foods” or “nutraceuticals” are foods or dietary components or food ingredients that may provide a health benefit beyond basic nutrition. Functional foods are regulated by authorities (e.g. by the FDA in US) according to their intended use and the nature of claims made on the package. Functional foods can be produced by various methods and processes known in the art including, but not limited to synthesis (chemical or microbial), extraction from a biological material, mixing functional ingredient or component to a regular food product, fermentation or using a biotechnological process. A functional food may exert its effects directly in the human body or it may function e.g. through human intestinal bacterial flora.


The polypeptides encoded by the HT associated genes disclosed in table 1 of this invention can be used as molecular targets towards which functional foods claiming health benefit in HT can be developed. In one embodiment a functional food may be developed to compensate altered biological activity of a polypeptide encoded by a HT risk gene set forth in table 1 or a related metabolic pathway. For example if the reduced biological activity of a HT risk gene encoded polypeptide or a related metabolic pathway is associated with increased risk of hypertension a functional food may be developed to activate or stabilize the HT risk gene encoded polypeptide, or to contain a metabolite which is normally produced by the HT risk gene encoded polypeptide. Similarly, if the increased biological activity of a HT risk gene encoded polypeptide or a related metabolic pathway is associated with increased risk of hypertension a functional food may be developed either to inhibit the expression of the HT risk gene or to inhibit the biological activity of the HT risk gene encoded polypeptide or a related metabolic pathway.


EXPERIMENTAL SECTION
Example 1
Hypertension Study in Eastern Finnish, Ashkenazi Jewish, German and English Subjects: the Study Subjects and Genome Wide Scanning Using Illumina's HumanHap300

The subjects for this hypertension whole genome association study were selected from the 500 T2D cases and the 497 T2D-free controls of the Jurilab's whole genome association study in type 2 diabetes (DiaGen study) covered by the U.S. patent application Ser. No. 60/863,438. The 586 hypertension study subjects included 114 hypertensive cases and 114 controls from Eastern Finland, 110 hypertensive cases and 110 controls from Israel (Ashkenazi Jewish), 41 hypertensive cases and 41 controls from Germany and 28 hypertensive cases and 28 controls from England.


Definition of Cases and Controls

The current work was based on 293 hypertensive cases and 293 normotensive controls, a total of 586 subjects. The cases had either previous diagnosis of HT or medication for hypertension. The controls had neither diagnosis of HT nor antihypertensive medication.


Both the cases and controls had the following:

    • 1. A written informed consent which will allow us to use data and samples for the commercial applications,
    • 2. Extracted DNA or whole blood for DNA extraction, plasma and serum,
    • 3. Information (data) on age, gender and ethnicity (for matching) and
    • 4. Information about the family history of diseases defined in the questionnaire.


From each of the four populations (Eastern Finns, Ashkenazi Jews, Germans and English), an equal number of cases and controls were selected and matched for gender.


Eastern Finnish (EF) Study Subjects

The current population of the North Savo is over 250,000 people. The population is genetically homogenous and has a high prevalence of type 2 diabetes. Mailed health-related surveys show consistently very high participation rates. There is almost no illiteracy. The “North Savo Health Survey” was approved by the local ethics committee and it was carried out in October to December, 2003. The survey was targeted to all households in the municipalities of Kuopio, Karttula, Lapinlahti, Leppävirta, Maaninka, Rautalampi, Siilinjäri, Suonenjoki, Tervo, Vehmersalmi, and Vesanto. The number of households was about 70,000 and the number of people over 18 years old was about 200,000. A letter was sent to each household containing three personal and one common questionnaire. The three oldest persons who were at least 18 years of age in the household were asked to fill in the personal questionnaire and one of them to fill in the common family data questionnaire, and return them in the same single return envelope. Only persons, who gave the consent to obtain their hospital records and who provided their personal identification code, were asked to return the questionnaire. The “North Savo Project” included the collection of disease, family, drug response and contact information. By the end of 2004, 17,100 participants were surveyed. The North Savo Survey data were used to identify probands with hypertension.


The study subjects were participants in the “SOHFA” study. The “SOHFA” (Study of Diabetic, Obese and Hypertensive Families in the Northern Savo Genetic Epidemiology Cohort Study) is a contractual study, in which the University of Kuopio is the contractee.


Both systolic and diastolic BPs were measured in the morning by a nurse with a mercury sphygmomanometer. The measuring protocol included three measurements in standing position with 5-minute intervals. The mean of all three measurements were used as SBP and DBP. Body mass index (BMI) was computed as the ratio of weight to the square of height (kg/m2). Waist-to-hip ratio (WHR) was calculated as the ratio of waist circumference (average of one measure taken after inspiration and one taken after expiration at the midpoint between the lowest rib and the iliac crest) to hip circumference (measured at the level of the trochanter major). Age and tobacco smoking were recorded on a self-administered questionnaire checked by an interviewer.


Ashkenazi Jewish (AJ) DiaGen Study Subjects

Subjects included in the study were collected in Israel by the physicians in charge in specialized clinics. Subjects were diagnosed with type 2 Diabetes Mellitus according to the etiologic classification of Diabetes Mellitus proposed by the International Expert Committee under the sponsorship of the American Diabetes Association on May 1997, We included in the study 200 subjects (82 males and 118 females, mean age 64), each with 3 or more blood relatives of second degree or closer, suffering from T2D.


Matching 200 healthy control subjects (82 males and 118 females, mean age 74) were collected from the Israeli blood bank and elderly patients visiting general practitioners clinics. All subjects were of Ashkenazi Jewish origin. The study was approved by the appropriate ethics committees and participants had signed informed consent forms. The 400 AJ DiaGen study subjects included 110 HT cases and 110 normotensive controls.


German (GE) and English (UK) DiaGen Study Subjects

In Germany, cases were sampled from T2D patients from the Hospital of Diabetes and Metabolic Diseases (Karlsburg, Germany) and the diabetes dispensary unit of the Department of Endocrinology of the Ernst-Moritz-Arndt University (Greifswald, Germany). The controls were sampled from the non-diabetic examinees of the population based SHIP study cohort (Luedemann et al 2002). Total of 49 cases (24 females and 25 males) and 50 matched healthy controls (24 females and 26 males) from Germany were included in the DiaGen study. The 99 GE DiaGen study subjects included 41 HT cases and 41 normotensive controls.


From England total of 50 cases (31 females and 19 males) and 50 matched healthy controls (31 females and 19 males) were included in the DiaGen study. The controls were selected from the examinees of the Age and Cognitive Performance Research Centres (ACPRC) volunteer panel, a group of over 6000 older adults who have been previously described in detail (Rabbitt et al, 2004). A cohort of approximately 2000 of these individuals has DNA archived in the Dyne-Steel DNA bank. A group of 456 of these volunteers, residents of Greater Manchester, had previously taken part in a research study in 2001 which included medical history, including that of Diabetes Mellitus, and measurement of HbA1C. From the original cohort of 456, a sample of 50 individuals was identified to sex match diabetic cases from Manchester. Each individual had an HbA1C below 5.5% and at telephone interview of family diabetes mellitus history in 2006, reported no evidence of diabetes mellitus in parents or siblings. The University of Manchester research ethics committee approved the study and each individual completed an individual form of consent. The 100 UKi DiaGen study subjects included 28 HT cases and 28 HT normotensive controls.


Genomic DNA Isolation and Quality Testing

High molecular weight genomic DNA from EF samples was extracted from frozen venous whole blood using standard methods (proteinase K digestion, phenol-chloroform extractions and precipitation) and dissolved in standard TE buffer. The quantity and purity of each DNA sample was determined by absorbance measurements done with NanoDrop ND-1000 Spectrophotometer (NanoDrop Technologies, Wilmington, Del. USA). A sample was qualified for genome wide scan (GWS) analysis if A260/A280 ratio was ≧1.7. Before GWS analysis the samples were diluted to concentration of 60 ng/μl in reduced EDTA TE buffer (TEKnova, Hollister, Calif., USA).


Genome-Wide Scanning Using Illumina's HumanHap300

The whole-genome genotyping of the DNA samples was performed by using Illumina's Sentrix HumanHap300 BeadChips and Infinium II genotyping assay. The HumanHap300 BeadChip contained over 317,000 tagSNP markers derived from the International HapMap Project. TagSNPs are loci that can serve as proxies for many other SNPs. The use of tagSNPs greatly improves the power of association studies as only a subset of loci needs to be genotyped while maintaining the same information and power as if one had genotyped a larger number of SNPs.


The Infinium II genotyping with the HumanHap300 BeadChip assays was performed according to the “Single-Sample BeadChip Manual process” described in detail in “Infinium™ II Assay System Manual” provided by Illumina (San Diego, Calif., USA). Briefly, 750 ng of genomic DNA from a sample was subjected to whole-genome amplification. The amplified DNA was fragmented, precipitated and resuspended to hybridization buffer. The resuspended sample was heat denatured and then applied to one Sentrix HumanHap300 beadchip. After overnight hybridization mis- and non-hybridized DNA was washed away from the BeadChip and allele-specific single-base extension of the oligonucleotides on the BeadChip was performed in a Tecan GenePaint rack, using labeled deoxynucleotides and the captured DNA as a template. After staining of the extended DNA, the BeadChips were washed and scanned with the BeadArray Reader (Illumina) and genotypes from samples were called by using the BeadStudio software (Illumina).


Infinium II genotyping with the HumanHap300 BeadChips were done for 500 T2D cases and 497 T2D-free controls including the 586 hypertension study subjects.


Example 2
Statistical Analyses of the GWS Data of the Hypertension Study (Example 1.)
Initial SNP Selection for Statistical Analysis

Prior to the statistical analysis, SNP quality was assessed on the basis of three values: the call rate (CR), minor allele frequency (MAF), and Hardy-Weinberg equilibrium (H-W). The CR is the proportion of samples genotyped successfully. It does not take into account whether the genotypes are correct or not. The call rate was calculated as: CR=number of samples with successful genotype call/total number of samples. The MAF is the frequency of the allele that is less frequent in the study sample. MAF was calculated as: MAF=min(p, q), where p is frequency of the SNP allele ‘A’ and q is frequency of the SNP allele ‘B’; p=(number of samples with “AA”-genotype+0.5*number of samples with “AB”-genotype)/total number of samples with successful genotype call; q=1−p. SNPs that are homozygous (MAF=0) cannot be used in genetic analysis and were thus discarded. H-W equilibrium is tested for controls. The test is based on the standard Chi-square test of goodness of fit. The observed genotype distribution is compared with the expected genotype distribution under H-W equilibrium. For two alleles this distribution is p2, 2pq, and q2 for genotypes ‘AA’, ‘AB’ and ‘BB’, respectively. If the SNP is not in H-W equilibrium it can be due to genotyping error or some unknown population dynamics (e.g. random drift, selection).


Following criteria were used in the statistical analysis: CR>90%, MAF>1%, and H-W equilibrium Chi-square test statistic <27.5 (the control group). A total of 315,917 Illumina300K SNPs fulfilled the above criteria.


Single SNP Analysis

Differences in allele distributions between cases and controls were screened for all SNPs. The screening was carried out using the standard Chi-square independence test with 1 df (allele distribution, 2×2 table). SNPs that gave a P-value less tan 0.001 (Chi-square with 1 df of 10.23 or more) were considered statistically significant and reported in the tables. Odds ratio was calculated as ad/bc, where a is the number of minor alleles in cases, b is the number of major alleles in cases, c is the number of minor allele in controls, and d is the number of major alleles in controls. Minor allele was defined as the allele for a given SNP that had smaller frequency than the other allele in the control group.


Genotype Analysis

Logistic regression (R-programming language) with three genetic models were tested: additive, recessive and dominance. As an example if the alleles of the SNP are A and C then additive model tests the linear increase in disease risk from genotype AA to AC to CC. In the dominance and recessive model heterozygous genotypes are combined with either AA or CC genotypes.


Haplotype Analysis

The data set was analyzed with a haplotype pattern mining algorithm with HPM software (Toivonen H T et al, 2000). For HPM software, genotypes must be phase known to determine which alleles come from the mother and which from the father. Without family data, phases must be estimated based on population data. We used the HaploRec program (Eronen L et al, 2004) to estimate the phases. For phase-known data HPM finds all haplotype patterns that are in concordance with the phase configuration. The length of the haplotype patterns can vary. As an example, if there are four SNPs and an individual has alleles A T for SNP1, C C for SNP2, C G for SNP3, and A C for SNP4, then HPM considers haplotype patterns that are in concordance with the estimated phase (done by HaploRec). If the estimated phase is ACGA (from the mother/father) and TCCC (from the father/mother) then HPM considers only two patterns (of length 4 SNPs): ACGA and TCCC. A SNP is scored based on the number of times it is included in a haplotype pattern that differs between cases and controls (a threshold Chi-square value can be selected by the user). Significance of the score values was tested based on permutation tests. Several parameters can be modified in the HPM program including the Chi-square threshold value (−x), the maximum haplotype pattern length (−l), the maximum number of wildcards that can be included in a haplotype pattern (−w), and the number of permutation tests in order to estimate the P-value (−p).


Results of the GWS Study (Example 1.)

In Table 1. the genes associated with hypertension are listed. Table 2 gives the SNP markers with the strongest association with HT in the individual marker analysis. The analysis is based on 140 HT cases and 182 healthy controls from East Finland. Below is the list of the tables where results of different statistical analysis are presented:


Table 3. Haplotype genomic regions with the strongest association with HT in the haplotype sharing analysis (HaploRec+HPM) with 8 SNPs. The analysis is based on 140 HT cases and 182 healthy controls from East Finland.


Table 4. Haplotypes with the strongest association with HT based on HaploRec+HPM analysis with 8 SNPs. The analysis is based on 140 HT cases and 182 healthy controls from East Finland.


Table 5. SNP markers with the strongest association with hypertension in the individual marker analysis. The analysis is based on the combined data of 110 HT cases and 110 healthy controls from the Ashkenazi Jewish population, 114 HT cases and 114 healthy controls from the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT cases and 28 healthy controls from the English population.


Table 6. SNP markers with the strongest association with hypertension in the regression analysis with an additive genotype model and T2D as a covariate. The analysis is based on the combined data of 110 HT cases and 110 healthy controls from the Ashkenazi Jewish population, 114 HT cases and 114 healthy controls from the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT cases and 28 healthy controls from the English population.


Table 7. SNP markers with the strongest association with hypertension in the regression analysis with a recessive genotype model and T2D as a covariate. The analysis is based on the combined data of 110 HT cases and 110 healthy controls from the Ashkenazi Jewish population, 114 HT cases and 114 healthy controls from the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT cases and 28 healthy controls from the English population.


Table 8. SNP markers with the strongest association with hypertension in the regression analysis with a dominant genotype model and T2D as a covariate. The analysis is based on the combined data of 110 HT cases and 110 healthy controls from the Ashkenazi Jewish population, 114 HT cases and 114 healthy controls from the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT cases and 28 healthy controls from the English population.


Table 9. Haplotype genomic regions with the strongest association with hypertension in the haplotype sharing analysis (HaploRec+HPM) with 5 SNPs. The analysis is based on the combined data of 110 HT cases and 110 healthy controls from the Ashkenazi Jewish population, 114 HT cases and 114 healthy controls from the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT cases and 28 healthy controls from the English population.


Table 10. Haplotypes with the strongest association with hypertension based on HaploRec+HPM analysis with 5 SNPs. The analysis is based on the combined data of 110 HT cases and 110 healthy controls from the Ashkenazi Jewish population, 114 HT cases and 114 healthy controls from the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT cases and 28 healthy controls from the English population.


Example 3
Examples of the Content of the In Vitro Diagnostic Assays

The score that predicts the probability of HT may be calculated e.g. using a logistic regression equation: probability of HT=1/[1+e (−(−a+Σ(bi*Xi))], where e is Napier's constant, Xi are variables related to the HT, bi are coefficients of these variables in the logistic function, and a is the constant term in the logistic function, and wherein a and bi are preferably determined in the population in which the method is to be used, and Xi are preferably selected among the variables that have been measured in the population in which the method is to be used.


As an example the probability of HT may be estimated with the model Prob(HT)=1/[1+e(−(−a+b1x1+b2x2+b3x3+b4x4)], where bi's are coefficients depending on the population and combination of xi's and for each individual x1-x4 are any combination of the SNPs from the following list of SNPs: rs1721355, rs561264, rs2153184, rs9564765, rs8066575, rs6698312, rs2301301, rs7406978, rs2245192, and rs747250. The model may also include additional SNPs from the tables 2-10 or some of the xi's may be other than SNPs including haplotypes, lifestyle and environmental factors.


IMPLICATIONS AND CONCLUSIONS

We have discovered a total of 425 HT associated genes, in which any HT associated biomarkers can be used to predict HT, and thus these markers can be used to develop molecular diagnostic tests for HT or a HT related condition. In addition, we have disclosed a set of 1874 SNP markers predicting HT. The markers can also be used as part of pharmacogenetic tests used to predict the efficacy of a HT therapy and guide the selection of effective and safe treatment for a subject. The genes discovered are also useful in development of novel therapies such as drugs and dietary interventions for HT or a HT related condition. The genes and markers of this invention can also be used to screen, identify and test novel antihypertensive agents and compounds.


While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.









TABLE 1







Genes associated with hypertension (425 genes).










GENE_ID
GENE
CHR
Patent_ID_number and Priority_date













57529
KIAA1318
X
US 60/819,014 filed on JULY_07_2006


91851
CHRDL1
X
US 60/819,014 filed on JULY_07_2006


284222
FLJ34907
18 
US 60/819,014 filed on JULY_07_2006


81469
OR2G3
1
US 60/819,014 filed on JULY_07_2006


57559
STAMBPL1
10 
US 60/867,454 filed on NOV_28_2006


4952
OCRL
X
US 60/867,454 filed on NOV_28_2006


6594
SMARCA1
X
US 60/867,454 filed on NOV_28_2006


5354
PLP1
X
US 60/819,014 filed on JULY_07_2006


55787
CXorf15
X
US 60/867,454 filed on NOV_28_2006


392222
LOC392222
8
US 60/819,014 filed on JULY_07_2006


5152
PDE9A
21 
US 60/867,454 filed on NOV_28_2006


1312
COMT
22 
US 60/867,454 filed on NOV_28_2006


6197
RPS6KA3
X
US 60/867,454 filed on NOV_28_2006


2892
GRIA3
X
US 60/819,014 filed on JULY_07_2006


152742
LOC152742
4
US 60/819,014 filed on JULY_07_2006


29
ABR
17 
US 60/867,454 filed on NOV_28_2006


26047
CNTNAP2
7
US 11/245,248 filed on NOV2004-AUG2005


286
ANK1
8
US 60/819,014 filed on JULY_07_2006


6480
ST6GAL1
3
US 60/867,454 filed on NOV_28_2006


10914
PAPOLA
14 
US 60/819,014 filed on JULY_07_2006


122481
AK7
14 
US 60/867,454 filed on NOV_28_2006


4772
NFATC1
18 
US 60/819,014 filed on JULY_07_2006


651082
LOC651082
15 
US 60/867,454 filed on NOV_28_2006


145567
TTC7B
14 
US 60/819,014 filed on JULY_07_2006


117583
ALS2CR19
2
US 60/819,014 filed on JULY_07_2006


96764
NCOA6IP
8
US 60/819,014 filed on JULY_07_2006


5101
PCDH9
13 
US 60/819,014 filed on JULY_07_2006


647339
LOC647339
13 
US 60/867,454 filed on NOV_28_2006


147807
ZNF524
19 
US 60/867,454 filed on NOV_28_2006


163033
ZNF579
19 
US 60/867,454 filed on NOV_28_2006


388565
LOC388565
19 
US 60/867,454 filed on NOV_28_2006


3552
IL1A
2
US 60/819,014 filed on JULY_07_2006


150468
FLJ40629
2
US 60/819,014 filed on JULY_07_2006


651534
LOC651534
12 
US 60/867,454 filed on NOV_28_2006


5986
RFNG
17 
US 60/867,454 filed on NOV_28_2006


53942
CNTN5
11 
US 60/819,014 filed on JULY_07_2006


164781
WDR69
2
US 60/867,454 filed on NOV_28_2006


1756
DMD
X
US 60/819,014 filed on JULY_07_2006


528
ATP6V1C1
8
US 60/867,454 filed on NOV_28_2006


79905
TMC7
16 
US 60/867,454 filed on NOV_28_2006


7988
ZNF212
7
US 60/867,454 filed on NOV_28_2006


651362
LOC651362
8
US 60/867,454 filed on NOV_28_2006


400576
FLJ45831
17 
US 60/867,454 filed on NOV_28_2006


55799
CACNA2D3
3
US 60/867,454 filed on NOV_28_2006


9104
RGN
X
US 60/819,014 filed on JULY_07_2006


3232
HOXD3
2
US 60/867,454 filed on NOV_28_2006


400693
LOC400693
19 
US 60/819,014 filed on JULY_07_2006


255926
ADAM5
8
US 60/867,454 filed on NOV_28_2006


10417
SPON2
4
US 60/867,454 filed on NOV_28_2006


8749
ADAM18
8
US 60/867,454 filed on NOV_28_2006


161176
C14orf49
14 
US 60/819,014 filed on JULY_07_2006


651311
LOC651311
11 
US 60/867,454 filed on NOV_28_2006


286094
LOC286094
8
US 60/867,454 filed on NOV_28_2006


10178
ODZ1
X
US 60/867,454 filed on NOV_28_2006


79701
FLJ22222
17 
US 60/867,454 filed on NOV_28_2006


64094
SMOC2
6
US 60/819,014 filed on JULY_07_2006


23205
BG1
15 
US 11/245,248 filed on NOV2004-AUG2005


9658
ZNF516
18 
US 60/867,454 filed on NOV_28_2006


943
TNFRSF8
1
US 60/819,014 filed on JULY_07_2006


161357
MAMDC1
14 
US 60/819,014 filed on JULY_07_2006


8825
LIN7A
12 
US 60/867,454 filed on NOV_28_2006


3673
ITGA2
5
US 60/867,454 filed on NOV_28_2006


51422
PRKAG2
7
US 60/867,454 filed on NOV_28_2006


90
ACVR1
2
US 11/245,248 filed on NOV2004-AUG2005


491
ATP2B2
3
US 60/867,454 filed on NOV_28_2006


1838
DTNB
2
US 60/867,454 filed on NOV_28_2006


2898
GRIK2
6
US 60/867,454 filed on NOV_28_2006


4313
MMP2
16 
US 60/819,014 filed on JULY_07_2006


5581
PRKCE
2
US 11/245,248 filed on NOV2004-AUG2005


8499
PPFIA2
12 
US 60/867,454 filed on NOV_28_2006


9586
CREB5
7
US 60/867,454 filed on NOV_28_2006


10046
CXorf6
X
US 60/867,454 filed on NOV_28_2006


10369
CACNG2
22 
US 60/819,014 filed on JULY_07_2006


11055
ZPBP
7
US 60/867,454 filed on NOV_28_2006


23233
SEC15L2
2
US 60/819,014 filed on JULY_07_2006


25817
TAFA5
22 
US 60/819,014 filed on JULY_07_2006


55691
FRMD4A
10 
US 60/819,014 filed on JULY_07_2006


60676
PAPPA2
1
US 60/819,014 filed on JULY_07_2006


79068
FTO
16 
US 60/867,454 filed on NOV_28_2006


139324
CXorf43
X
US 60/867,454 filed on NOV_28_2006


149986
C20orf40
20 
US 60/819,014 filed on JULY_07_2006


169044
COL22A1
8
US 60/819,014 filed on JULY_07_2006


219578
FLJ32110
7
US 60/819,014 filed on JULY_07_2006


441629
LOC441629
12 
US 60/819,014 filed on JULY_07_2006


648551
LOC648551
22 
US 60/867,454 filed on NOV_28_2006


387648
LOC387648
10 
US 60/819,014 filed on JULY_07_2006


1949
EFNB3
17 
US 60/867,454 filed on NOV_28_2006


84626
KIAA1862
7
US 60/819,014 filed on JULY_07_2006


3077
HFE
6
US 60/867,454 filed on NOV_28_2006


8364
HIST1H4C
6
US 60/867,454 filed on NOV_28_2006


340156
LOC340156
6
US 60/819,014 filed on JULY_07_2006


5536
PPP5C
19 
US 60/819,014 filed on JULY_07_2006


57107
C6orf210
6
US 60/819,014 filed on JULY_07_2006


6793
STK10
5
US 60/867,454 filed on NOV_28_2006


1902
EDG2
9
US 60/819,014 filed on JULY_07_2006


2104
ESRRG
1
US 60/867,454 filed on NOV_28_2006


6919
TCEA2
20 
US 60/867,454 filed on NOV_28_2006


286053
C8orf36
8
US 60/819,014 filed on JULY_07_2006


23098
SARM1
17 
US 60/819,014 filed on JULY_07_2006


55843
ARHGAP15
2
US 60/867,454 filed on NOV_28_2006


4892
NRAP
10 
US 60/867,454 filed on NOV_28_2006


199731
IGSF4C
19 
US 60/867,454 filed on NOV_28_2006


8621
CDC2L5
7
US 60/867,454 filed on NOV_28_2006


5660
PSAP
10 
US 60/867,454 filed on NOV_28_2006


27445
PCLO
7
US 60/867,454 filed on NOV_28_2006


8829
NRP1
10 
US 60/819,014 filed on JULY_07_2006


6660
SOX5
12 
US 60/819,014 filed on JULY_07_2006


50863
HNT
11 
US 60/819,014 filed on JULY_07_2006


773
CACNA1A
19 
US 60/819,014 filed on JULY_07_2006


5211
PFKL
21 
US 60/867,454 filed on NOV_28_2006


10098
TSPAN5
4
US 60/867,454 filed on NOV_28_2006


160364
MICL
12 
US 60/819,014 filed on JULY_07_2006


22871
NLGN1
3
US 60/867,454 filed on NOV_28_2006


649922
LOC649922
5
US 60/867,454 filed on NOV_28_2006


9968
TNRC11
X
US 60/819,014 filed on JULY_07_2006


781
CACNA2D1
7
US 60/867,454 filed on NOV_28_2006


4286
MITF
3
US 60/867,454 filed on NOV_28_2006


10752
CHL1
3
US 60/819,014 filed on JULY_07_2006


23705
IGSF4
11 
US 60/867,454 filed on NOV_28_2006


26085
KLK13
19 
US 60/867,454 filed on NOV_28_2006


151473
SLC16A14
2
US 60/819,014 filed on JULY_07_2006


340596
LHFPL1
X
US 60/819,014 filed on JULY_07_2006


391353
LOC391353
2
US 60/819,014 filed on JULY_07_2006


392533
LOC392533
X
US 60/819,014 filed on JULY_07_2006


442237
LOC442237
6
US 60/867,454 filed on NOV_28_2006


23523
CABIN1
22 
US 60/867,454 filed on NOV_28_2006


648941
LOC648941
22 
US 60/867,454 filed on NOV_28_2006


4255
MGMT
10 
US 60/867,454 filed on NOV_28_2006


649173
LOC649173
17 
US 60/867,454 filed on NOV_28_2006


57143
ADCK1
14 
US 60/819,014 filed on JULY_07_2006


2048
EPHB2
1
US 60/867,454 filed on NOV_28_2006


55227
LRRC1
6
US 60/819,014 filed on JULY_07_2006


137868
SGCZ
8
US 11/245,248 filed on NOV2004-AUG2005


651758
LOC651758
2
US 60/867,454 filed on NOV_28_2006


63905
MANBAL
20 
US 60/867,454 filed on NOV_28_2006


3479
IGF1
12 
US 60/819,014 filed on JULY_07_2006


5475
PPEF1
X
US 60/867,454 filed on NOV_28_2006


1823
DSC1
18 
US 60/819,014 filed on JULY_07_2006


7748
ZNF195
11 
US 60/867,454 filed on NOV_28_2006


23129
PLXND1
3
US 60/867,454 filed on NOV_28_2006


200150
PLD5
1
US 60/867,454 filed on NOV_28_2006


7010
TEK
9
US 60/867,454 filed on NOV_28_2006


26280
IL1RAPL2
X
US 60/867,454 filed on NOV_28_2006


2175
FANCA
16 
US 60/867,454 filed on NOV_28_2006


55869
HDAC8
X
US 60/819,014 filed on JULY_07_2006


84623
KIRREL3
11 
US 60/867,454 filed on NOV_28_2006


81608
FIP1L1
4
US 60/819,014 filed on JULY_07_2006


9213
XPR1
1
US 60/867,454 filed on NOV_28_2006


9265
PSCD3
7
US 60/867,454 filed on NOV_28_2006


114781
BTBD9
6
US 60/867,454 filed on NOV_28_2006


401398
LOC401398
7
US 60/867,454 filed on NOV_28_2006


2334
AFF2
X
US 60/867,454 filed on NOV_28_2006


84056
KATNAL1
13 
US 60/867,454 filed on NOV_28_2006


610
HCN2
19 
US 60/867,454 filed on NOV_28_2006


2900
GRIK4
11 
US 60/867,454 filed on NOV_28_2006


6792
CDKL5
X
US 60/819,014 filed on JULY_07_2006


126917
LOC126917
1
US 60/867,454 filed on NOV_28_2006


154215
TCBA1
6
US 11/245,248 filed on NOV2004-AUG2005


158038
LRRN6C
9
US 11/245,248 filed on NOV2004-AUG2005


158521
FMR1NB
X
US 60/867,454 filed on NOV_28_2006


203062
TSNARE1
8
US 60/867,454 filed on NOV_28_2006


254065
BRODL
X
US 60/819,014 filed on JULY_07_2006


642216
LOC642216
5
US 60/867,454 filed on NOV_28_2006


219743
TYSND1
10 
US 60/819,014 filed on JULY_07_2006


389293
LOC389293
5
US 60/819,014 filed on JULY_07_2006


9705
ST18
8
US 60/867,454 filed on NOV_28_2006


55326
AGPAT5
8
US 60/867,454 filed on NOV_28_2006


23613
PRKCBP1
20 
US 60/819,014 filed on JULY_07_2006


83716
CRISPLD2
16 
US 60/867,454 filed on NOV_28_2006


653983
LOC653983
4
US 60/867,454 filed on NOV_28_2006


149134
LOC149134
1
US 60/819,014 filed on JULY_07_2006


170679
PSORS1C1
6
US 60/867,454 filed on NOV_28_2006


23041
KIAA1040
12 
US 60/867,454 filed on NOV_28_2006


222255
ATXN7L4
7
US 60/867,454 filed on NOV_28_2006


644055
LOC644055
2
US 60/867,454 filed on NOV_28_2006


392670
LOC392670
7
US 60/867,454 filed on NOV_28_2006


440193
LOC440193
14 
US 60/819,014 filed on JULY_07_2006


391475
LOC391475
2
US 60/867,454 filed on NOV_28_2006


9759
HDAC4
2
US 60/867,454 filed on NOV_28_2006


9962
SLC23A2
20 
US 60/867,454 filed on NOV_28_2006


10666
CD226
18 
US 60/867,454 filed on NOV_28_2006


3720
JARID2
6
US 60/867,454 filed on NOV_28_2006


1826
DSCAM
21 
US 60/819,014 filed on JULY_07_2006


285195
SLC9A9
3
US 60/819,014 filed on JULY_07_2006


392456
LOC392456
X
US 60/819,014 filed on JULY_07_2006


57624
KIAA1486
2
US 60/867,454 filed on NOV_28_2006


649120
LOC649120
5
US 60/867,454 filed on NOV_28_2006


386617
KCTD8
4
US 60/867,454 filed on NOV_28_2006


199920
C1orf168
1
US 60/867,454 filed on NOV_28_2006


10186
LHFP
13 
US 60/867,454 filed on NOV_28_2006


51084
CRYL1
13 
US 60/819,014 filed on JULY_07_2006


959
TNFSF5
X
US 60/819,014 filed on JULY_07_2006


11278
KLF12
13 
US 60/819,014 filed on JULY_07_2006


55289
ACOXL
2
US 60/819,014 filed on JULY_07_2006


8974
P4HA2
5
US 60/867,454 filed on NOV_28_2006


64839
FBXL17
5
US 11/245,248 filed on NOV2004-AUG2005


580
BARD1
2
US 11/245,248 filed on NOV2004-AUG2005


647489
LOC647489
18 
US 60/867,454 filed on NOV_28_2006


2272
FHIT
3
US 60/819,014 filed on JULY_07_2006


4745
NELL1
11 
US 11/245,248 filed on NOV2004-AUG2005


64420
SUSD1
9
US 60/867,454 filed on NOV_28_2006


441496
LOC441496
X
US 60/819,014 filed on JULY_07_2006


442457
LOC442457
X
US 60/819,014 filed on JULY_07_2006


122046
MGC40178
13 
US 60/867,454 filed on NOV_28_2006


27328
PCDH11X
X
US 60/819,014 filed on JULY_07_2006


81849
ST6GALNAC5
1
US 60/867,454 filed on NOV_28_2006


272
AMPD3
11 
US 60/867,454 filed on NOV_28_2006


84000
TMPRSS13
11 
US 60/867,454 filed on NOV_28_2006


3990
LIPC
15 
US 60/867,454 filed on NOV_28_2006


139163
LOC139163
X
US 60/867,454 filed on NOV_28_2006


390683
LOC390683
16 
US 60/819,014 filed on JULY_07_2006


1630
DCC
18 
US 60/819,014 filed on JULY_07_2006


10642
IMP-1
17 
US 60/867,454 filed on NOV_28_2006


9645
MICAL2
11 
US 60/867,454 filed on NOV_28_2006


26059
CAST1
3
US 60/867,454 filed on NOV_28_2006


57540
PTCHD2
1
US 60/867,454 filed on NOV_28_2006


79611
FLJ21963
12 
US 60/819,014 filed on JULY_07_2006


10345
TRDN
6
US 60/819,014 filed on JULY_07_2006


8548
BLZF1
1
US 60/867,454 filed on NOV_28_2006


5530
PPP3CA
4
US 60/867,454 filed on NOV_28_2006


375449
LOC375449
5
US 60/819,014 filed on JULY_07_2006


57533
TBC1D14
4
US 60/819,014 filed on JULY_07_2006


441062
LOC441062
5
US 60/819,014 filed on JULY_07_2006


3557
IL1RN
2
US 60/867,454 filed on NOV_28_2006


5144
PDE4D
5
US 60/867,454 filed on NOV_28_2006


23274
KIAA0350
16 
US 60/867,454 filed on NOV_28_2006


341350
OVCH1
12 
US 60/819,014 filed on JULY_07_2006


27075
TSPAN13
7
US 60/867,454 filed on NOV_28_2006


7068
THRB
3
US 60/867,454 filed on NOV_28_2006


9843
HEPH
X
US 60/867,454 filed on NOV_28_2006


84629
KIAA1856
7
US 60/819,014 filed on JULY_07_2006


152330
CNTN4
3
US 60/819,014 filed on JULY_07_2006


253582
C6orf191
6
US 60/867,454 filed on NOV_28_2006


408
ARRB1
11 
US 60/867,454 filed on NOV_28_2006


126859
C1orf125
1
US 60/867,454 filed on NOV_28_2006


23779
ARHGAP8
22 
US 60/867,454 filed on NOV_28_2006


651344
LOC651344
11 
US 60/867,454 filed on NOV_28_2006


85302
FBF1
17 
US 60/867,454 filed on NOV_28_2006


7204
TRIO
5
US 60/867,454 filed on NOV_28_2006


26577
PCOLCE2
3
US 60/867,454 filed on NOV_28_2006


5286
PIK3C2A
11 
US 60/867,454 filed on NOV_28_2006


27253
PCDH17
13 
US 60/819,014 filed on JULY_07_2006


90293
KLHL13
X
US 60/819,014 filed on JULY_07_2006


347694
ECEL1P2
2
US 60/867,454 filed on NOV_28_2006


1607
DGKB
7
US 60/819,014 filed on JULY_07_2006


463
ATBF1
16 
US 60/867,454 filed on NOV_28_2006


5119
PCOLN3
16 
US 60/867,454 filed on NOV_28_2006


124044
MGC26885
16 
US 60/867,454 filed on NOV_28_2006


283455
KSR2
12 
US 60/867,454 filed on NOV_28_2006


2185
PTK2B
8
US 60/819,014 filed on JULY_07_2006


254827
NAALADL2
3
US 60/819,014 filed on JULY_07_2006


79446
MGC4645
14 
US 11/245,248 filed on NOV2004-AUG2005


3760
KCNJ3
2
US 60/819,014 filed on JULY_07_2006


284186
TMEM105
17 
US 60/867,454 filed on NOV_28_2006


388790
LOC388790
20 
US 60/819,014 filed on JULY_07_2006


651301
LOC651301
3
US 60/867,454 filed on NOV_28_2006


22987
SV2C
5
US 60/867,454 filed on NOV_28_2006


254170
FBXO33
14 
US 60/867,454 filed on NOV_28_2006


11142
PKIG
20 
US 60/867,454 filed on NOV_28_2006


5167
ENPP1
6
US 60/867,454 filed on NOV_28_2006


29119
CTNNA3
10 
US 11/245,248 filed on NOV2004-AUG2005


5087
PBX1
1
US 60/867,454 filed on NOV_28_2006


1600
DAB1
1
US 11/245,248 filed on NOV2004-AUG2005


1770
DNAH9
17 
US 60/819,014 filed on JULY_07_2006


11141
IL1RAPL1
X
US 60/819,014 filed on JULY_07_2006


23005
MAPKBP1
15 
US 60/867,454 filed on NOV_28_2006


26984
SEC22L2
3
US 60/867,454 filed on NOV_28_2006


2888
GRB14
2
US 60/867,454 filed on NOV_28_2006


5651
PRSS7
21 
US 60/867,454 filed on NOV_28_2006


9628
RGS6
14 
US 60/867,454 filed on NOV_28_2006


649004
LOC649004
2
US 60/867,454 filed on NOV_28_2006


6928
TCF2
17 
US 60/867,454 filed on NOV_28_2006


8228
DXS1283E
X
US 60/819,014 filed on JULY_07_2006


84941
HSH2D
19 
US 60/867,454 filed on NOV_28_2006


648814
LOC648814
8
US 60/867,454 filed on NOV_28_2006


23072
HECW1
7
US 60/867,454 filed on NOV_28_2006


7498
XDH
2
US 60/867,454 filed on NOV_28_2006


79789
CLMN
14 
US 60/867,454 filed on NOV_28_2006


1012
CDH13
16 
US 11/245,248 filed on NOV2004-AUG2005


4685
NCAM2
21 
US 60/819,014 filed on JULY_07_2006


11043
MID2
X
US 60/819,014 filed on JULY_07_2006


51097
CGI-49
1
US 60/819,014 filed on JULY_07_2006


54777
C10orf92
10 
US 60/867,454 filed on NOV_28_2006


647525
LOC647525
10 
US 60/867,454 filed on NOV_28_2006


650079
LOC650079
9
US 60/867,454 filed on NOV_28_2006


104
ADARB1
21 
US 60/867,454 filed on NOV_28_2006


7402
UTRN
6
US 11/245,248 filed on NOV2004-AUG2005


57214
KIAA1199
15 
US 60/819,014 filed on JULY_07_2006


23012
STK38L
12 
US 60/867,454 filed on NOV_28_2006


642172
LOC642172
13 
US 60/867,454 filed on NOV_28_2006


28667
TRAV16
14 
US 60/867,454 filed on NOV_28_2006


7174
TPP2
13 
US 60/867,454 filed on NOV_28_2006


641864
LOC641864
7
US 60/867,454 filed on NOV_28_2006


170692
ADAMTS18
16 
US 60/819,014 filed on JULY_07_2006


652214
LOC652214
2
US 60/867,454 filed on NOV_28_2006


4281
MID1
X
US 60/867,454 filed on NOV_28_2006


4045
LSAMP
3
US 60/819,014 filed on JULY_07_2006


54868
TMEM104
17 
US 60/867,454 filed on NOV_28_2006


51696
HECA
6
US 60/867,454 filed on NOV_28_2006


2903
GRIN2A
16 
US 60/867,454 filed on NOV_28_2006


6862
T
6
US 11/245,248 filed on NOV2004-AUG2005


5332
PLCB4
20 
US 60/867,454 filed on NOV_28_2006


23362
PSD3
8
US 11/245,248 filed on NOV2004-AUG2005


56999
ADAMTS9
3
US 60/819,014 filed on JULY_07_2006


220108
FLJ30707
13 
US 60/867,454 filed on NOV_28_2006


55698
FLJ10324
7
US 60/867,454 filed on NOV_28_2006


55658
RNF126
19 
US 60/867,454 filed on NOV_28_2006


9731
GlyBP
1
US 60/867,454 filed on NOV_28_2006


2736
GLI2
2
US 60/819,014 filed on JULY_07_2006


154386
C6orf195
6
US 60/819,014 filed on JULY_07_2006


401548
SNX30
9
US 60/867,454 filed on NOV_28_2006


23095
KIF1B
1
US 60/867,454 filed on NOV_28_2006


4872
NPM1P3
16 
US 60/819,014 filed on JULY_07_2006


5579
PRKCB1
16 
US 60/819,014 filed on JULY_07_2006


23200
ATP11B
3
US 60/867,454 filed on NOV_28_2006


129684
CNTNAP5
2
US 60/819,014 filed on JULY_07_2006


414260
C10orf136
10 
US 60/867,454 filed on NOV_28_2006


648118
LOC648118
X
US 60/867,454 filed on NOV_28_2006


2863
GPR39
2
US 60/819,014 filed on JULY_07_2006


6563
SLC14A1
18 
US 60/867,454 filed on NOV_28_2006


64072
CDH23
10 
US 60/819,014 filed on JULY_07_2006


151742
PPM1L
3
US 60/867,454 filed on NOV_28_2006


5077
PAX3
2
US 60/819,014 filed on JULY_07_2006


441822
LOC441822
18 
US 60/819,014 filed on JULY_07_2006


2742
GLRA2
X
US 60/867,454 filed on NOV_28_2006


9957
HS3ST1
4
US 60/867,454 filed on NOV_28_2006


200132
TCTEX1D1
1
US 60/867,454 filed on NOV_28_2006


9899
SV2B
15 
US 60/867,454 filed on NOV_28_2006


10954
PDIA5
3
US 60/867,454 filed on NOV_28_2006


11102
RPP14
3
US 60/819,014 filed on JULY_07_2006


83893
SPATA16
3
US 60/867,454 filed on NOV_28_2006


1962
EHHADH
3
US 60/867,454 filed on NOV_28_2006


7290
HIRA
22 
US 60/819,014 filed on JULY_07_2006


6529
SLC6A1
3
US 60/867,454 filed on NOV_28_2006


285498
LOC285498
4
US 60/867,454 filed on NOV_28_2006


2917
GRM7
3
US 11/245,248 filed on NOV2004-AUG2005


79772
MCTP1
5
US 60/867,454 filed on NOV_28_2006


283682
LOC283682
15 
US 60/867,454 filed on NOV_28_2006


651419
LOC651419
5
US 60/867,454 filed on NOV_28_2006


9037
SEMA5A
5
US 60/819,014 filed on JULY_07_2006


9071
CLDN10
13 
US 60/819,014 filed on JULY_07_2006


6522
SLC4A2
7
US 60/819,014 filed on JULY_07_2006


26146
TRAF3IP1
2
US 11/245,248 filed on NOV2004-AUG2005


91582
MGC52010
22 
US 60/819,014 filed on JULY_07_2006


123355
LRRC28
15 
US 60/867,454 filed on NOV_28_2006


22874
PLEKHA6
1
US 60/867,454 filed on NOV_28_2006


57492
ARID1B
6
US 60/819,014 filed on JULY_07_2006


55714
ODZ3
4
US 60/867,454 filed on NOV_28_2006


1948
EFNB2
13 
US 60/867,454 filed on NOV_28_2006


128553
ZNF218
20 
US 60/867,454 filed on NOV_28_2006


28232
SLCO3A1
15 
US 11/245,248 filed on NOV2004-AUG2005


81792
ADAMTS12
5
US 11/245,248 filed on NOV2004-AUG2005


5794
PTPRH
19 
US 60/819,014 filed on JULY_07_2006


8828
NRP2
2
US 60/819,014 filed on JULY_07_2006


8997
HAPIP
3
US 11/245,248 filed on NOV2004-AUG2005


9369
NRXN3
14 
US 11/245,248 filed on NOV2004-AUG2005


51751
HIGD1B
17 
US 60/867,454 filed on NOV_28_2006


114792
KIAA1900
6
US 60/819,014 filed on JULY_07_2006


154796
AMOT
X
US 60/819,014 filed on JULY_07_2006


15Pt
MGC34646
8
US 60/867,454 filed on NOV_28_2006


400955
LOC400955
2
US 60/867,454 filed on NOV_28_2006


6870
TACR3
4
US 60/867,454 filed on NOV_28_2006


8139
GAN
16 
US 60/867,454 filed on NOV_28_2006


8760
CDS2
20 
US 60/867,454 filed on NOV_28_2006


64759
TNS3
7
US 60/867,454 filed on NOV_28_2006


1807
DPYS
8
US 60/867,454 filed on NOV_28_2006


152189
CKLFSF8
3
US 60/819,014 filed on JULY_07_2006


433
ASGR2
17 
US 60/867,454 filed on NOV_28_2006


3782
KCNN3
1
US 60/867,454 filed on NOV_28_2006


3607
FOXK2
17 
US 60/867,454 filed on NOV_28_2006


25913
POT1
7
US 60/867,454 filed on NOV_28_2006


57419
SLC24A3
20 
US 60/819,014 filed on JULY_07_2006


9180
OSMR
5
US 60/819,014 filed on JULY_07_2006


1002
CDH4
20 
US 60/867,454 filed on NOV_28_2006


57186
C20orf74
20 
US 60/867,454 filed on NOV_28_2006


11095
ADAMTS8
11 
US 60/867,454 filed on NOV_28_2006


55733
MART2
1
US 60/819,014 filed on JULY_07_2006


124045
C16orf55
16 
US 60/867,454 filed on NOV_28_2006


441284
LOC441284
7
US 60/819,014 filed on JULY_07_2006


54840
APTX
9
US 60/867,454 filed on NOV_28_2006


1010
CDH12
5
US 60/867,454 filed on NOV_28_2006


2918
GRM8
7
US 60/867,454 filed on NOV_28_2006


4211
MEIS1
2
US 60/819,014 filed on JULY_07_2006


9019
MPZL1
1
US 60/867,454 filed on NOV_28_2006


10246
SLC17A2
6
US 60/819,014 filed on JULY_07_2006


23170
KIAA0153
22 
US 60/867,454 filed on NOV_28_2006


22999
RIMS1
6
US 60/867,454 filed on NOV_28_2006


650912
LOC650912
13 
US 60/867,454 filed on NOV_28_2006


11262
SP140
2
US 60/819,014 filed on JULY_07_2006


9201
DCAMKL1
13 
US 60/867,454 filed on NOV_28_2006


253558
LYCAT
2
US 60/867,454 filed on NOV_28_2006


412
STS
X
US 60/867,454 filed on NOV_28_2006


10057
ABCC5
3
US 60/819,014 filed on JULY_07_2006


51760
SYT17
16 
US 60/867,454 filed on NOV_28_2006


392517
LOC392517
X
US 60/819,014 filed on JULY_07_2006


494118
SPANX-N1
X
US 60/867,454 filed on NOV_28_2006


1124
CHN2
7
US 60/867,454 filed on NOV_28_2006


648089
LOC648089
5
US 60/867,454 filed on NOV_28_2006


150946
LOC150946
2
US 60/819,014 filed on JULY_07_2006


152485
LOC152485
4
US 60/867,454 filed on NOV_28_2006


5218
PFTK1
7
US 60/867,454 filed on NOV_28_2006


245973
ATP6V1C2
2
US 60/867,454 filed on NOV_28_2006


6196
RPS6KA2
6
US 11/245,248 filed on NOV2004-AUG2005


137695
FLJ32370
8
US 60/819,014 filed on JULY_07_2006


51360
MBTPS2
X
US 60/819,014 filed on JULY_07_2006


80731
KIAA1679
2
US 60/867,454 filed on NOV_28_2006


5797
PTPRM
18 
US 11/245,248 filed on NOV2004-AUG2005


6483
SIAT4B
16 
US 60/819,014 filed on JULY_07_2006


26074
C20orf26
20 
US 60/867,454 filed on NOV_28_2006


84708
LNX
4
US 60/819,014 filed on JULY_07_2006


649035
LOC649035
12 
US 60/867,454 filed on NOV_28_2006


9111
NMI
2
US 60/867,454 filed on NOV_28_2006


83857
TMTC1
12 
US 60/819,014 filed on JULY_07_2006


92291
CAPN13
2
US 60/819,014 filed on JULY_07_2006


344595
LOC344595
3
US 60/867,454 filed on NOV_28_2006


2066
ERBB4
2
US 11/245,248 filed on NOV2004-AUG2005


647947
LOC647947
4
US 60/867,454 filed on NOV_28_2006


1395
CRHR2
7
US 60/867,454 filed on NOV_28_2006


2139
EYA2
20 
US 60/819,014 filed on JULY_07_2006


151258
FLJ39822
2
US 60/867,454 filed on NOV_28_2006


1385
CREB1
2
US 60/819,014 filed on JULY_07_2006


5688
PSMA7
20 
US 60/819,014 filed on JULY_07_2006


10052
GJA7
17 
US 60/867,454 filed on NOV_28_2006


55742
PARVA
11 
US 60/867,454 filed on NOV_28_2006


126410
FLJ39501
19 
US 60/819,014 filed on JULY_07_2006
















TABLE 2







SNP markers with the strongest association with HT in the individual marker analysis.


The analysis is based on 140 HT cases and 182 healthy controls from East Finland.















Gene locus









and


dbSNP rs ID
Gene ID
Chromosome
Position
Variats
Minor Allele
Allele X2
Odds ratio


















rs901185
FLJ34907
284222
18
10844509
‘C/T’
G
28.03
0.16


rs7328290


13
71394581
‘A/G’
A
21.53
3.16


rs12379069


9
24065368
‘C/T’
A
19.33
2.03


rs7931411
CNTN5
53942
11
99259555
‘A/G’
G
19.25
2.03


rs7814270


8
33590441
‘A/G’
A
18.58
2.01


rs10511739


9
24081342
‘A/G’
G
18.56
2.00


rs1910236


3
59409460
‘C/T’
A
17.98
1.97


rs7333943


13
58515848
‘G/T’
C
17.87
2.71


rs1938684


11
68986287
‘C/T’
A
17.30
2.21


rs2209902
PCDH9
5101
13
66600753
‘C/T’
A
17.12
2.34


rs6812187


4
21295968
‘C/T’
G
16.94
1.99


rs2824669


21
18457462
‘A/C’
C
16.88
1.95


rs1395000


4
85197861
‘A/G’
G
16.85
1.96


rs2290999
LOC400693
400693
19
42830727
‘A/G’
G
16.83
2.29


rs10107668


8
33643721
‘C/T’
G
16.48
1.97


rs2012192
C14orf49
161176
14
94998087
‘A/G’
A
16.37
0.42


rs7995254
PCDH9
5101
13
66501746
‘C/T’
G
16.31
2.56


rs4708483
SMOC2
64094
6
168865533
‘C/T’
A
15.87
2.11


rs3813577
BG1
23205
15
76314308
‘A/G’
G
15.84
0.51


rs501525
TNFRSF8
943
1
12115071
‘A/G’
G
15.77
1.89


rs2504070


6
152177087
‘C/T’
A
15.65
1.99


rs17517037
PCDH9
5101
13
66597199
‘C/T’
A
15.61
2.15


rs17560594
MAMDC1
161357
14
46530953
‘C/T’
G
15.57
2.38


rs3913663


4
21283866
‘G/T’
C
15.51
1.96


rs6896456


5
134605656
‘A/G’
A
15.38
2.94


rs1394139


4
21283327
‘C/T’
G
15.30
1.95


rs1370923


2
222825345
‘A/G’
A
15.23
2.54


rs7097635
LOC387648
387648
10
31000212
‘A/G’
G
15.09
1.86


rs915251


6
107579760
‘A/G’
A
15.06
1.86


rs10402423


19
1497180
‘A/G’
A
15.06
2.81


rs12673933
CNTNAP2
26047
7
147441753
‘C/T’
G
15.06
0.49


rs731489
KIAA1862
84626
7
148798930
‘A/G’
A
15.05
1.89


rs10518621


4
134122347
‘C/T’
A
15.00
0.44


rs1461656
LOC340156
340156
6
2661859
‘A/G’
A
14.87
0.31


rs759290
PPP5C
5536
19
51583951
‘C/T’
G
14.85
0.51


rs6568470
C6orf210
57107
6
107607740
‘A/G’
A
14.84
1.96


rs1453590
CNTN5
53942
11
99271543
‘A/C’
A
14.81
0.49


rs3739709
EDG2
1902
9
110717409
‘C/T’
A
14.78
0.43


rs4881232


10
3935400
‘A/C’
C
14.75
1.85


rs7901450


10
120200634
‘G/T’
C
14.69
1.86


rs9828674


3
64668140
‘G/T’
C
14.54
1.93


rs2239908
SARM1
23098
17
23749392
‘C/T’
A
14.52
0.53


rs3820623


1
224413997
‘C/T’
A
14.50
0.46


rs7984277


13
57299434
‘A/G’
G
14.29
4.04


rs6433781


2
180040816
‘C/T’
G
14.29
0.16


rs2167163


18
73004290
‘A/G’
A
14.28
3.19


rs6534907


4
134100931
‘C/T’
G
14.24
0.51


rs2836079


21
38276905
‘C/T’
G
14.24
0.50


rs11936235
LOC152742
152742
4
13794650
‘C/T’
A
14.24
2.71


rs7815570


8
135966827
‘C/T’
A
14.13
1.98


rs1389626
LOC387648
387648
10
31011114
‘A/G’
G
14.12
1.82


rs3780869
NRP1
8829
10
33587471
‘A/G’
A
14.11
0.21


rs16896934


4
17992019
‘C/T’
G
14.09
0.38


rs4848300


2
113244137
‘C/T’
G
14.04
0.52


rs3922562
SOX5
6660
12
24250132
‘C/T’
A
14.03
0.49


rs574322
HNT
50863
11
131326210
‘C/T’
A
14.01
2.03


rs2302080
CACNA1A
773
19
13217380
‘C/T’
G
13.99
1.82


rs906236


10
30891225
‘A/C’
A
13.93
1.90


rs686148
MICL
160364
12
10020961
‘C/T’
A
13.93
0.37


rs2214552


7
19548460
‘C/T’
G
13.93
1.85


rs7088506
LOC387648
387648
10
31022758
‘C/T’
G
13.92
1.85


rs17561
IL1A
3552
2
113253454
‘G/T’
A
13.88
0.52


rs12681358
COL22A1
169044
8
139794900
‘C/T’
A
13.88
2.27


rs2027993
SARM1
23098
17
23731073
‘A/C’
A
13.87
0.54


rs6844871


4
162268685
‘C/T’
A
13.81
1.86


rs4960948


8
87165300
‘A/G’
G
13.78
1.81


rs1549118
ADCK1
57143
14
77449437
‘C/T’
A
13.71
0.51


rs1538549


1
191736712
‘A/G’
A
13.71
2.21


rs7835385
COL22A1
169044
8
139778987
‘G/T’
C
13.68
2.27


rs1883632
LRRC1
55227
6
53888391
‘A/G’
A
13.67
1.82


rs17119719
SGCZ
137868
8
14436692
‘C/T’
G
13.67
1.81


rs741231
PPP5C
5536
19
51586003
‘A/C’
A
13.65
0.48


rs7098281


10
92897589
‘G/T’
C
13.64
0.43


rs7151137


14
94278193
‘C/T’
A
13.63
0.36


rs1992116
MMP2
4313
16
54085392
‘C/T’
A
13.57
0.54


rs3886870
PRKCE
5581
2
45954129
‘A/G’
A
13.56
0.41


rs7136446
IGF1
3479
12
101340982
‘C/T’
G
13.54
0.52


rs12886812
TTC7B
145567
14
90269540
‘C/T’
G
13.51
0.46


rs4360824


13
57707459
‘C/T’
A
13.50
1.80


rs9951631
DSC1
1823
18
26995905
‘C/T’
A
13.50
3.56


rs1445097


18
48008752
‘A/G’
A
13.48
1.83


rs1441669


4
29265718
‘A/G’
G
13.46
1.80


rs4684011


3
77600301
‘C/T’
A
13.46
0.54


rs2876263


6
135096061
‘C/T’
G
13.36
1.89


rs916351


20
45971417
‘A/G’
A
13.36
1.80


rs564127


7
79540870
‘C/T’
G
13.24
0.38


rs11725230
FIP1L1
81608
4
54153000
‘C/T’
A
13.23
0.54


rs10053765


5
99021831
‘C/T’
G
13.21
0.52


rs4686599


3
193327814
‘C/T’
G
13.17
0.24


rs4853186


2
76118450
‘C/T’
A
13.15
0.37


rs7791484


7
153594167
‘A/G’
G
13.14
1.78


rs264176


18
10891607
‘C/T’
A
13.11
0.40


rs10774863


12
115353876
‘C/T’
G
13.09
0.54


rs869636
NRP1
8829
10
33612045
‘C/T’
G
13.07
0.54


rs690901


5
18032928
‘C/T’
G
13.06
2.31


rs4746969
TYSND1
219743
10
71570195
‘G/T’
C
13.06
2.15


rs7641489


3
45263538
‘C/T’
A
13.06
0.36


rs2591797
LOC389293
389293
5
62113826
‘C/T’
G
13.03
0.54


rs6676641
PAPPA2
60676
1
173188880
‘G/T’
C
13.01
1.96


rs911946
SMOC2
64094
6
168861132
‘C/T’
G
12.99
2.30


rs2048005


4
85180915
‘A/C’
A
12.99
1.78


rs4855460


3
70229264
‘G/T’
A
12.99
0.36


rs761021
PRKCBP1
23613
20
45327366
‘C/T’
A
12.98
0.40


rs6694274
LOC149134
149134
1
243280207
‘A/G’
G
12.96
1.97


rs1499306


13
68030461
‘C/T’
A
12.94
0.52


rs4904117


14
83011020
‘A/G’
A
12.89
0.35


rs941763
LOC440193
440193
14
90890999
‘A/G’
A
12.85
0.33


rs674685


1
191863856
‘G/T’
A
12.84
2.16


rs7648557


3
64658255
‘G/T’
A
12.83
1.80


rs10508468
FRMD4A
55691
10
13958759
‘C/T’
G
12.82
1.84


rs2039183


9
111037906
‘A/C’
A
12.82
0.50


rs6782243
SLC9A9
285195
3
144891970
‘A/G’
G
12.77
1.77


rs732994


21
41155829
‘A/G’
G
12.77
0.56


rs1454635


9
2780307
‘C/T’
G
12.75
0.56


rs17403547


2
186117324
‘G/T’
C
12.72
4.30


rs2047141


10
31064141
‘C/T’
G
12.72
1.80


rs12146943
CRYL1
51084
13
19974875
‘A/G’
A
12.71
0.55


rs1324059
KLF12
11278
13
73241529
‘A/G’
A
12.62
0.54


rs12612914
ACOXL
55289
2
111383160
‘A/G’
A
12.60
2.01


rs12132639


1
61152188
‘A/G’
A
12.59
2.38


rs4709105


6
166586396
‘A/G’
A
12.56
1.77


rs9655857


7
125367411
‘C/T’
G
12.56
1.81


rs1474239


8
20904371
‘G/T’
C
12.55
1.92


rs10518848


15
67966716
‘A/G’
A
12.52
1.77


rs738519


22
35446851
‘C/T’
A
12.52
2.31


rs13417114
SEC15L2
23233
2
72344951
‘A/C’
A
12.49
0.51


rs717821
FHIT
2272
3
60490818
‘C/T’
G
12.45
2.30


rs8059561
LOC390683
390683
16
22107225
‘C/T’
G
12.43
2.04


rs1881586
FRMD4A
55691
10
13959631
‘C/T’
G
12.42
1.78


rs1219937


9
25891396
‘C/T’
A
12.41
2.28


rs7238242
DCC
1630
18
48276299
‘A/G’
G
12.41
1.76


rs10862248
FLJ21963
79611
12
80051990
‘G/T’
C
12.38
0.52


rs9320932
TRDN
10345
6
123786321
‘C/T’
G
12.36
1.81


rs10508274


10
4105602
‘A/G’
G
12.34
0.33


rs7040955


9
102050875
‘C/T’
A
12.34
0.50


rs6585465


10
119610549
‘C/T’
G
12.33
1.76


rs2697668


8
90964181
‘A/G’
G
12.32
1.86


rs257699
LOC375449
375449
5
66170467
‘A/G’
G
12.31
2.09


rs11939691
TBC1D14
57533
4
7101749
‘C/T’
A
12.30
1.76


rs1513089
LOC441062
441062
5
17965365
‘A/C’
C
12.30
2.19


rs2323218


6
166532508
‘C/T’
A
12.30
2.11


rs599140


1
191877580
‘C/T’
A
12.29
2.12


rs2642749
LOC389293
389293
5
62137231
‘A/G’
G
12.25
1.76


rs10492377
OVCH1
341350
12
29511714
‘C/T’
G
12.24
2.90


rs7791057
KIAA1856
84629
7
5205913
‘A/G’
G
12.22
1.82


rs2217228


12
9267916
‘C/T’
A
12.20
1.76


rs8130020


21
41154053
‘C/T’
A
12.18
1.75


rs7003452


8
35140966
‘A/G’
A
12.18
1.75


rs12274588


11
25733789
‘A/G’
A
12.17
0.33


rs2396104


7
108701750
‘C/T’
A
12.16
1.91


rs7930159


11
69133252
‘A/G’
A
12.13
1.79


rs2168908


4
181107283
‘C/T’
G
12.12
2.14


rs1850264


3
201067
‘A/G’
A
12.11
0.57


rs10891888


11
115123297
‘G/T’
A
12.11
1.92


rs12649451


4
172690498
‘C/T’
A
12.10
0.46


rs1389913


8
116231399
‘C/T’
A
12.10
2.49


rs3850970


12
31674144
‘C/T’
G
12.08
0.54


rs1879188
PTK2B
2185
8
27249840
‘G/T’
C
12.06
1.95


rs1879189
PTK2B
2185
8
27254801
‘A/G’
G
12.06
1.95


rs1461272
NAALADL2
254827
3
176362774
‘C/T’
A
12.06
1.75


rs10492602


13
57737145
‘G/T’
C
12.06
6.85


rs534230


6
143080834
‘A/G’
A
12.06
1.88


rs941924
MGC4645
79446
14
99962502
‘C/T’
A
12.04
0.56


rs6494794


15
31039019
‘C/T’
G
12.03
2.25


rs2839084


21
46269612
‘C/T’
G
12.02
1.77


rs1838674
KCNJ3
3760
2
155477049
‘A/G’
G
12.02
2.45


rs12481484
LOC388790
388790
20
19730668
‘A/G’
A
12.01
0.39


rs6751378


2
78014623
‘C/T’
G
12.01
1.74


rs11771128


7
111669244
‘A/G’
A
12.00
2.06


rs2164349


3
179018450
‘A/G’
G
11.99
0.49


rs911491


9
4232464
‘A/G’
G
11.99
1.80


rs9373941
C6orf210
57107
6
107758722
‘C/T’
G
11.98
0.53


rs10798460
PAPPA2
60676
1
173215774
‘A/G’
A
11.94
2.42


rs852766
DAB1
1600
1
57998529
‘A/G’
G
11.94
1.74


rs11712613


3
67384940
‘A/G’
G
11.94
1.74


rs11655963
DNAH9
1770
17
11605556
‘A/G’
A
11.94
2.04


rs431474


19
22020632
‘C/T’
A
11.93
1.73


rs6538861


12
97252571
‘C/T’
G
11.93
2.48


rs9285195


13
53568213
‘C/T’
G
11.93
0.53


rs10852366


16
13458041
‘C/T’
A
11.93
0.56


rs1332879


9
80921182
‘C/T’
G
11.91
0.55


rs16931920


9
14533181
‘A/C’
C
11.91
3.11


rs9586037


13
102469005
‘G/T’
A
11.90
0.23


rs4952779
PRKCE
5581
2
45972026
‘A/G’
A
11.89
1.75


rs1880787


3
39792498
‘C/T’
G
11.87
2.38


rs11138526


9
80005011
‘G/T’
A
11.87
2.38


rs7151991


14
31705323
‘A/G’
A
11.84
0.51


rs1507198


13
68131600
‘C/T’
G
11.81
1.74


rs7630843


3
198681
‘C/T’
G
11.81
1.85


rs9307048


4
89506749
‘C/T’
A
11.81
1.85


rs2034875


9
20209315
‘C/T’
A
11.79
0.51


rs4268714


15
29462745
‘A/G’
G
11.77
0.55


rs4131501
UTRN
7402
6
145115486
‘C/T’
G
11.76
0.45


rs7195117


16
13520820
‘A/G’
A
11.76
1.74


rs3892145
TBC1D14
57533
4
7112156
‘C/T’
G
11.75
1.73


rs10771858


12
31669994
‘A/G’
G
11.75
1.73


rs758896
FLJ32110
219578
7
88491181
‘A/C’
C
11.75
1.73


rs12372944
KIAA1199
57214
15
78922504
‘C/T’
A
11.75
1.89


rs2396274


2
226715533
‘A/G’
A
11.74
1.99


rs6800226


3
193336351
‘C/T’
G
11.74
0.26


rs2839081


21
46265743
‘C/T’
G
11.73
1.73


rs7613237


3
185223836
‘C/T’
G
11.71
2.30


rs632912


18
8457707
‘A/G’
A
11.71
4.92


rs13052628


21
41330970
‘C/T’
A
11.71
4.92


rs4559036


5
160209255
‘A/C’
C
11.71
2.41


rs41386
SEC15L2
23233
2
72341431
‘A/G’
G
11.69
0.50


rs2062206


2
67448093
‘G/T’
C
11.69
0.57


rs6966462


7
153595086
‘G/T’
C
11.68
1.88


rs1978628
ADAMTS18
170692
16
76002114
‘A/G’
G
11.67
0.48


rs10516437


4
100147223
‘A/G’
G
11.66
0.56


rs3092526
PRKCBP1
23613
20
45290615
‘A/G’
G
11.65
0.43


rs1594693


19
37309839
‘C/T’
A
11.64
1.78


rs11637685
KIAA1199
57214
15
78936022
‘C/T’
A
11.63
2.53


rs4941343


18
61347817
‘A/G’
G
11.61
2.23


rs10867485


9
80104890
‘A/G’
G
11.61
2.03


rs4240161
LSAMP
4045
3
117137111
‘A/G’
A
11.61
0.57


rs199253


6
143366889
‘C/T’
A
11.58
1.72


rs2278677
T
6862
6
166546198
‘C/T’
A
11.57
2.05


rs10175158
PRKCE
5581
2
45965912
‘C/T’
A
11.56
1.72


rs10175198
PRKCE
5581
2
45965765
‘A/G’
A
11.56
1.72


rs4953266
PRKCE
5581
2
45965664
‘A/G’
G
11.56
1.72


rs6789298
ADAMTS9
56999
3
64648855
‘C/T’
A
11.56
2.06


rs1458669


4
181122612
‘C/T’
A
11.56
2.06


rs1993546


4
70020652
‘C/T’
A
11.54
0.51


rs4965671


15
98905466
‘A/G’
G
11.54
2.08


rs9347108


6
166557484
‘A/G’
A
11.53
2.14


rs895491
GLI2
2736
2
121295057
‘A/G’
G
11.52
0.57


rs12652513


5
99057352
‘A/G’
G
11.51
0.33


rs10489477
PAPPA2
60676
1
173294265
‘C/T’
A
11.49
2.26


rs131003


22
47485954
‘G/T’
A
11.49
0.41


rs12770610
CDH23
64072
10
72876293
‘C/T’
G
11.48
1.72


rs4284884
GPR39
2863
2
133087118
‘A/G’
G
11.48
0.56


rs2561642


5
18135523
‘C/T’
A
11.48
1.73


rs1503994


4
21289743
‘C/T’
A
11.47
1.92


rs10498134
PAX3
5077
2
222930485
‘C/T’
G
11.47
1.72


rs2135845


17
6787797
‘C/T’
G
11.47
1.72


rs575291
LOC441822
441822
18
63653262
‘C/T’
A
11.46
2.44


rs7775153


6
137827982
‘C/T’
A
11.45
0.53


rs4689558
TBC1D14
57533
4
7038538
‘A/G’
G
11.44
1.72


rs17661314
FHIT
2272
3
60462114
‘A/C’
C
11.44
2.00


rs421239


5
172955019
‘A/G’
A
11.44
0.57


rs997448


3
64935253
‘A/G’
G
11.42
2.51


rs706411
DAB1
1600
1
58004642
‘A/G’
A
11.42
0.58


rs13094898
RPP14
11102
3
58265183
‘A/G’
A
11.41
0.36


rs4749567


10
30885044
‘A/G’
A
11.40
1.76


rs9958350


18
69134108
‘A/G’
G
11.38
1.79


rs9618567
HIRA
7290
22
17788260
‘C/T’
A
11.38
3.79


rs243842
MMP2
4313
16
54084923
‘C/T’
G
11.36
1.71


rs1470964


8
115871388
‘A/G’
A
11.34
1.73


rs421548
SEMA5A
9037
5
9561979
‘C/T’
A
11.33
2.46


rs10514626


2
19419621
‘A/G’
A
11.33
2.46


rs4246958


11
68968411
‘C/T’
G
11.31
1.71


rs7984974
CLDN10
9071
13
94926858
‘A/G’
G
11.31
1.71


rs2303933
SLC4A2
6522
7
150204447
‘A/G’
A
11.30
1.79


rs1109793
MGC52010
91582
22
38254446
‘C/T’
G
11.30
1.79


rs11847484


14
95515268
‘A/G’
G
11.30
0.39


rs287871
ARID1B
57492
6
157293419
‘C/T’
G
11.29
1.71


rs6494940


15
69592172
‘A/G’
G
11.28
2.22


rs246565


5
71845003
‘A/C’
A
11.27
0.48


rs246580


5
71851370
‘C/T’
A
11.27
0.48


rs1462404


5
99102291
‘C/T’
G
11.22
0.38


rs7652210
CKLFSF8
152189
3
32364379
‘C/T’
A
11.22
1.85


rs7283829


21
46252267
‘A/G’
A
11.21
1.74


rs11775958
PTK2B
2185
8
27325801
‘G/T’
C
11.19
1.93


rs171508


8
54081989
‘C/T’
G
11.19
1.77


rs4752130


10
119678690
‘C/T’
G
11.18
0.57


rs7747120


6
52706541
‘A/G’
A
11.17
5.44


rs4763736


12
11964019
‘C/T’
G
11.17
1.73


rs4921165


5
160212958
‘G/T’
C
11.16
2.21


rs1399130


4
28257074
‘A/G’
G
11.14
1.70


rs11225285


11
101883403
‘C/T’
A
11.14
2.72


rs420444
OSMR
9180
5
38893123
‘A/C’
C
11.14
1.90


rs908720


2
226720486
‘A/G’
G
11.11
1.94


rs7554508
MART2
55733
1
207025945
‘C/T’
A
11.11
1.71


rs1005516
LOC441284
441284
7
140267483
‘C/T’
A
11.11
1.70


rs9346693


6
168566847
‘A/C’
C
11.10
1.71


rs3890755
MEIS1
4211
2
66656254
‘C/T’
G
11.07
1.70


rs6540951


1
10813991
‘A/G’
A
11.07
0.42


rs6940007
SLC17A2
10246
6
26039936
‘A/C’
C
11.06
4.31


rs878554


14
93675932
‘C/T’
A
11.06
0.52


rs11743832


5
51230147
‘C/T’
G
11.06
0.57


rs11630449


15
29402033
‘C/T’
G
11.05
0.50


rs8074227


17
12484440
‘G/T’
C
11.01
1.84


rs1223016


4
172618238
‘A/G’
G
11.00
0.58


rs4665830
LOC150946
150946
2
26310865
‘A/G’
G
11.00
0.58


rs4446382


4
135263866
‘A/G’
A
10.98
0.50


rs11780975


8
103536662
‘A/C’
A
10.98
0.12


rs10501022


11
25712397
‘C/T’
G
10.98
0.33


rs6997351
FLJ32370
137695
8
56814300
‘A/G’
G
10.98
0.57


rs7027886


9
2788358
‘A/C’
A
10.97
0.59


rs11647932
SIAT4B
6483
16
69022319
‘C/T’
A
10.95
2.27


rs12325419


16
68926410
‘A/G’
A
10.95
2.27


rs10503533


8
15030038
‘A/G’
G
10.95
1.82


rs7151110
TTC7B
145567
14
90222235
‘C/T’
G
10.95
0.49


rs7603494


2
47815747
‘C/T’
G
10.95
1.70


rs6937983
C6orf210
57107
6
107773941
‘A/G’
A
10.95
1.70


rs7981816


13
71540844
‘A/G’
G
10.93
2.99


rs6769747
CHL1
10752
3
219949
‘A/G’
G
10.91
2.50


rs4864767
LNX
84708
4
54208064
‘A/G’
A
10.91
0.57


rs1517927


3
64977356
‘A/G’
A
10.89
1.99


rs9679386
CAPN13
92291
2
30864638
‘C/T’
A
10.89
0.57


rs32790


5
35466853
‘A/G’
G
10.88
0.30


rs9350132


6
19498105
‘C/T’
A
10.88
2.22


rs2178531


12
11512616
‘C/T’
G
10.87
0.34


rs3733787


5
5131313
‘A/G’
A
10.87
1.72


rs2279307


12
83190484
‘C/T’
G
10.86
0.45


rs6561970


13
58021020
‘A/G’
G
10.86
0.46


rs1384394


2
213664375
‘C/T’
A
10.86
2.64


rs12653539


5
98501952
‘A/C’
C
10.86
0.07


rs10483395


14
31708664
‘A/G’
A
10.85
2.01


rs7872903


9
133513846
‘C/T’
G
10.85
0.47


rs1809366


15
31051600
‘A/G’
G
10.84
0.52


rs899466


15
31051493
‘A/G’
G
10.84
0.52


rs41420


2
72313909
‘C/T’
A
10.84
0.52


rs13078878


3
64980991
‘C/T’
G
10.83
2.17


rs2593430
CAPN13
92291
2
30863635
‘C/T’
G
10.83
0.59


rs2233696
PLP1
5354
X
102846545
‘C/T’
G
23.15
2.22


rs5909473


X
18179407
‘A/G’
G
18.82
2.78


rs2765386
DMD
1756
X
32825545
‘C/T’
G
18.56
0.39


rs2366517


X
136785639
‘C/T’
G
18.22
2.01


rs3007187


X
112965574
‘A/G’
A
17.22
0.47


rs12012576


X
21572835
‘A/G’
G
17.10
0.48


rs2366513


X
136776197
‘A/G’
G
16.73
1.95


rs10521502


X
102861176
‘A/G’
A
16.57
2.16


rs5978303


X
9008007
‘A/G’
G
16.37
1.97


rs5910338


X
117242500
‘C/T’
G
16.23
3.30


rs5910340


X
117247923
‘C/T’
G
16.23
3.30


rs2765385
DMD
1756
X
32823299
‘A/G’
A
15.67
0.41


rs4827759


X
143796824
‘A/G’
A
15.56
2.17


rs616364
GRIA3
2892
X
122315581
‘A/G’
G
15.53
2.10


rs12558663


X
98465719
‘G/T’
A
15.50
19.07


rs6418743


X
21541534
‘C/T’
G
15.24
0.53


rs4503212
RGN
9104
X
46697712
‘A/G’
G
14.75
0.47


rs2886700


X
136747068
‘C/T’
G
14.56
1.85


rs2031556
DMD
1756
X
32837563
‘C/T’
A
14.52
0.50


rs2814862
DMD
1756
X
32821726
‘A/C’
A
14.39
0.44


rs5987579


X
102817760
‘A/C’
A
14.39
1.87


rs5937060


X
70024726
‘C/T’
G
14.15
1.85


rs12840573
TNRC11
9968
X
70121139
‘A/G’
A
13.85
3.77


rs6527253
DMD
1756
X
32838651
‘C/T’
G
13.67
0.50


rs2313032


X
25506084
‘A/G’
A
13.47
1.83


rs3012658
HDAC8
55869
X
71349766
‘C/T’
G
13.26
0.06


rs7880245


X
5238573
‘C/T’
A
13.17
1.87


rs4460510


X
145845745
‘G/T’
A
13.15
1.81


rs7058356


X
5252012
‘A/G’
G
13.12
1.99


rs3922743


X
13910650
‘A/G’
G
12.99
1.78


rs2813809


X
146355970
‘A/G’
A
12.94
0.53


rs2622953


X
121245542
‘G/T’
A
12.81
0.15


rs1936648
LOC392456
392456
X
45905900
‘A/G’
G
12.77
2.51


rs5951469


X
21608265
‘C/T’
A
12.70
0.56


rs3092921
TNFSF5
959
X
135468520
‘C/T’
A
12.63
0.23


rs6627187


X
150623478
‘C/T’
G
12.52
1.80


rs2574054
PCDH11X
27328
X
91385669
‘A/G’
A
12.50
1.76


rs7878576


X
21596302
‘A/G’
A
12.36
1.75


rs5905269


X
115300034
‘A/C’
A
12.26
0.54


rs1573036


X
109626213
‘A/G’
A
12.16
0.56


rs5942651


X
109633767
‘A/G’
G
12.16
0.56


rs475827
PLP1
5354
X
102836217
‘C/T’
A
12.13
0.50


rs845188


X
140102408
‘A/G’
G
12.06
1.75


rs986342
IL1RAPL1
11141
X
28601486
‘G/T’
A
11.94
2.60


rs2240584
DXS1283E
8228
X
7693630
‘A/G’
A
11.84
1.76


rs4585878


X
44967214
‘A/G’
G
11.79
0.55


rs5931268


X
136791119
‘G/T’
A
11.72
0.56


rs6527813


X
13298834
‘C/T’
A
11.70
0.48


rs5969826


X
150622572
‘A/G’
G
11.69
1.76


rs2761647


X
95078803
‘A/C’
C
11.45
0.31


rs4911823


X
114478198
‘C/T’
G
11.45
1.76


rs1401413


X
113553486
‘A/G’
A
11.18
0.24


rs5945988


X
113542162
‘A/G’
A
11.18
0.24


rs5934569


X
9088619
‘G/T’
A
11.18
0.48


rs845127


X
7635061
‘A/G’
A
11.15
0.35


rs2071211
MBTPS2
51360
X
21629701
‘A/G’
A
10.97
0.59


rs1560517


X
13297246
‘A/G’
A
10.96
0.54


rs4829455
AMOT
154796
X
111870035
‘A/C’
A
10.95
2.27


rs10465305


X
87621994
‘A/G’
A
10.90
0.51


rs4828697


X
151337295
‘C/T’
G
10.85
2.20





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Sequence_ID: Sequence identification number


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


Minor Allele: SNP allele or its complementary nucleotide that is less common in the control population.


Allele_X2: Chi-squared test based on allele frequencies


Odds ratio: Calculated for the minor allele.


Gene_content: Genes positioned within 100 Kbp up and downstream from the physical position of the SNPs based on NCBI Human Genome Build 36.1













TABLE 3







Haplotype genomic regions with the strongest association with HT in the


haplotype sharing analysis (HaploRec + HPM) with 8 SNPs. The analysis


is based on 140 HT cases and 182 healthy controls from East Finland.













Gene locus







and


dbSNP rs ID
Gene ID
Chromosome
Position
Variats
P value
















rs6676641
PAPPA2
60676
1
173188880
‘G/T’
0.0003


rs12084712
PAPPA2
60676
1
173214758
‘A/G’
<0.0001


rs10798460
PAPPA2
60676
1
173215774
‘A/G’
<0.0001


rs11801416
PAPPA2
60676
1
173223334
‘C/T’
<0.0001


rs2206509
PAPPA2
60676
1
173238947
‘C/T’
0.0004


rs2901091


2
72294583
‘C/T’
0.0006


rs975612


2
72300989
‘A/C’
0.0002


rs41420


2
72313909
‘C/T’
0.0001


rs41419
SEC15L2
23233
2
72314465
‘A/G’
0.0001


rs41402
SEC15L2
23233
2
72330710
‘A/C’
0.0001


rs41386
SEC15L2
23233
2
72341431
‘A/G’
<0.0001


rs194235
SEC15L2
23233
2
72342517
‘A/G’
<0.0001


rs13417114
SEC15L2
23233
2
72344951
‘A/C’
0.0003


rs7565922
SEC15L2
23233
2
72353375
‘A/G’
0.0006


rs11897719
SLC16A14
151473
2
230754953
‘C/T’
0.0002


rs12475755


2
230761259
‘A/G’
<0.0001


rs4613264


2
230768956
‘A/G’
<0.0001


rs12162384


2
230785037
‘A/C’
0.0001


rs7599215


2
230786451
‘G/T’
0.0001


rs12694836


2
230813653
‘A/G’
0.0001


rs6436908


2
230820952
‘C/T’
0.0002


rs6764952


3
178984873
‘A/C’
0.0006


rs4857745


3
178988464
‘C/T’
0.0001


rs1984961


3
178992805
‘A/G’
<0.0001


rs1004448


3
178992971
‘C/T’
0.0001


rs2863060


3
178997416
‘A/G’
0.0001


rs4857746


3
179003470
‘C/T’
0.0002


rs7651231


3
179007870
‘A/G’
0.0001


rs9861373


3
179010065
‘A/G’
<0.0001


rs4857747


3
179014549
‘C/T’
<0.0001


rs2164349


3
179018450
‘A/G’
<0.0001


rs7641262


3
179025554
‘C/T’
<0.0001


rs1561030


3
179034481
‘A/G’
<0.0001


rs4857750


3
179047846
‘A/G’
<0.0001


rs10936959


3
179073776
‘A/G’
0.0001


rs7612209


3
179079691
‘A/G’
0.001


rs6534907


4
134100931
‘C/T’
0.0009


rs1868251


4
134112404
‘A/G’
0.0001


rs10518621


4
134122347
‘C/T’
<0.0001


rs10518622


4
134122952
‘A/G’
0.0006


rs10486903
FLJ32110
219578
7
88427903
‘C/T’
0.0008


rs10486904
FLJ32110
219578
7
88429704
‘G/T’
0.0006


rs10486905
FLJ32110
219578
7
88435260
‘C/T’
0.0001


rs2189052
FLJ32110
219578
7
88438850
‘C/T’
0.0002


rs720142
FLJ32110
219578
7
88444330
‘A/G’
<0.0001


rs2214339
FLJ32110
219578
7
88457940
‘A/G’
<0.0001


rs7799723
FLJ32110
219578
7
88458675
‘C/T’
0.0003


rs7844565
COL22A1
169044
8
139755924
‘C/T’
0.0005


rs7839680
COL22A1
169044
8
139762863
‘A/G’
0.0002


rs4909443
COL22A1
169044
8
139770093
‘A/G’
0.0001


rs4909444
COL22A1
169044
8
139770391
‘G/T’
<0.0001


rs7835385
COL22A1
169044
8
139778987
‘G/T’
<0.0001


rs4243905
COL22A1
169044
8
139783913
‘A/G’
<0.0001


rs4074052
COL22A1
169044
8
139785008
‘C/T’
<0.0001


rs11166837
COL22A1
169044
8
139791315
‘C/T’
<0.0001


rs12681358
COL22A1
169044
8
139794900
‘C/T’
0.0001


rs9324493
COL22A1
169044
8
139797163
‘A/G’
0.0008


rs10509845


10
109510824
‘C/T’
0.0005


rs2418977


10
109511578
‘G/T’
0.0004


rs7912221


10
109515057
‘A/C’
0.0002


rs2900778


10
109517065
‘A/C’
0.0002


rs2418976


10
109529198
‘A/C’
<0.0001


rs4431961


10
109529269
‘C/T’
<0.0001


rs2900784


10
109539457
‘A/C’
0.0002


rs1025888
CNTN5
53942
11
99252539
‘A/G’
0.0002


rs7931411
CNTN5
53942
11
99259555
‘A/G’
0.0001


rs10501927
CNTN5
53942
11
99262939
‘G/T’
<0.0001


rs1971156
CNTN5
53942
11
99263024
‘C/T’
<0.0001


rs1453590
CNTN5
53942
11
99271543
‘A/C’
0.0003


rs2769556


13
67976305
‘A/G’
0.0005


rs9541407


13
67978683
‘G/T’
0.0003


rs1240891


13
67980008
‘A/C’
0.0002


rs904510


13
67986542
‘C/T’
0.0002


rs7997100


13
67988075
‘C/T’
0.0004


rs12184778


13
68006426
‘A/G’
0.0002


rs976211


13
68016099
‘A/C’
0.0003


rs17557736


13
68027160
‘A/G’
0.0002


rs9571951


13
68030249
‘C/T’
0.0002


rs1499306


13
68030461
‘C/T’
<0.0001


rs2248276


13
68033135
‘A/G’
0.0001


rs9541444


13
68045251
‘C/T’
0.0002


rs287312


13
68069581
‘A/G’
0.0004


rs287320


13
68073566
‘G/T’
0.0004


rs287327


13
68076868
‘A/G’
0.0003


rs10507750


13
68079566
‘A/G’
0.0002


rs287409


13
68103919
‘A/G’
0.0002


rs9541476


13
68110347
‘C/T’
0.0003


rs7151991


14
31705323
‘A/G’
0.0002


rs10483395


14
31708664
‘A/G’
0.0001


rs17098539


14
31711014
‘G/T’
<0.0001


rs4476082


14
31722876
‘A/C’
0.0003


rs2147829
TTC7B
145567
14
90233622
‘C/T’
0.0004


rs3814841
TTC7B
145567
14
90234219
‘C/T’
0.0003


rs1742098
TTC7B
145567
14
90238170
‘C/T’
0.0002


rs1749704
TTC7B
145567
14
90239107
‘G/T’
<0.0001


rs1535321
TTC7B
145567
14
90240579
‘C/T’
<0.0001


rs1749718
TTC7B
145567
14
90253080
‘C/T’
<0.0001


rs1742083
TTC7B
145567
14
90256423
‘C/T’
<0.0001


rs8018904
TTC7B
145567
14
90259730
‘G/T’
0.0001


rs12886812
TTC7B
145567
14
90269540
‘C/T’
0.0001


rs730043
TTC7B
145567
14
90279368
‘G/T’
0.0005


rs7158495
TTC7B
145567
14
90281628
‘C/T’
0.0005


rs1535188
C14orf49
161176
14
94997166
‘C/T’
0.0006


rs2012192
C14orf49
161176
14
94998087
‘A/G’
<0.0001


rs3783290
C14orf49
161176
14
94999953
‘G/T’
0.0006


rs9302671
MMP2
4313
16
54079226
‘G/T’
0.001


rs243842
MMP2
4313
16
54084923
‘C/T’
0.0001


rs1992116
MMP2
4313
16
54085392
‘C/T’
<0.0001


rs243840
MMP2
4313
16
54085660
‘A/G’
0.0001


rs243834
MMP2
4313
16
54094188
‘A/G’
0.0007


rs6142710


20
60091799
‘A/G’
<0.0001


rs6142711


20
60095481
‘A/G’
<0.0001


rs6142946


20
60106460
‘G/T’
<0.0001


rs2038687
C20orf40
149986
20
60140435
‘C/T’
0.0001


rs2057169
PSMA7
5688
20
60145679
‘C/T’
0.001


rs7892324


X
6529033
‘C/T’
0.0005


rs6638625


X
6562245
‘A/G’
0.0002


rs6639674


X
6568014
‘A/G’
<0.0001


rs968021


X
18136978
‘G/T’
0.0003


rs5955619


X
18137779
‘A/G’
0.0001


rs5909473


X
18179407
‘A/G’
<0.0001


rs5955621
CDKL5
6792
X
18209165
‘A/G’
0.0003


rs2061249
DMD
1756
X
32077365
‘C/T’
0.0004


rs331322
DMD
1756
X
32077588
‘A/G’
<0.0001


rs331321
DMD
1756
X
32078204
‘A/G’
<0.0001


rs331320
DMD
1756
X
32078628
‘C/T’
<0.0001


rs5927962
DMD
1756
X
32081017
‘C/T’
0.0001


rs331318
DMD
1756
X
32084123
‘C/T’
0.0004


rs483812


X
102802880
‘C/T’
<0.0001


rs568707


X
102813341
‘C/T’
<0.0001


rs5987579


X
102817760
‘A/C’
<0.0001


rs554412


X
102821525
‘C/T’
<0.0001


rs475827
PLP1
5354
X
102836217
‘C/T’
<0.0001


rs521895
PLP1
5354
X
102842557
‘A/G’
<0.0001


rs2233696
PLP1
5354
X
102846545
‘C/T’
<0.0001


rs2294152
PLP1
5354
X
102849879
‘G/T’
<0.0001


rs10521502


X
102861176
‘A/G’
0.0001


rs5942641


X
109549379
‘A/G’
0.0007


rs1573036


X
109626213
‘A/G’
<0.0001


rs5942651


X
109633767
‘A/G’
<0.0001


rs197023
CHRDL1
91851
X
109774532
‘C/T’
0.0001


rs12689346
CHRDL1
91851
X
109810107
‘C/T’
0.0004


rs5985312


X
110000370
‘A/G’
0.0007


rs5910156


X
116445879
‘C/T’
0.0004


rs5912022


X
116457000
‘C/T’
<0.0001


rs6646995


X
116468033
‘G/T’
<0.0001


rs5958727


X
116515613
‘C/T’
0.0004


rs742217


X
136286956
‘A/G’
0.0003


rs2859257


X
136309117
‘A/G’
<0.0001


rs6635446


X
136326022
‘C/T’
0.0001


rs6635777


X
137993914
‘G/T’
0.0002


rs5974805


X
137998316
‘A/G’
0.0001


rs12558495


X
138027981
‘C/T’
<0.0001


rs5974808


X
138035117
‘A/G’
0.0002


rs2813808


X
146353663
‘A/G’
0.0006


rs5951805


X
146353775
‘C/T’
<0.0001


rs2813809


X
146355970
‘A/G’
<0.0001


rs7890402


X
146360070
‘A/G’
0.0001


rs742581


X
149201394
‘C/T’
0.0005


rs614511


X
149208402
‘A/G’
0.0001


rs5925535


X
149210151
‘C/T’
<0.0001


rs693913


X
149212422
‘C/T’
<0.0001


rs10776290


X
149224831
‘A/C’
0.0001


rs5924915


X
149231128
‘A/G’
0.0002


rs2814855
DMD
1756
X
32813402
‘C/T’
0.0008


rs2814862
DMD
1756
X
32821726
‘A/C’
0.0001


rs2765385
DMD
1756
X
32823299
‘A/G’
0.0002


rs982767
DMD
1756
X
32824337
‘C/T’
0.0004


rs2765386
DMD
1756
X
32825545
‘C/T’
0.0003


rs2031554
DMD
1756
X
32833444
‘C/T’
0.0002


rs2031556
DMD
1756
X
32837563
‘C/T’
0.0001


rs6527253
DMD
1756
X
32838651
‘C/T’
0.0002


rs6624142
LOC441496
441496
X
64188190
‘C/T’
0.0004


rs10465337


X
64806428
‘A/G’
0.0001


rs5918959


X
64810327
‘C/T’
0.0001


rs2366551


X
136746208
‘C/T’
0.0005


rs2886700


X
136747068
‘C/T’
0.0002


rs2366513


X
136776197
‘A/G’
0.0001


rs2366517


X
136785639
‘C/T’
0.0001


rs5931268


X
136791119
‘G/T’
0.0002


rs5931272


X
136803377
‘A/G’
0.001


rs1551504


X
136807832
‘A/C’
0.001


rs1560303


X
136813658
‘A/G’
0.0007


rs6528506


X
136827208
‘C/T’
0.0005


rs5929877


X
136854327
‘A/G’
0.0004


rs11795896


X
136865816
‘C/T’
0.0005


rs12556519


X
136867643
‘G/T’
0.0004


rs6635565


X
136889896
‘C/T’
0.0008


rs5929883


X
136902901
‘C/T’
0.0009


rs585602


X
136922918
‘A/G’
0.0009


rs5936254


X
148064327
‘C/T’
0.0006


rs764908


X
148082914
‘C/T’
0.0001


rs12859656


X
148095061
‘A/G’
0.0001


rs1882731


X
148111861
‘C/T’
0.0003


rs9698926


X
149093381
‘C/T’
0.0001


rs4953260
PRKCE
5581
2
45945370
‘C/T’
0.0007


rs4953262
PRKCE
5581
2
45952444
‘A/G’
0.0005


rs3886870
PRKCE
5581
2
45954129
‘A/G’
0.0001


rs935672
PRKCE
5581
2
45957610
‘C/T’
0.0003


rs4953266
PRKCE
5581
2
45965664
‘A/G’
0.0001


rs10175198
PRKCE
5581
2
45965765
‘A/G’
0.0001


rs10175158
PRKCE
5581
2
45965912
‘C/T’
0.0005


rs2395845


2
222818820
‘A/C’
0.0006


rs1370923


2
222825345
‘A/G’
0.0001


rs13385121


2
222828210
‘A/G’
0.0003


rs1370920


2
222830630
‘A/C’
0.0007


rs358830


4
21264567
‘A/G’
0.0006


rs1394135


4
21274584
‘C/T’
0.0002


rs1394139


4
21283327
‘C/T’
0.0001


rs3913663


4
21283866
‘G/T’
0.0001


rs1503994


4
21289743
‘C/T’
0.0001


rs10000010


4
21294943
‘C/T’
0.0001


rs6812187


4
21295968
‘C/T’
0.0002


rs1105377


4
21300252
‘A/G’
0.0004


rs12523677


6
138972758
‘C/T’
0.0009


rs7761956


6
138976745
‘A/C’
0.001


rs9495159


6
138981368
‘A/C’
0.0003


rs6931390


6
138983096
‘A/G’
0.0001


rs10085294


6
138983780
‘A/G’
0.0004


rs7841080


8
33547819
‘A/G’
0.0007


rs1530344


8
33562618
‘C/T’
0.0003


rs7814270


8
33590441
‘A/G’
0.0001


rs10107668


8
33643721
‘C/T’
0.0006


rs1579274


8
41778080
‘G/T’
0.0008


rs10103618


8
41783053
‘A/G’
0.0004


rs1549064


8
41803645
‘A/C’
0.0001


rs2102360


8
41807985
‘A/G’
0.0008


rs10501022


11
25712397
‘C/T’
0.0003


rs2349308


11
25729898
‘A/G’
0.0004


rs12274588


11
25733789
‘A/G’
0.0002


rs1493663


11
25735615
‘C/T’
0.0002


rs1908162


11
25753546
‘A/C’
0.0001


rs1018022


11
25763400
‘A/G’
0.0001


rs813321
LOC441629
441629
12
10774689
‘A/G’
0.001


rs753202
LOC441629
441629
12
10777130
‘C/T’
0.0001


rs797175
LOC441629
441629
12
10785837
‘A/G’
0.0002


rs155010
PCDH9
5101
13
66489493
‘C/T’
0.0008


rs260172
PCDH9
5101
13
66496347
‘G/T’
0.0008


rs7995254
PCDH9
5101
13
66501746
‘C/T’
0.0001


rs260148
PCDH9
5101
13
66505392
‘G/T’
0.0002


rs1927812
PCDH9
5101
13
66596990
‘C/T’
0.0008


rs17517037
PCDH9
5101
13
66597199
‘C/T’
0.0001


rs2209902
PCDH9
5101
13
66600753
‘C/T’
0.0001


rs1543618
PCDH9
5101
13
66606571
‘A/G’
0.001


rs7149784


14
96127751
‘A/G’
0.001


rs4905507


14
96135250
‘A/C’
0.0004


rs1570558


14
96141360
‘C/T’
0.0002


rs234605


14
96141802
‘A/G’
0.0001


rs6587312
TAFA5
25817
22
47458658
‘A/G’
0.0005


rs132262
TAFA5
25817
22
47462572
‘A/G’
0.0001


rs131969


22
47472166
‘A/G’
0.0001


rs13057753


22
47476180
‘C/T’
0.0001


rs131003


22
47485954
‘G/T’
0.0001


rs17177527


22
47487073
‘A/G’
0.0003


rs10521553
LHFPL1
340596
X
111687038
‘C/T’
0.0009


rs7050419
LHFPL1
340596
X
111690411
‘C/T’
0.0003


rs12687789
LHFPL1
340596
X
111702031
‘G/T’
0.0002


rs2851733
GRIA3
2892
X
122316606
‘A/G’
0.0007


rs592807
GRIA3
2892
X
122317191
‘C/T’
0.0002


rs503118
GRIA3
2892
X
122319758
‘C/T’
0.0003


rs5910006
GRIA3
2892
X
122341190
‘C/T’
0.0002


rs4546784
LOC392533
392533
X
122355199
‘A/G’
0.0002


rs5911634
LOC392533
392533
X
122359484
‘A/C’
0.0003


rs1815919
LOC392533
392533
X
122361044
‘A/G’
0.0006


rs5911644
LOC392533
392533
X
122370314
‘A/G’
0.0006


rs930631


X
145902706
‘C/T’
0.0006


rs5951926


X
145903446
‘A/G’
0.0002


rs12851378


X
145938989
‘C/T’
0.0002


rs12156967


X
145942822
‘C/T’
0.0002


rs5951934


X
145950994
‘A/G’
0.0008


rs5904725


X
146024839
‘C/T’
0.001


rs2780882


1
63117448
‘A/C’
0.0004


rs2780883


1
63122640
‘A/G’
0.0005


rs2065585


1
63126422
‘A/G’
0.0002


rs2050249


1
63127755
‘A/C’
0.0003


rs7559122
LOC391353
391353
2
16287758
‘A/G’
0.0002


rs7560874
LOC391353
391353
2
16291356
‘A/G’
0.0002


rs2048874
FLJ40629
150468
2
113240198
‘C/T’
0.0002


rs4848300


2
113244137
‘C/T’
0.0002


rs17561
IL1A
3552
2
113253454
‘G/T’
0.0002


rs6746923


2
113269657
‘A/G’
0.0003


rs10496444


2
113269899
‘C/T’
0.0004


rs4849122


2
113277152
‘A/G’
0.0002


rs4849123


2
113285270
‘C/T’
0.0002


rs12469600


2
113288588
‘C/T’
0.0004


rs7630843


3
198681
‘C/T’
0.0005


rs1850264


3
201067
‘A/G’
0.0005


rs7632811


3
209726
‘G/T’
0.001


rs1516338
CHL1
10752
3
211759
‘C/T’
0.0007


rs17329247
CHL1
10752
3
216913
‘A/G’
0.0005


rs6769747
CHL1
10752
3
219949
‘A/G’
0.0002


rs9809528
CHL1
10752
3
225758
‘A/G’
0.0005


rs4685447
CHL1
10752
3
227068
‘A/C’
0.0002


rs7831515
FLJ32440
286053
8
126201998
‘C/T’
0.0007


rs10094316
FLJ32440
286053
8
126219985
‘C/T’
0.0004


rs13253942
FLJ32440
286053
8
126223831
‘A/G’
0.0002


rs12544146
FLJ32440
286053
8
126241522
‘A/G’
0.0004


rs10093813
FLJ32440
286053
8
126286445
‘C/T’
0.0002


rs4330708
FLJ32440
286053
8
126302381
‘G/T’
0.0004


rs3955404
FLJ32440
286053
8
126323441
‘C/T’
0.0007


rs4749567


10
30885044
‘A/G’
0.0008


rs4749568


10
30887013
‘C/T’
0.0004


rs906236


10
30891225
‘A/C’
0.0002


rs12099631


12
83139088
‘A/G’
0.0009


rs728084


12
83170810
‘A/G’
0.0008


rs2279307


12
83190484
‘C/T’
0.0002


rs1564606


12
83199601
‘G/T’
0.0005


rs9538278


13
58510378
‘A/G’
0.0003


rs7333943


13
58515848
‘G/T’
0.0002


rs6562004


13
58517819
‘A/G’
0.0006


rs803804


13
70497303
‘A/G’
0.0006


rs9542557


13
70507666
‘A/G’
0.0002


rs1395354


13
70514920
‘A/G’
0.0002


rs2135488


13
70515776
‘C/T’
0.0006


rs1683378
FLJ34907
284222
18
10833483
‘C/T’
0.0009


rs901185
FLJ34907
284222
18
10844509
‘C/T’
0.0002


rs11874473
FLJ34907
284222
18
10853849
‘A/C’
0.0004


rs11659801
FLJ34907
284222
18
10858838
‘A/G’
0.0004


rs196956


18
10882653
‘A/G’
0.0005


rs264167


18
10886327
‘G/T’
0.0009


rs264176


18
10891607
‘C/T’
0.0009


rs12012576


X
21572835
‘A/G’
0.0003


rs7878576


X
21596302
‘A/G’
0.0004


rs5951469


X
21608265
‘C/T’
0.0009


rs2224075
DMD
1756
X
32596618
‘G/T’
0.0004


rs1015377
DMD
1756
X
32610610
‘A/C’
0.0003


rs5972689
DMD
1756
X
32619678
‘A/G’
0.0005


rs5937044


X
69983714
‘A/G’
0.001


rs5937060


X
70024726
‘C/T’
0.0003


rs3125945


X
70041757
‘A/G’
0.0007


rs12841491
BRODL
254065
X
79835631
‘A/G’
0.0003


rs1997686


X
141888741
‘C/T’
0.0007


rs5908533


X
141889739
‘C/T’
0.0004


rs5907387


X
141893710
‘C/T’
0.0003


rs5951913


X
145841872
‘A/G’
0.0007


rs4460510


X
145845745
‘G/T’
0.0003


rs6535510


4
85188903
‘C/T’
0.0003


rs1395000


4
85197861
‘A/G’
0.0004


rs1827814


4
85212132
‘A/G’
0.0006


rs4423888


4
125833487
‘A/C’
0.0003


rs2318064
TCBA1
154215
6
124231122
‘A/G’
0.0008


rs6924068
TCBA1
154215
6
124232587
‘A/G’
0.0003


rs11154196
TCBA1
154215
6
124259412
‘A/G’
0.0007


rs1373762


18
48008075
‘A/G’
0.0004


rs1445097


18
48008752
‘A/G’
0.0003


rs920938


18
48031307
‘A/C’
0.0004


rs7238445


18
48035542
‘A/G’
0.0008


rs2839081


21
46265743
‘C/T’
0.0003


rs2839084


21
46269612
‘C/T’
0.0009


rs12856241


X
42617791
‘C/T’
0.0007


rs11797347


X
42619916
‘A/G’
0.0004


rs2497938
LOC442457
442457
X
66346039
‘C/T’
0.0004


rs6625187
LOC442457
442457
X
66459416
‘C/T’
0.0009


rs1716758


X
117241790
‘A/G’
0.0007


rs5910338


X
117242500
‘C/T’
0.0004


rs5910340


X
117247923
‘C/T’
0.0007


rs1781994


X
117251385
‘A/G’
0.001


rs13013240


2
154378937
‘A/G’
0.0004


rs2594264
FHIT
2272
3
60489776
‘A/G’
0.0007


rs717821
FHIT
2272
3
60490818
‘C/T’
0.0004


rs4688500


3
64651333
‘C/T’
0.001


rs10470707


3
64652777
‘A/G’
0.0004


rs4234678


3
64654405
‘C/T’
0.0006


rs7648557


3
64658255
‘G/T’
0.0004


rs9828674


3
64668140
‘G/T’
0.0004


rs6534743


4
131072373
‘A/G’
0.0004


rs1470968


8
115879414
‘A/C’
0.0007


rs1013527


8
115890222
‘G/T’
0.0005


rs13252246


8
115890469
‘A/G’
0.0004


rs10505228


8
115908486
‘C/T’
0.0006


rs7901450


10
120200634
‘G/T’
0.0004


rs2040322
NELL1
4745
11
21319903
‘A/G’
0.0004


rs10833511
NELL1
4745
11
21321150
‘G/T’
0.0006


rs6483768
NELL1
4745
11
21328115
‘A/C’
0.0008


rs12558663


X
98465719
‘G/T’
0.0005


rs5955985


X
116802803
‘A/G’
0.0007


rs5910260


X
116803867
‘A/C’
0.0005


rs6603347
KLHL13
90293
X
116839006
‘A/G’
0.0005


rs7880254


X
129289361
‘A/G’
0.0008


rs2411857


X
129305419
‘C/T’
0.0007


rs5977297


X
129333622
‘C/T’
0.0006


rs5977301


X
129344002
‘A/C’
0.0005


rs4830190


X
129348212
‘A/G’
0.0006


rs4926448
CGI-49
51097
1
243252908
‘C/T’
0.0006


rs4926440
CGI-49
51097
1
243255059
‘C/T’
0.0007


rs6694274
LOC149134
149134
1
243280207
‘A/G’
0.0005


rs10027062


4
172681785
‘A/G’
0.0005


rs12649451


4
172690498
‘C/T’
0.0009


rs12184555
PCDH17
27253
13
57180524
‘C/T’
0.0005


rs10498645


14
95332505
‘A/G’
0.0009


rs6575549


14
95333063
‘C/T’
0.0005


rs1957923


14
95344355
‘A/G’
0.0007


rs4786026
NPM1P3
4872
16
5355972
‘A/G’
0.0007


rs9929602


16
5363159
‘A/C’
0.0006


rs485335


16
5365169
‘A/G’
0.0005


rs507215


16
5368557
‘C/T’
0.0005


rs2870478


19
62080707
‘A/C’
0.0005


rs5917070
LOC392517
392517
X
106840233
‘A/G’
0.0009


rs2300101
MID2
11043
X
106947702
‘C/T’
0.001


rs5916793
MID2
11043
X
106953693
‘A/C’
0.0006


rs5931610


X
138141139
‘A/C’
0.0007


rs6418811


X
138161892
‘A/G’
0.0006


rs9388813


6
130965020
‘A/G’
0.0006


rs564127


7
79540870
‘C/T’
0.0006


rs2396104


7
108701750
‘C/T’
0.0006


rs7016063


8
55568807
‘C/T’
0.0006


rs7909332


10
109509005
‘A/G’
0.0006


rs1023033
PCDH9
5101
13
66544115
‘A/G’
0.0009


rs1927822
PCDH9
5101
13
66547600
‘C/T’
0.0006


rs10873145


14
61749543
‘A/G’
0.0006


rs1104708


14
61758158
‘A/G’
0.0007


rs9951631
DSC1
1823
18
26995905
‘C/T’
0.0006


rs6018359
PRKCBP1
23613
20
45307330
‘C/T’
0.0006


rs761021
PRKCBP1
23613
20
45327366
‘C/T’
0.0006


rs8132319
NCAM2
4685
21
21349566
‘C/T’
0.0006


rs7058356


X
5252012
‘A/G’
0.0007


rs4826788


X
5305855
‘C/T’
0.0008


rs12009051


X
45883560
‘C/T’
0.0007


rs2043072
CNTNAP5
129684
2
124873071
‘C/T’
0.001


rs2584353
CNTNAP5
129684
2
124875522
‘G/T’
0.0007


rs2964911


5
163656859
‘C/T’
0.0007


rs10250289
KIAA1862
84626
7
148783329
‘A/G’
0.0009


rs731489
KIAA1862
84626
7
148798930
‘A/G’
0.0007


rs11780975


8
103536662
‘A/C’
0.0007


rs777801


8
116245300
‘C/T’
0.0007


rs1888952


9
16248118
‘C/T’
0.0007


rs10756747


9
16249346
‘A/G’
0.001


rs10120750


9
87215060
‘A/G’
0.0007


rs574322
HNT
50863
11
131326210
‘C/T’
0.0007


rs1022866
PCDH9
5101
13
66480115
‘A/G’
0.0007


rs11646540
PRKCB1
5579
16
24031685
‘A/G’
0.0007


rs1995171


16
50137027
‘A/C’
0.0007


rs4784368


16
50151691
‘C/T’
0.0008


rs1189852
FLJ34907
284222
18
10817757
‘C/T’
0.0007


rs7504149


18
63985504
‘A/C’
0.0009


rs491920


18
63993805
‘G/T’
0.0007


rs758119
DXS1283E
8228
X
7697726
‘A/G’
0.0008


rs1795600


X
7716680
‘C/T’
0.0008


rs4829455
AMOT
154796
X
111870035
‘A/C’
0.0008


rs5973962
AMOT
154796
X
111873526
‘C/T’
0.001


rs620730
AMOT
154796
X
111879310
‘C/T’
0.0008


rs10913257
PAPPA2
60676
1
173510267
‘G/T’
0.0008


rs7607623


2
35641207
‘A/G’
0.0008


rs849523
NRP2
8828
2
206421442
‘C/T’
0.0008


rs10498133
PAX3
5077
2
222929810
‘G/T’
0.0008


rs2134358
CNTN4
152330
3
2447785
‘C/T’
0.0008


rs9838361
HAPIP
8997
3
125517439
‘G/T’
0.0008


rs9819507


3
185249403
‘C/T’
0.0008


rs2642749
LOC389293
389293
5
62137231
‘A/G’
0.0008


rs12523684
KIAA1900
114792
6
97536824
‘A/G’
0.0008


rs1933459
KIAA1900
114792
6
97545010
‘A/G’
0.0009


rs1019906
DGKB
1607
7
14176024
‘C/T’
0.0008


rs2194910


8
54250695
‘C/T’
0.0009


rs7007275


8
54269163
‘G/T’
0.0008


rs10511739


9
24081342
‘A/G’
0.001


rs4977917


9
24095508
‘A/G’
0.0008


rs937872


13
68252838
‘A/G’
0.0008


rs759290
PPP5C
5536
19
51583951
‘C/T’
0.0008


rs2288419
PTPRH
5794
19
60385056
‘A/G’
0.0009


rs2288523
PTPRH
5794
19
60394722
‘G/T’
0.0008


rs504507


20
874585
‘A/G’
0.0008


rs530652


20
878560
‘C/T’
0.0008


rs2824669


21
18457462
‘A/C’
0.001


rs909260


21
18459878
‘A/G’
0.0008


rs2186343


21
38258803
‘G/T’
0.0008


rs1539902


21
38259079
‘A/G’
0.0008


rs2983097


X
102472426
‘A/G’
0.0009


rs7539699


1
244075613
‘A/G’
0.0009


rs997448


3
64935253
‘A/G’
0.0009


rs562
ABCC5
10057
3
185120547
‘C/T’
0.0009


rs3109915


4
55480475
‘A/G’
0.0009


rs628572


6
16873481
‘A/G’
0.0009


rs10097861
PTK2B
2185
8
27244435
‘A/G’
0.0009


rs1879188
PTK2B
2185
8
27249840
‘G/T’
0.0009


rs723231


8
126018234
‘G/T’
0.0009


rs7025486


9
121501957
‘A/G’
0.0009


rs7320321


13
105089064
‘A/G’
0.0009


rs158074


21
18303801
‘C/T’
0.0009


rs157740


21
18325093
‘A/G’
0.0009


rs4911823


X
114478198
‘C/T’
0.001


rs1029307


X
138041664
‘C/T’
0.001


rs6683479


1
190196142
‘A/G’
0.001


rs2551640
CREB1
1385
2
208233399
‘A/G’
0.001


rs2244503


3
64920911
‘C/T’
0.001


rs11926273


3
149211480
‘C/T’
0.001


rs7613237


3
185223836
‘C/T’
0.001


rs1461656
LOC340156
340156
6
2661859
‘A/G’
0.001


rs1708552


6
67101152
‘G/T’
0.001


rs911946
SMOC2
64094
6
168861132
‘C/T’
0.001


rs4518582


7
135798488
‘C/T’
0.001


rs7830593


8
23000640
‘A/G’
0.001


rs10867485


9
80104890
‘A/G’
0.001


rs3012797


9
135049961
‘A/G’
0.001


rs2382712


9
135050485
‘C/T’
0.001


rs7984277


13
57299434
‘A/G’
0.001


rs2060261
FLJ39501
126410
19
15482180
‘A/G’
0.001





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Sequence_ID: Sequence identification number


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


P-value: P-value based on permutation test


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 35.1


Gene_content: Genes positioned within 100 Kbp up and downstream (End) from the physical position of the SNPs bordering the haplotype genomic region based on NCBI Human Genome Build 36.1













TABLE 4







Haplotypes with the strongest association with HT based on HaploRec + HPM analysis with 8


SNPs. The analysis is based on 140 HT cases and 182 healthy controls from East Finland.















Gene locus









and


dbSNP rs ID
Gene ID
Chromosome
Position
Variats
Risk Allele
Chi square
P value


















rs7539699


1
244075613
‘A/G’
G
24.69
6.74E−07


rs10925085
OR2G3
81469
1
244078202
‘C/T’
A


rs869111
OR2G3
81469
1
244078408
‘A/G’
G


rs10489818


1
117811285
‘A/G’
G
20.71
5.35E−06


rs6661142


1
117818118
‘C/T’
A


rs4659053


1
117820901
‘G/T’
C


rs1963278


1
117827285
‘A/G’
A


rs4261104


1
117831576
‘C/T’
A


rs1877341
ALS2CR19
117583
2
206173074
‘C/T’
A
20.26
6.77E−06


rs759450
ALS2CR19
117583
2
206185110
‘A/G’
G


rs12474620
ALS2CR19
117583
2
206199530
‘A/G’
G


rs992159
ALS2CR19
117583
2
206217051
‘A/C’
C


rs2041832
ALS2CR19
117583
2
206262643
‘A/G’
G


rs6731822
FLJ40629
150468
2
113230056
‘C/T’
G
19.78
8.68E−06


rs2048874
FLJ40629
150468
2
113240198
‘C/T’
G


rs4848300


2
113244137
‘C/T’
A


rs17561
IL1A
3552
2
113253454
‘G/T’
C


rs7648557


3
64658255
‘G/T’
A
23.65
1.16E−06


rs9828674


3
64668140
‘G/T’
C


rs11936235
LOC152742
152742
4
13794650
‘C/T’
A
21.33
3.86E−06


rs3846401
LOC152742
152742
4
13803752
‘A/G’
A


rs3846407
LOC152742
152742
4
13808194
‘G/T’
A


rs7654692
LOC152742
152742
4
13810072
‘A/G’
G


rs1426123
LOC152742
152742
4
13814053
‘A/C’
C


rs3846413
LOC152742
152742
4
13816480
‘C/T’
A


rs4698716


4
13824643
‘C/T’
A


rs3846415


4
13829206
‘A/G’
A


rs9640521
CNTNAP2
26047
7
147429304
‘G/T’
A
20.75
5.24E−06


rs13244714
CNTNAP2
26047
7
147433108
‘A/G’
A


rs12673933
CNTNAP2
26047
7
147441753
‘C/T’
A


rs6981891
LOC392222
392222
8
55554449
‘A/G’
A
22.96
1.65E−06


rs16920368
LOC392222
392222
8
55555406
‘A/G’
A


rs10504166
LOC392222
392222
8
55556364
‘G/T’
C


rs11786806


8
55561942
‘C/T’
A


rs7830517


8
55566337
‘A/G’
G


rs10109281


8
55568620
‘A/G’
G


rs7016063


8
55568807
‘C/T’
A


rs6473938


8
55586240
‘C/T’
A


rs7814270


8
33590441
‘A/G’
G
22.15
2.52E−06


rs10107668


8
33643721
‘C/T’
A


rs6981979
ANK1
286
8
41731412
‘C/T’
A
20.49
5.98E−06


rs11997827
ANK1
286
8
41741060
‘C/T’
G


rs11780780
ANK1
286
8
41742759
‘A/G’
G


rs13255458
ANK1
286
8
41755228
‘C/T’
G


rs879638
ANK1
286
8
41770625
‘C/T’
A


rs1579274


8
41778080
‘G/T’
C


rs10103618


8
41783053
‘A/G’
A


rs1549064


8
41803645
‘A/C’
C


rs16922271
NCOA6IP
96764
8
56885245
‘C/T’
G
20.14
7.21E−06


rs12155521


8
56920362
‘G/T’
A


rs12676220


8
56923173
‘C/T’
A


rs574847


12
91259931
‘C/T’
G
20.55
5.81E−06


rs427560


12
91279485
‘A/C’
A


rs3890018


12
91282738
‘G/T’
A


rs337653


12
91296145
‘C/T’
A


rs389714


12
91299920
‘A/G’
G


rs7328290


13
71394581
‘A/G’
A
20.93
4.75E−06


rs9542777


13
71394590
‘A/G’
A


rs1571393
PCDH9
5101
13
66560186
‘A/G’
A
20.09
7.39E−06


rs9529185
PCDH9
5101
13
66572148
‘A/G’
G


rs9317636
PCDH9
5101
13
66573353
‘C/T’
A


rs17516342
PCDH9
5101
13
66580629
‘C/T’
A


rs1927825
PCDH9
5101
13
66586299
‘A/G’
G


rs1927826
PCDH9
5101
13
66588057
‘A/G’
G


rs9571713
PCDH9
5101
13
66591183
‘C/T’
A


rs2875517
PCDH9
5101
13
66594146
‘A/G’
A


rs260172
PCDH9
5101
13
66496347
‘G/T’
A
19.78
8.71E−06


rs7995254
PCDH9
5101
13
66501746
‘C/T’
A


rs2147829
TTC7B
145567
14
90233622
‘C/T’
A
20.28
6.70E−06


rs3814841
TTC7B
145567
14
90234219
‘C/T’
G


rs1742098
TTC7B
145567
14
90238170
‘C/T’
A


rs1749704
TTC7B
145567
14
90239107
‘G/T’
A


rs1535321
TTC7B
145567
14
90240579
‘C/T’
A


rs1749718
TTC7B
145567
14
90253080
‘C/T’
G


rs1742083
TTC7B
145567
14
90256423
‘C/T’
A


rs8018904
TTC7B
145567
14
90259730
‘G/T’
C


rs901185
FLJ34907
284222
18
10844509
‘C/T’
G
27.87
1.30E−07


rs11874473
FLJ34907
284222
18
10853849
‘A/C’
A


rs11659801
FLJ34907
284222
18
10858838
‘A/G’
A


rs196956


18
10882653
‘A/G’
G


rs1189852
FLJ34907
284222
18
10817757
‘C/T’
A
20.71
5.33E−06


rs9962727
FLJ34907
284222
18
10822851
‘C/T’
A


rs9807627
FLJ34907
284222
18
10831164
‘A/G’
G


rs1683376
FLJ34907
284222
18
10832934
‘A/G’
G


rs1683378
FLJ34907
284222
18
10833483
‘C/T’
G


rs901185
FLJ34907
284222
18
10844509
‘C/T’
G


rs8099113
NFATC1
4772
18
75367142
‘A/G’
G
20.33
6.53E−06


rs1078633
NFATC1
4772
18
75369498
‘G/T’
C


rs372741
NFATC1
4772
18
75370277
‘C/T’
A


rs177820
NFATC1
4772
18
75377952
‘C/T’
A


rs2044750
NFATC1
4772
18
75380738
‘A/G’
G


rs9518
NFATC1
4772
18
75389794
‘C/T’
A


rs1437606


18
27019528
‘C/T’
G
20.17
7.10E−06


rs1469945


18
27023130
‘C/T’
A


rs2919996


18
27023635
‘C/T’
G


rs4447498


18
27037686
‘C/T’
G


rs502716


20
874397
‘A/G’
G
19.78
8.67E−06


rs504507


20
874585
‘A/G’
A


rs530652


20
878560
‘C/T’
A


rs480789


20
880618
‘C/T’
A


rs6140734


20
882313
‘A/G’
G


rs550408


20
882948
‘C/T’
A


rs2001902


22
46890123
‘A/C’
A
20.45
6.13E−06


rs133519


22
46897247
‘G/T’
C


rs9615272


22
46901575
‘A/G’
G


rs941418


22
46905131
‘A/G’
G


rs926233


22
46908479
‘A/G’
G


rs6008577


22
46910609
‘A/G’
A


rs133530


22
46911963
‘A/G’
G


rs6649483


X
148947202
‘C/T’
A
29.35
6.05E−08


rs9778461


X
149023178
‘A/G’
A


rs3897225


X
149042894
‘A/C’
A


rs12394687


X
149058726
‘C/T’
A


rs12398405


X
149062629
‘A/C’
A


rs9698926


X
149093381
‘C/T’
A


rs9781523


X
149099941
‘A/G’
G


rs9284560


X
149104836
‘C/T’
A


rs12014072


X
109436852
‘A/C’
A
29.27
6.31E−08


rs10521528
KIAA1318
57529
X
109495297
‘A/G’
A


rs6567866


X
109509009
‘C/T’
A


rs5942641


X
109549379
‘A/G’
G


rs1573036


X
109626213
‘A/G’
G


rs5942651


X
109633767
‘A/G’
A


rs197023
CHRDL1
91851
X
109774532
‘C/T’
A


rs12689346
CHRDL1
91851
X
109810107
‘C/T’
A





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Sequence_ID: Sequence identification number


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


Risk_allele: Allele in at-risk haplotype


Chi_square: Chi-squared test based on allele frequencies


P-value: P-value based on the chi-square test













TABLE 5







SNP markers with the strongest association with hypertension in the individual marker analysis. The analysis is based on the


combined data of 110 HT cases and 110 healthy controls from the Ashkenazi Jew population, 114 HT cases and 114 healthy controls


from the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT cases and 28 healthy


controls from the English population.

















Gene locus










and


dbSNP rs ID
Priority date
Gene ID
Chromosome
Position
Variats
Minor Allele
Allele X2
Odds ratio



















RS1721355
3
WDR69
164781
2
228491220
‘A/G’
G
18.72
0.60


RS561264
3


2
238994718
‘A/C’
C
18.27
1.78


RS2153184
3


1
162470621
‘A/G’
A
17.82
1.70


RS9564765
3


13
70431786
‘A/G’
G
17.79
1.74


RS8066575
3
FLJ45831
400576
17
14631647
‘C/T’
G
17.76
0.57


RS6698312
3


1
162473439
‘G/T’
A
17.60
1.76


RS2301301
3
HOXD3
3232
2
176740513
‘C/T’
G
16.94
1.66


RS7406978
3
ABR
29
17
983909
‘C/T’
A
16.79
1.62


RS2245192
3


7
113789771
‘C/T’
G
16.69
0.51


RS747250
3
LOC651311
651311
11
129776888
‘G/T’
A
16.29
1.61


RS1332855
3


9
82827607
‘G/T’
C
16.25
0.49


RS10516684
3


4
84529735
‘C/T’
A
16.16
0.45


RS11650418
3
ABR
29
17
1025021
‘G/T’
A
16.03
0.62


RS2256182
3


8
93637241
‘C/T’
A
15.99
0.58


RS590218
3
ZNF516
9658
18
72198871
‘A/G’
G
15.83
0.52


RS16928804
3


9
128033773
‘A/C’
A
15.82
0.49


RS4399939
3


4
162037658
‘C/T’
A
15.54
0.54


RS13100475
3


3
192637284
‘A/G’
A
15.35
0.56


RS9546945
3


13
84406708
‘C/T’
G
15.20
1.60


RS1183060
3


9
82849539
‘C/T’
G
15.18
0.49


RS2881507
3


1
162492876
‘A/G’
A
15.10
1.68


RS7141
3
EFNB3
1949
17
7555326
‘A/G’
G
15.08
1.62


RS1464706
3


3
947112
‘C/T’
G
15.08
0.59


RS1369704
3
DTNB
1838
2
25477094
‘A/G’
G
15.00
0.62


RS2458686
3


10
2548037
‘G/T’
A
14.98
0.52


RS1543680
3
HIST1H4C
8364
6
26211156
‘A/G’
A
14.95
0.54


RS707889
3
HFE
3077
6
26203910
‘C/T’
A
14.95
0.54


RS261988
3


5
95866641
‘A/G’
G
14.65
1.57


RS11088668
3


21
18448920
‘C/T’
A
14.65
1.97


RS4902242
3


14
63299842
‘C/T’
G
14.43
0.52


RS934083
3
CACNA2D3
55799
3
54765419
‘C/T’
G
14.42
1.56


RS1476240
3
ZPBP
11055
7
50003183
‘A/G’
G
14.32
1.73


RS8131179
3
PDE9A
5152
21
42955270
‘C/T’
A
14.07
0.62


RS941223
3


12
19912392
‘A/G’
G
13.96
1.57


RS7571570
3
DTNB
1838
2
25475034
‘C/T’
A
13.91
0.63


RS9854395
3


3
47561518
‘A/G’
A
13.89
2.01


RS959678
3
ZPBP
11055
7
50031156
‘A/G’
A
13.83
1.71


RS16007
3
CACNA1A
773
19
13331316
‘A/G’
A
13.79
4.29


RS2267064
3
LOC648941
648941
22
22874632
‘G/T’
C
13.77
1.73


RS873833
3
CABIN1
23523
22
22757878
‘C/T’
G
13.77
1.73


RS1159673
3


2
6623910
‘G/T’
C
13.75
1.71


RS138981
3


22
41927759
‘A/G’
A
13.75
1.92


RS4873814
3


8
144793335
‘A/G’
G
13.73
1.89


RS1149907
3


10
8190108
‘A/G’
A
13.73
1.55


RS1981736
3


2
66689823
‘A/G’
A
13.70
1.81


RS2901483
3


2
62618776
‘A/G’
A
13.70
0.53


RS4234091
3
LOC651758
651758
2
241559700
‘A/G’
A
13.67
1.72


RS7151518
3


14
101104559
‘A/G’
A
13.66
0.64


RS7288568
3
LOC648551
648551
22
47595366
‘C/T’
A
13.62
0.59


RS3020835
3


7
141681285
‘A/C’
C
13.61
1.54


RS4611181
3
ZNF195
7748
11
3349321
‘C/T’
G
13.48
1.75


RS4688807
3
PLXND1
23129
3
130791953
‘C/T’
A
13.46
0.62


RS861077
3


2
238992522
‘A/C’
C
13.43
1.62


RS425246
3
PLD5
200150
1
240470883
‘A/G’
A
13.41
0.47


RS9506903
3


13
22150146
‘C/T’
G
13.39
0.63


RS10492602
2


13
57737145
‘G/T’
C
13.37
3.70


RS2152066
3
TEK
7010
9
27178862
‘G/T’
A
13.36
0.63


RS1374868
3


3
74781680
‘A/G’
A
13.32
1.98


RS8044769
3
FTO
79068
16
52396636
‘C/T’
A
13.30
0.65


RS2391671
3
CREB5
9586
7
28518902
‘A/G’
G
13.29
1.63


RS499899
3


6
20109726
‘C/T’
A
13.28
1.61


RS1891999
3


9
137226410
‘G/T’
A
13.25
1.58


RS13054531
3


22
46392057
‘A/C’
A
13.22
0.32


RS4651073
3
XPR1
9213
1
178867222
‘A/G’
G
13.22
0.64


RS1384634
3
ZPBP
11055
7
50035023
‘C/T’
G
13.20
1.54


RS6904723
3
BTBD9
114781
6
38544295
‘A/C’
A
13.20
1.53


RS4294708
3


13
84403995
‘C/T’
A
13.15
1.65


RS6538861
2


12
97274234
‘C/T’
G
13.15
1.88


RS11911479
3


21
18463191
‘C/T’
G
13.04
0.54


RS3850701
3


21
41988902
‘A/C’
A
13.03
0.30


RS310025
3


16
79980481
‘A/G’
A
12.88
0.62


RS6892814
3
STK10
6793
5
171502017
‘A/G’
A
12.88
0.64


RS1833036
3
ESRRG
2104
1
214773635
‘A/C’
C
12.85
1.53


RS2837713
3
DSCAM
1826
21
40873626
‘A/C’
A
12.77
1.52


RS3898917
3


11
5284937
‘G/T’
C
12.77
0.62


RS11685593
3


2
127604591
‘C/T’
A
12.76
1.76


RS6028637
3


20
37816039
‘C/T’
A
12.75
2.19


RS10507024
3
LOC651534
651534
12
91935819
‘A/G’
A
12.75
2.37


RS2837709
3
DSCAM
1826
21
40861610
‘A/C’
A
12.73
1.52


RS3848521
3


19
62264525
‘A/G’
G
12.67
1.62


R81812315
3


15
25522899
‘C/T’
G
12.67
1.77


RS1874622
3
CRISPLD2
83716
16
83455234
‘A/G’
G
12.62
0.50


RS6803083
3


3
79852274
‘G/T’
C
12.61
0.65


RS1399333
3


4
10878977
‘C/T’
G
12.57
1.66


RS17254891
3


3
61419483
‘C/T’
G
12.55
1.75


RS3751812
3
FTO
79068
16
52375961
‘G/T’
A
12.54
1.52


RS10876351
3


12
51482966
‘A/G’
G
12.54
1.60


RS9591885
3


13
57981372
‘C/T’
G
12.53
3.58


RS2671689
3


17
44918120
‘C/T’
G
12.53
1.98


RS8050136
3
FTO
79068
16
52373776
‘A/C’
A
12.51
1.52


RS199694
3
ST6GALNAC5
81849
1
77276843
‘A/G’
G
12.49
1.96


RS4399918
3
NLGN1
22871
3
175087027
‘C/T’
G
12.48
0.50


RS936960
3
LIPC
3990
15
56539169
‘A/C’
A
12.46
0.43


RS3827256
3
PFKL
5211
21
44565251
‘A/G’
A
12.43
1.53


RS17329247
2
CHL1
10752
3
216913
‘A/G’
A
12.43
1.51


RS1425531
3


4
143645481
‘C/T’
A
12.40
0.62


RS2007215
3
PTCND2
57540
1
11460564
‘A/G’
A
12.39
0.66


RS2837716
3
DSCAM
1826
21
40875564
‘A/G’
A
12.36
1.51


RS1022790
3


20
10678759
‘A/G’
G
12.33
1.51


RS632912
2


18
8457707
‘A/G’
A
12.29
2.44


RS2748173
3
BTBD9
114781
6
38638120
‘A/G’
G
12.28
1.61


RS711129
3


12
76568088
‘C/T’
G
12.26
0.53


RS4735183
3


8
93638119
‘G/T’
C
12.24
0.63


RS11733672
3


4
4653806
‘C/T’
A
12.22
1.67


RS2824669
2


21
18457462
‘A/C’
A
12.20
0.65


RS1605438
3


8
132605749
‘A/G’
G
12.20
0.66


RS10513838
3


3
190715335
‘A/G’
G
12.19
2.27


RS9614576
3
ARHGAP8
23779
22
43603961
‘C/T’
G
12.16
0.66


RS493524
3
LOC651344
651344
11
78758254
‘C/T’
A
12.16
0.58


RS4865755
3
ITGA2
3673
5
52326944
‘C/T’
G
12.11
0.63


RS4788480
3
ATBF1
463
16
71493187
‘C/T’
A
12.11
1.60


RS2369146
3


1
157934819
‘A/G’
A
12.10
0.59


RS1093304
3
KSR2
283455
12
116414534
‘C/T’
A
12.07
1.66


RS462769
3
MGC26885
124044
16
88290764
‘A/G’
A
12.07
1.51


RS10962917
3


9
17220086
‘A/G’
A
12.06
0.57


RS1495942
3


1
243142007
‘A/C’
A
12.06
2.24


RS220836
3
IGSF4
23705
11
114807081
‘A/G’
G
12.05
1.58


RS10511820
1
LRRN6C
158038
9
28045603
‘A/C’
C
12.03
0.65


RS983789
3


1
157862306
‘G/T’
A
12.02
1.91


RS2864474
3
TMEM105
284186
17
76916744
‘A/G’
G
12.01
0.61


RS7630843
2


3
198681
‘C/T’
G
12.01
1.58


RS3813587
3


19
22591133
‘A/C’
C
12.00
1.61


RS2249963
3


8
11512635
‘C/T’
G
12.00
0.66


RS1955716
3
FBXO33
254170
14
38969200
‘C/T’
G
11.99
0.60


RS1038853
3


4
108397270
‘A/C’
C
11.98
1.50


RS4809656
3


20
45903393
‘G/T’
C
11.98
2.32


RS2360090
3


2
195053028
‘A/G’
G
11.96
1.74


RS6974985
3


7
149034703
‘C/T’
A
11.96
0.58


RS9695286
3


9
109812888
‘C/T’
A
11.94
1.50


RS6604634
3
ESRRG
2104
1
214787878
‘A/G’
A
11.93
1.50


RS6989616
3
ST18
9705
8
53272861
‘G/T’
A
11.92
0.36


RS2166512
3


2
176779427
‘A/G’
G
11.92
1.52


RS2785910
3


6
96439227
‘C/T’
G
11.92
1.52


RS252682
3


5
106702415
‘A/G’
G
11.91
0.64


RS1556867
3


1
162480310
‘C/T’
A
11.91
1.67


RS6778227
3


3
182516536
‘C/T’
G
11.90
1.51


RS1579303
3


5
180427946
‘A/G’
A
11.90
0.61


RS7802349
3


7
85105110
‘C/T’
G
11.87
0.38


RS11138526
2


9
81965277
‘G/T’
A
11.84
2.16


RS2322606
3
PTK2B
2185
8
27242840
‘A/G’
A
11.84
1.68


RS7501939
3
TCF2
6928
17
33175269
‘C/T’
A
11.84
1.52


RS4922157
3


8
20206493
‘C/T’
G
11.83
1.52


RS6923737
3
BTBD9
114781
6
38591542
‘C/T’
G
11.83
0.66


RS9309828
3


3
79843464
‘A/G’
A
11.82
0.63


RS6746082
3
DTNB
1838
2
25512748
‘A/C’
C
11.82
0.62


RS5026446
3


18
74163927
‘C/T’
A
11.80
0.48


RS7203175
3
CDH13
1012
16
82261890
‘C/T’
G
11.80
2.10


RS10245474
3
ATXN7L4
222255
7
105249944
‘A/C’
A
11.79
0.62


RS7613818
3
CAST1
26059
3
55995199
‘A/G’
G
11.78
0.67


RS9690428
3


7
52755728
‘C/T’
G
11.77
0.65


RS956037
3
TRAV16
28667
14
21528535
‘C/T’
G
11.73
0.21


RS199689
3
ST6GALNAC5
81849
1
77267267
‘A/C’
C
11.72
1.57


RS7008482
3
C8orf36
286053
8
126336812
‘G/T’
C
11.71
1.52


RS10215277
3
LOC641864
641864
7
141492186
‘C/T’
A
11.71
0.62


RS12120303
3


1
66742956
‘A/G’
A
11.69
0.54


RS12128593
3


1
66747467
‘C/T’
G
11.69
0.54


RS6826645
3


4
44959803
‘A/G’
A
11.69
1.56


RS10187702
3
LOC652214
652214
2
58723279
‘C/T’
G
11.67
1.71


RS12534779
3


7
135472243
‘A/G’
G
11.65
1.50


RS936495
3


6
89209198
‘A/C’
C
11.61
0.51


RS2267796
3
GRIN2A
2903
16
9884214
‘G/T’
C
11.58
0.62


RS2607605
3


8
24700639
‘C/T’
G
11.57
1.73


RS4945348
3
LOC651344
651344
11
78797081
‘C/T’
G
11.57
0.54


RS165774
3
COMT
1312
22
18332561
‘A/G’
A
11.56
0.63


RS11993467
3
PSD3
23362
8
18701941
‘C/T’
A
11.56
1.49


RS2838818
3
ADARB1
104
21
45465445
‘A/G’
G
11.55
1.49


RS9686666
3


5
23398686
‘A/G’
G
11.54
1.49


RS3787011
3
RNF126
55658
19
612080
‘A/G’
A
11.54
2.47


RS6447440
3


4
44955705
‘C/T’
G
11.54
1.55


RS2167644
3
LRRN6C
158038
9
28076344
‘A/G’
G
11.52
0.62


RS208003
3


7
19821959
‘C/T’
A
11.52
0.60


RS7771891
3
C6orf195
154386
6
2570303
‘A/G’
G
11.52
1.66


RS2794515
3


1
157913168
‘A/G’
A
11.52
0.62


RS9363388
3


6
66308721
‘C/T’
G
11.51
0.63


RS3847437
3


10
11492266
‘C/T’
A
11.51
2.56


RS7333943
2


13
58515848
‘G/T’
C
11.51
1.77


RS11794056
3
SNX30
401548
9
114644464
‘A/G’
G
11.51
0.63


RS3760578
3
SLC14A1
6563
18
41556974
‘A/G’
A
11.48
1.49


RS11940185
3


4
19506456
‘A/G’
A
11.48
1.49


RS3748971
3
ECEL1P2
347694
2
232958927
‘A/G’
A
11.44
2.08


RS1005142
3
SV2B
9899
15
89585011
‘C/T’
G
11.42
2.61


RS10864069
3


1
212013892
‘A/C’
A
11.41
1.50


RS220860
3
IGSF4
23705
11
114799274
‘A/C’
C
11.41
1.60


RS1515441
3
SPATA16
83893
3
174317984
‘A/G’
A
11.40
2.09


RS7335330
3
LHFP
10186
13
38905199
‘C/T’
A
11.40
1.69


RS11919819
3
SPATA16
83893
3
174315997
‘G/T’
A
11.40
1.93


RS707896
3


6
26224403
‘A/G’
A
11.40
0.57


RS6016142
3


20
37734221
‘C/T’
A
11.40
2.04


RS1670533
3
LOC285498
285498
4
1068187
‘C/T’
G
11.37
1.65


RS12650866
3


4
84514285
‘A/C’
A
11.37
0.59


RS7651591
3
GRM7
2917
3
6898647
‘C/T’
G
11.36
1.98


RS2655074
3


11
11157434
‘G/T’
A
11.36
1.51


RS5768405
3


22
46941844
‘C/T’
G
11.33
1.53


RS10899922
3
C10orf136
414260
10
43661970
‘A/G’
G
11.30
1.51


RS509063
3
TRAF3IP1
26146
2
238960439
‘C/T’
A
11.30
1.64


RS1123003
3


4
141658315
‘C/T’
G
11.29
1.70


RS7791608
3
KIAA1862
84626
7
149052706
‘A/G’
G
11.29
0.52


RS767460
3
CNTN4
152330
3
2716787
‘A/G’
G
11.29
0.63


RS12615237
3


2
44131231
‘C/T’
G
11.28
0.59


RS6831180
3


4
84523758
‘C/T’
A
11.27
0.60


RS2897074
3


4
155157135
‘A/C’
A
11.26
1.49


RS2283458
3
SLCO3A1
28232
15
90490116
‘C/T’
A
11.26
0.67


RS6586906
3


8
20222955
‘A/G’
G
11.25
1.57


RS3822292
3
TACR3
6870
4
104776161
‘A/G’
G
11.24
1.92


RS10485483
3
CDS2
8760
20
5106354
‘A/C’
A
11.24
0.51


RS1411850
3


6
66305145
‘C/T’
G
11.24
0.63


RS8051575
3
GAN
8139
16
79958316
‘G/T’
A
11.24
1.48


RS532040
3


11
129081186
‘C/T’
A
11.23
1.64


RS10922232
3


1
187789366
‘G/T’
C
11.22
1.48


RS10495029
3
ESRRG
2104
1
214792606
‘C/T’
G
11.21
0.66


RS1510510
3


2
239164074
‘G/T’
A
11.21
1.89


RS1476880
3


4
24345356
‘G/T’
A
11.21
1.49


RS3760352
3
ASGR2
433
17
6960602
‘C/T’
G
11.20
0.64


RS1870943
3


12
88192283
‘C/T’
G
11.20
2.06


RS6550169
3
LOC651301
651301
3
32888097
‘C/T’
A
11.19
1.48


RS7770868
3
BTBD9
114781
6
38572604
‘A/C’
A
11.18
1.48


RS977576
3


5
52592967
‘C/T’
G
11.17
1.48


RS6980380
3
PRKAG2
51422
7
151018453
‘C/T’
G
11.17
1.71


RS11768400
3


7
84893471
‘A/G’
G
11.17
0.67


RS10773557
3


12
127638497
‘A/C’
A
11.16
0.67


RS6136703
3
SLC24A3
57419
20
19320443
‘C/T’
A
11.15
2.23


RS2001902
2


22
46948268
‘A/C’
C
11.15
1.55


RS1986437
3


12
81067405
‘A/G’
A
11.14
0.61


RS10484432
3


6
26116855
‘A/G’
A
11.14
0.61


RS10223320
3


5
158506964
‘C/T’
G
11.14
1.48


RS2291347
3
ADAMTS8
11095
11
129791976
‘A/G’
G
11.13
1.48


RS11665875
3


19
6951401
‘C/T’
G
11.12
1.48


RS7923262
3


10
71895542
‘A/G’
G
11.12
0.66


RS3858054
3


9
8243589
‘C/T’
G
11.11
1.49


RS459920
3
C16orf55
124045
16
88258328
‘C/T’
A
11.11
1.48


RS6872241
3


5
151061730
‘C/T’
G
11.10
1.56


RS13105217
3


4
65064629
‘C/T’
G
11.10
0.64


RS10513039
3


5
9974028
‘A/G’
A
11.10
1.56


RS2492624
3


9
29928824
‘A/G’
G
11.09
0.66


RS4547623
3


22
36322650
‘A/G’
A
11.08
1.50


RS17862309
3
GRM8
2918
7
126598442
‘C/T’
G
11.07
0.12


RS138957
3
KIAA0153
23170
22
41914173
‘G/T’
C
11.06
1.64


RS4145462
3
MPZL1
9019
1
165985123
‘A/G’
A
11.06
0.12


RS9506776
3
LOC650912
650912
13
21518850
‘C/T’
A
11.05
1.52


RS1926324
3
DCAMKL1
9201
13
35582443
‘C/T’
A
11.03
1.57


RS2269903
3
CHN2
1124
7
29213934
‘A/C’
C
11.02
1.99


RS410202
3


4
44946963
‘C/T’
G
11.01
1.54


RS2560623
3


5
116742235
‘A/G’
A
11.01
0.48


RS1037973
3
GAN
8139
16
79957577
‘C/T’
A
11.00
0.67


RS12038863
3


1
178843066
‘A/C’
C
11.00
0.49


R82934477
3
CRISPLD2
83716
16
83480748
‘A/C’
A
10.97
0.67


RS9558678
3


13
105554332
‘C/T’
G
10.95
0.56


RS1327904
3
C20orf26
26074
20
20168568
‘A/C’
C
10.94
1.51


RS2458291
3
ATP6V1C1
528
8
104138327
‘C/T’
A
10.94
1.67


RS181246
3


17
53561087
‘G/T’
A
10.93
0.64


RS1282129
3


1
111424262
‘A/G’
G
10.92
1.49


RS7943619
3


11
105863808
‘C/T’
G
10.91
1.54


RS2164498
3
LOC649035
649035
12
31250477
‘A/G’
A
10.91
0.55


RS9790415
3


4
141648328
‘A/G’
G
10.90
1.68


RS1391619
3


11
5412505
‘C/T’
G
10.90
0.59


RS1332339
3


9
25946931
‘A/G’
G
10.89
0.52


RS12184120
3


7
92556975
‘A/G’
A
10.89
0.50


RS3922855
3


15
24625657
‘C/T’
G
10.89
0.63


RS911745452
3


5
83182789
‘C/T’
A
10.87
1.70


RS12026602
3


1
11440984
‘C/T’
G
10.85
0.68


RS950942
3


13
70429810
‘C/T’
A
10.85
1.48


RS2045065
3
LOC647947
647947
4
1042488
‘C/T’
A
10.85
1.63


RS1439354
3


4
44296521
‘G/T’
C
10.85
0.64


RS2299554
3
GRM8
2918
7
126644390
‘C/T’
G
10.84
0.36


RS2284218
3
CRHR2
1395
7
30680858
‘C/T’
G
10.84
0.67


RS1463342
3
FLJ39822
151258
2
165520674
‘A/G’
A
10.83
0.61


RS2447523
3


11
33418920
‘A/G’
G
10.83
0.61


RS1206810
3
EYA2
2139
20
45128769
‘C/T’
A
10.83
0.65


RS13251222
3


8
79207857
‘A/G’
G
10.83
0.63


RS5583190
3
CACNA2D3
55799
3
54702117
‘A/C’
C
10.83
1.47


RS1331205
3


6
66326120
‘A/G’
G
10.83
0.64


RS1264215
3
HEPH
9843
X
65337334
‘C/T’
A
12.22
0.00


RS5845127
2


X
7785325
‘A/G’
A
16.73
0.38


RS5955922
3


X
17970012
‘C/T’
G
15.78
2.36


RS3788776
3
ODZ1
10178
X
123512044
‘A/G’
G
15.96
2.25


RS2178544
3


X
7934954
‘G/T’
C
11.41
0.52


RS6527728
3
CXorf15
55787
X
16729886
‘A/G’
A
23.11
2.79


RS6522746
3


X
93236536
‘C/T’
A
14.02
2.10


RS596987
3


X
144193420
‘A/G’
G
11.43
0.55


RS995895
3


X
144258291
‘A/G’
A
14.58
0.52


RS5905817
3


X
44180283
‘A/C’
A
14.25
0.51


RS7063947
3


X
141196819
‘A/G’
A
11.02
1.65


RS4898198
3


X
24977352
‘A/C’
C
11.37
0.61


RS1531812
3


X
5712016
‘C/T’
A
16.62
0.54


RS5986723
3


X
24965806
‘A/G’
G
11.34
0.61


RS5961851
3


X
5722793
‘A/G’
G
18.56
1.85


RS11091940
3


X
93198011
‘A/G’
G
12.59
1.64


RS5970648
3


X
22750361
‘C/T’
G
11.45
1.56


RS1458368
3
DMD
1756
X
31730435
‘A/G’
A
10.93
1.57


RS5936438
3
AFF2
2334
X
147694315
‘A/G’
A
12.74
0.62


RS1361680
3


X
93217606
‘A/G’
A
13.32
1.62


RS5983336
3


X
93209681
‘A/C’
C
12.98
1.61


RS10522062
3


X
93207413
‘A/G’
C
12.75
1.60


RS4503212
2
RGN
9104
X
46826402
‘A/G’
G
17.15
0.58


RS3850163
3


X
28355558
‘G/T’
C
12.06
1.57


RS3863537
3


X
13030051
‘C/T’
G
11.18
0.65


RS5962469
3
IL1RAPL2
26280
X
104285901
‘A/G’
A
13.36
0.63


RS6616567
3
IL1RAPL2
26280
X
104244418
‘C/T’
A
12.44
0.64


RS5953334
3
LOC139163
139163
X
49330138
‘C/T’
C
12.44
0.64


RS5931268
2


X
136893265
‘G/T’
A
13.33
0.64


RS5961861
3


X
5738176
‘C/T’
G
16.23
1.64


RS731426
3
CXorf6
10046
X
149395757
‘C/T’
A
13.01
1.56


RS5905269
2


X
115402180
‘A/C’
A
10.89
0.67


RS2366513
2


X
136878343
‘A/G’
G
17.83
1.67


RS2366517
2


X
136887785
‘C/T’
G
17.47
1.66


RS5918294
3


X
41854429
‘C/T’
A
19.01
1.70


RS1007490
3


X
22745174
‘C/T’
G
11.19
1.50


RS2886700
2


X
136849214
‘C/T’
G
18.51
1.68


RS1293468
3


X
122036209
‘C/T’
A
11.87
0.66


RS1293545
3


X
121956842
‘A/G’
G
11.85
0.66


RS5935799
3
GLRA2
2742
X
14641184
‘A/G’
A
11.44
1.50


RS909659
3


X
143894286
‘C/T’
G
11.98
1.51


RS2128519
3


X
5626964
‘C/T’
G
10.91
1.48


RS2269584
3
PPEF1
5475
X
18689642
‘A/G’
A
10.98
0.68


RS4825236
3
PPEF1
5475
X
18642674
‘C/T’
G
10.87
0.68


RS4825420
3


X
116062304
‘G/T’
A
10.83
1.48


RS7059239
3
PPEF1
5475
X
18622368
‘A/G’
A
11.49
1.49


RS5909201
3
PPEF1
5475
X
18623637
‘C/T’
A
11.49
1.49





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Priority_date: SNP listed in 1: US 11/245,248 2: US 60/819,014 3: US 60/867,454


Sequence_ID: Sequence identification number


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


Minor Allele: SNP allele or its complementary nucleotide that is less common in the control population.


Allele_X2: Chi-squared test based on allele frequencies


Odds ratio: Calculated for the minor allele.


Gene_content: Genes positioned within 100 Kbp up and downstream from the physical position of the SNPs based on NCBI Human Genome Build 36.













TABLE 6







SNP markers with the strongest association with hypertension in the regression analysis with an


additive genotype model and T2D as a covariate. The analysis is based on the combined data of 110 HT cases


and 110 healthy controls from the Ashkenazi Jew population, 114 HT cases and 114 healthy controls from


the East Finnish population, 41 HT cases and 41 healthy controls from the German population and 28 HT


cases and 28 healthy controls from the English population.
















Gene locus









and


dbSNP rs ID
Priority date
Gene ID
Chromosome
Position
Variats
Coefficient
P value


















RS2245192
3


7
113789771
‘C/T’
−0.83
1.23E−05


RS2458291
3
ATP6V1C1
528
8
104138327
‘C/T’
−0.81
2.01E−05


RS7406978
3
ABR
29
17
983909
‘C/T’
−0.58
2.06E−05


RS934083
3
CACNA2D3
55799
3
54765419
‘C/T’
0.57
2.64E−05


RS11088668
3


21
18448920
‘C/T’
−0.84
3.24E−05


RS2256182
3


8
93637241
‘C/T’
0.69
4.09E−05


RS6474169
3
ADAM18
8749
8
39697120
‘G/T’
0.58
5.24E−05


RS711129
3


12
76568088
‘C/T’
−0.89
5.85E−05


RS4891635
3


18
63741526
‘C/T’
0.99
6.71E−05


RS261988
3


5
95866641
‘A/G’
0.57
6.75E−05


RS165774
3
COMT
1312
22
18332561
‘A/G’
0.61
7.53E−05


RS1369704
3
DTNB
1838
2
25477094
‘A/G’
−0.59
9.82E−05


RS1022790
3


20
10678759
‘A/G’
0.55
1.07E−04


RS189947
3


21
17556641
‘A/C’
0.58
1.17E−04


RS6892814
3
STK10
6793
5
171502017
‘A/G’
0.55
1.19E−04


RS3900775
3
SMOC2
64094
6
168613353
‘C/T’
−0.74
1.28E−04


RS11650418
3
ABR
29
17
1025021
‘G/T’
0.54
1.30E−04


RS6444191
3
ST6GAL1
6480
3
188182304
‘A/G’
−0.55
1.32E−04


RS7141
3
EFNB3
1949
17
7555326
‘A/G’
0.57
1.40E−04


RS6828802
3


4
292934
‘C/T’
0.56
1.47E−04


RS2329727
3


7
51368212
‘A/G’
1.00
1.48E−04


RS2901483
3


2
62618776
‘A/G’
0.78
1.55E−04


RS290048
3


2
77381720
‘A/G’
−1.45
1.69E−04


RS17254891
3


3
61419483
‘C/T’
0.70
1.70E−04


RS6872241
3


5
151061730
‘C/T’
0.62
1.72E−04


RS1721355
3
WDR69
164781
2
228491220
‘A/G’
−0.52
1.72E−04


RS1384634
3
ZPBP
11055
7
50035023
‘C/T’
0.52
1.74E−04


RS1488547
3
NLGN1
22871
3
175008462
‘C/T’
0.56
1.86E−04


RS351211
3


15
72363918
‘G/T’
−0.64
1.94E−04


RS7648607
3
MITF
4286
3
69919626
‘A/C’
−0.51
1.97E−04


RS9564765
3


13
70431786
‘A/G’
0.56
1.99E−04


RS17699211
3


12
3903752
‘C/T’
0.81
2.08E−04


RS2447523
3


11
33418920
‘A/G’
−0.64
2.28E−04


RS4873814
3


8
144793335
‘A/G’
0.76
2.30E−04


RS1901388
3
ADAM18
8749
8
39672418
‘C/T’
0.53
2.35E−04


RS7539199
3


1
34855853
‘A/G’
0.78
2.39E−04


RS6980380
3
PRKAG2
51422
7
151018453
‘C/T’
0.71
2.43E−04


RS2249963
3


8
11512635
‘C/T’
−0.50
2.50E−04


RS7305776
3


12
76122239
‘A/G’
0.55
2.53E−04


RS12140392
3


1
186420880
‘A/C’
−0.61
2.55E−04


RS6574791
3


14
19800970
‘C/T’
−0.79
2.66E−04


RS4143444
3


6
91103018
‘C/T’
−0.83
2.67E−04


RS13074723
3
NLGN1
22871
3
175004791
‘A/G’
−0.55
2.85E−04


RS6466963
3
LOC401398
401398
7
124359524
‘A/G’
−0.53
2.89E−04


RS9863894
3
NLGN1
22871
3
174960398
‘C/T’
0.55
2.94E−04


RS4246861
3


9
25589995
‘C/T’
0.62
2.96E−04


RS2852217
3
GRIK4
2900
11
120152436
‘C/T’
0.56
2.98E−04


RS10833533
3


11
3214412
‘A/G’
−0.65
3.04E−04


RS2610725
3


6
89322376
‘C/T’
−0.51
3.09E−04


RS3130559
3
PSORS1C1
170679
6
31205280
‘C/T’
−0.56
3.16E−04


RS583190
3
CACNA2D3
55799
3
54702117
‘A/C’
0.47
3.24E−04


RS9309828
3


3
79843464
‘A/G’
0.56
3.27E−04


RS10519722
3
LOC644055
644055
2
6298399
‘A/G’
0.50
3.27E−04


RS2173086
3
KIAA1040
23041
12
61165237
‘A/G’
0.70
3.28E−04


RS10245474
3
ATXN7L4
222255
7
105249944
‘A/C’
0.59
3.29E−04


RS6604634
3
ESRRG
2104
1
214787878
‘A/G’
−0.49
3.35E−04


RS6128804
3


20
58403830
‘A/G’
0.62
3.47E−04


RS11025056
3


11
19186741
‘A/G’
−0.90
3.49E−04


RS1874622
3
CRISPLD2
83716
16
83455234
‘A/G’
−0.83
3.50E−04


RS1399333
3


4
10878977
‘C/T’
0.60
3.54E−04


RS17523117
3


5
124691426
‘A/G’
−0.52
3.54E−04


RS10962917
3


9
17220086
‘A/G’
0.69
3.55E−04


RS2723167
3


2
113337681
‘C/T’
−0.48
3.56E−04


RS13000621
3


2
181301492
‘A/G’
0.49
3.56E−04


RS7318557
3
LHFP
10186
13
38818286
‘C/T’
−0.54
3.58E−04


RS1744493
3


6
165577651
‘C/T’
−0.53
3.60E−04


RS7601055
3
KIAA1486
57624
2
226028326
‘C/T’
−0.96
3.63E−04


RS10506851
3
PPFIA2
8499
12
80662290
‘A/G’
−0.68
3.71E−04


RS6074018
3
MANBAL
63905
20
35358710
‘A/G’
−0.62
3.76E−04


RS9572943
3


13
71751202
‘C/T’
−0.72
3.78E−04


RS6890771
3


5
180014372
‘C/T’
0.49
3.95E−04


RS4688807
3
PLXND1
23129
3
130791953
‘C/T’
0.54
4.05E−04


RS7125888
3
AMPD3
272
11
10466848
‘C/T’
−0.50
4.09E−04


RS8010116
3


14
19793535
‘C/T’
−0.76
4.23E−04


RS12631548
3
CAST1
26059
3
56011031
‘C/T’
−0.68
4.34E−04


RS2861598
3
NLGN1
22871
3
175027506
‘C/T’
0.52
4.35E−04


RS2454043
3
ATP6V1C1
528
8
104139431
‘G/T’
0.52
4.39E−04


RS6436553
3
KIAA1486
57624
2
226002129
‘A/G’
−0.95
4.39E−04


RS4865755
3
ITGA2
3673
5
52326944
‘C/T’
−0.57
4.40E−04


RS6852347
3
PPP3CA
5530
4
102436590
‘C/T’
0.49
4.48E−04


RS11911479
3


21
18463191
‘C/T’
−0.72
4.50E−04


RS6500316
3


16
49108242
‘A/G’
−0.51
4.52E−04


RS7440788
3


4
59837784
‘C/T’
0.71
4.53E−04


RS1425531
3


4
143645481
‘C/T’
0.56
4.59E−04


RS204505
3


9
117927770
‘C/T’
−0.49
4.63E−04


RS1838733
3
PDE4D
5144
5
58569149
‘A/G’
−0.54
4.63E−04


RS846491
3
KATNAL1
84056
13
29743131
‘C/T’
0.81
4.70E−04


RS2165857
3
ABR
29
17
954904
‘C/T’
−0.49
4.72E−04


RS697550
3


5
14125453
‘G/T’
0.61
4.79E−04


RS12133017
3
C1orf125
126859
1
177708960
‘C/T’
0.49
4.81E−04


RS4447608
3


2
113322428
‘C/T’
−0.47
4.84E−04


RS2044961
3
LRRN6C
158038
9
28154645
‘A/G’
−0.48
4.84E−04


RS477558
3


1
18092414
‘A/G’
−0.47
4.86E−04


RS984923
3


8
24690660
‘A/G’
0.50
4.91E−04


RS6882366
3


5
95890449
‘C/T’
−0.51
4.91E−04


RS4735183
3


8
93638119
‘G/T’
−0.54
4.94E−04


RS10872824
3


10
133356838
‘A/G’
0.60
4.96E−04


RS1928863
3


9
12240170
‘A/G’
−0.47
4.97E−04


RS11791609
3


9
12246453
‘A/G’
0.48
4.97E−04


RS2040859
3
PIK3C2A
5286
11
17104753
‘C/T’
−0.56
5.00E−04


RS17140205
3


5
115970039
‘A/G’
−0.50
5.11E−04


RS6595959
3
LOC649922
649922
5
97938006
‘C/T’
0.65
5.15E−04


RS767460
3
CNTN4
152330
3
2716787
‘A/G’
−0.55
5.25E−04


RS6885761
3


5
154595473
‘A/G’
0.99
5.28E−04


RS11685593
3


2
127604591
‘C/T’
−0.61
5.31E−04


RS6550169
3
LOC651301
651301
3
32888097
‘C/T’
−0.47
5.34E−04


RS6926970
3
ENPP1
5167
6
132208983
‘A/C’
0.66
5.35E−04


RS827228
3
ARHGAP15
55843
2
143626189
‘C/T’
0.48
5.38E−04


RS1332855
3


9
82827607
‘G/T’
−0.70
5.40E−04


RS2934477
3
CRISPLD2
83716
16
83480748
‘A/C’
0.47
5.44E−04


RS8066575
3
FLJ45831
400576
17
14631647
‘C/T’
−0.53
5.45E−04


RS6038092
3


20
5137472
‘A/G’
−0.81
5.46E−04


RS2225213
3
C1orf125
126859
1
177725444
‘C/T’
0.48
5.48E−04


RS2283379
3
RGS6
9628
14
71998582
‘G/T’
−0.62
5.55E−04


RS1155847
3
PRSS7
5651
21
18626167
‘C/T’
−0.84
5.57E−04


RS7008482
3
C8orf36
286053
8
126336812
‘G/T’
0.48
5.60E−04


RS12038863
3


1
178843066
‘A/C’
−0.88
5.60E−04


RS1971877
3


2
6292967
‘A/G’
0.54
5.64E−04


RS7334289
3


13
37000990
‘C/T’
0.68
5.70E−04


RS7335400
3


13
37001152
‘A/C’
−0.68
5.70E−04


RS1544452
3


7
124168925
‘A/G’
−0.51
5.72E−04


RS590218
3
ZNF516
9658
18
72198871
‘A/G’
−0.67
5.77E−04


RS111524
3
HSH2D
84941
19
16126494
‘C/T’
−0.57
5.78E−04


RS12487554
3
SEC22L2
26984
3
124425472
‘A/G’
0.49
5.85E−04


RS1429376
3
XDH
7498
2
31442065
‘A/C’
0.58
5.87E−04


RS1795502
3
LIN7A
8825
12
79791804
‘A/C’
−0.63
5.88E−04


RS1163665
3
LIN7A
8825
12
79813991
‘C/T’
0.63
5.88E−04


RS2301301
3
HOXD3
3232
2
176740513
‘C/T’
0.47
5.96E−04


RS1383750
3
LOC401398
401398
7
124488002
‘C/T’
0.48
5.98E−04


RS827226
3
ARHGAP15
55843
2
143639083
‘C/T’
−0.47
6.00E−04


RS7901709
3


10
110273057
‘C/T’
−0.48
6.01E−04


RS1833036
3
ESRRG
2104
1
214773635
‘A/C’
0.47
6.05E−04


RS10743601
3
STK38L
23012
12
27300343
‘A/G’
0.60
6.10E−04


RS4807030
3


19
5340941
‘A/G’
0.52
6.13E−04


RS8063120
3


16
80352553
‘A/G’
−0.49
6.16E−04


RS1425533
3


4
143640625
‘C/T’
0.57
6.18E−04


RS11199496
3


10
122439906
‘C/T’
−0.51
6.18E−04


RS2391671
3
CREB5
9586
7
28518902
‘A/G’
0.52
6.19E−04


RS2703833
3
KCTD8
386617
4
44036287
‘C/T’
0.62
6.28E−04


RS4277860
3


5
67511708
‘A/G’
0.73
6.29E−04


RS11582225
3


1
162108767
‘C/T’
−0.67
6.39E−04


RS3863537
3


X
13030051
‘C/T’
−0.43
6.39E−04


RS6040345
3


20
11011477
‘A/G’
0.49
6.45E−04


RS2025245
3


13
37001577
‘A/G’
0.67
6.45E−04


RS2322606
3
PTK2B
2185
8
27242840
‘A/G’
−0.48
6.65E−04


RS1347744
3


4
166502051
‘A/G’
−0.47
6.66E−04


RS2167644
3
LRRN6C
158038
9
28076344
‘A/G’
−0.54
6.68E−04


RS12615237
3


2
44131231
‘C/T’
−0.63
6.70E−04


RS3750010
3
FLJ10324
55698
7
4867717
‘A/G’
0.92
6.78E−04


RS249740
3


5
141874445
‘C/T’
−0.61
6.79E−04


RS6870276
3


5
85590471
‘A/G’
−0.48
6.83E−04


RS4657284
3


1
161707341
‘A/G’
−0.70
6.86E−04


RS2306245
3
LOC653983
653983
4
852156
‘A/G’
0.49
6.95E−04


RS2072824
3
JARID2
3720
6
15616089
‘C/T’
0.67
6.97E−04


RS4465845
3


20
4402065
‘A/G’
−0.64
7.02E−04


RS10937103
3
ATP11B
23200
3
184096377
‘A/G’
−0.52
7.02E−04


RS4902242
3


14
63299842
‘C/T’
−0.71
7.06E−04


RS277037
3


8
132689881
‘C/T’
0.47
7.10E−04


RS744651
3


17
56918030
‘C/T’
−0.51
7.13E−04


RS1324997
3


13
52282657
‘A/G’
0.68
7.14E−04


RS9506903
3


13
22150146
‘C/T’
−0.51
7.18E−04


RS688630
3
TCTEX1D1
200132
1
66995554
‘A/G’
0.46
7.22E−04


RS1158717
3


6
115901074
‘C/T’
−0.62
7.24E−04


RS6965360
3


7
88818990
‘A/G’
−0.98
7.26E−04


RS2717229
3
PDIA5
10954
3
124362066
‘C/T’
0.46
7.32E−04


RS4651073
3
XPR1
9213
1
178867222
‘A/G’
−0.48
7.42E−04


RS364612
3


8
94124310
‘C/T’
−0.63
7.43E−04


RS3774051
3
EHHADH
1962
3
186424419
‘A/G’
0.58
7.44E−04


RS10223320
3


5
158506964
‘C/T’
0.46
7.46E−04


RS10521767
3


X
130284232
‘C/T’
0.59
7.61E−04


RS4777700
3
LOC283682
283682
15
92118937
‘A/G’
−0.65
7.63E−04


RS4731214
3


7
124230141
‘A/G’
−0.47
7.75E−04


RS11132149
3
ODZ3
55714
4
183907038
‘A/G’
−0.47
7.77E−04


RS6677410
3
BLZF1
8548
1
167619919
‘C/T’
−0.46
7.86E−04


RS4283967
3


7
124327771
‘C/T’
0.47
7.92E−04


RS987848
3


13
38779740
‘C/T’
0.51
7.96E−04


RS3816599
3
TSPAN13
27075
7
16782067
‘A/G’
−0.51
7.97E−04


RS903027
3
MGC34646
157807
8
62571982
‘G/T’
−0.66
8.04E−04


RS859170
3


21
17549488
‘C/T’
0.50
8.09E−04


RS373747
3


22
18535192
‘C/T’
−0.46
8.10E−04


RS2377098
3
ESRRG
2104
1
214782137
‘G/T’
0.48
8.13E−04


RS246107
3
P4HA2
8974
5
131574567
‘A/G’
−0.49
8.14E−04


RS189816
3
ARHGAP15
55843
2
143607496
‘C/T’
−0.49
8.19E−04


RS7201164
3


16
61224753
‘A/G’
−0.57
8.23E−04


RS521331
3


10
8264856
‘C/T’
0.53
8.28E−04


RS1335579
3
TCEA2
6919
20
62161757
‘A/G’
−0.49
8.32E−04


RS11651563
3
FOXK2
3607
17
78106672
‘C/T’
1.25
8.33E−04


RS13080275
3
CNTN4
152330
3
2721456
‘C/T’
0.50
8.34E−04


RS6961292
3
POT1
25913
7
124290425
‘A/G’
0.47
8.36E−04


RS10515283
1


5
98121571
‘C/T’
−0.53
8.38E−04


RS1282129
3


1
111424262
‘A/G’
0.48
8.38E−04


RS660048
3


3
76142189
‘C/T’
0.71
8.42E−04


RS1812315
3


15
25522899
‘C/T’
0.61
8.50E−04


RS6778227
3


3
182516536
‘C/T’
0.45
8.55E−04


RS10264288
3
LOC401398
401398
7
124361763
‘A/G’
0.47
8.61E−04


RS11761669
3
LOC401398
401398
7
124373537
‘A/G’
0.47
8.61E−04


RS12112909
3
LOC401398
401398
7
124372070
‘C/T’
−0.47
8.61E−04


RS11618001
3


13
66975757
‘A/G’
−0.77
8.63E−04


RS12538333
3
POT1
25913
7
124295593
‘C/T’
0.47
8.64E−04


RS6912194
3


6
115923850
‘A/G’
−0.61
8.65E−04


RS3848521
3


19
62264525
‘A/G’
0.53
8.65E−04


RS2897074
3


4
155157135
‘A/C’
−0.45
8.75E−04


RS25890
3


5
131465461
‘A/G’
−0.49
8.75E−04


RS873833
3
CABIN1
23523
22
22757878
‘C/T’
0.53
8.82E−04


RS2267064
3
LOC648941
648941
22
22874632
‘G/T’
0.53
8.82E−04


RS462769
3
MGC26885
124044
16
88290764
‘A/G’
−0.46
8.86E−04


RS774508
3


2
155155961
‘C/T’
0.83
8.93E−04


RS1010491
3
SP140
11262
2
230868765
‘A/G’
1.04
8.94E−04


RS12666427
3
POT1
25913
7
124266588
‘A/G’
−0.47
8.98E−04


RS4377885
3
POT1
25913
7
124320916
‘C/T’
−0.47
8.98E−04


RS10228682
3
POT1
25913
7
124325272
‘C/T’
−0.47
8.98E−04


RS1904975
3


7
124340038
‘A/G’
−0.47
8.98E−04


RS6973812
3
POT1
25913
7
124293986
‘C/T’
0.47
8.98E−04


RS13029963
3


2
122601190
‘A/G’
0.57
9.09E−04


RS589281
3
CACNA2D3
55799
3
54722284
‘C/T’
0.45
9.11E−04


RS1673130
3


19
9996687
‘C/T’
−0.47
9.15E−04


RS10953026
3
PFTK1
5218
7
90388127
‘A/G’
0.50
9.22E−04


RS2717272
3


3
183954066
‘C/T’
0.45
9.22E−04


RS1550357
3


5
124505300
‘C/T’
0.45
9.29E−04


RS9558678
3


13
105554332
‘C/T’
−0.66
9.37E−04


RS9977890
3
DSCAM
1826
21
40921882
‘C/T’
−0.51
9.37E−04


RS6604632
3
ESRRG
2104
1
214774201
‘A/G’
−0.45
9.43E−04


RS2305913
3
FBF1
85302
17
71434536
‘A/G’
−0.48
9.45E−04


RS3893376
3


4
15351172
‘C/T’
−0.51
9.46E−04


RS2834939
3


21
35754778
‘A/G’
0.50
9.47E−04


RS2278089
3
NMI
9111
2
151854918
‘A/C’
−0.47
9.59E−04


RS7959334
3
TMTC1
83857
12
29764061
‘C/T’
0.44
9.61E−04


RS896169
3


7
131500210
‘A/C’
−0.50
9.64E−04


RS10116548
3


9
12224642
‘C/T’
−0.46
9.68E−04


RS12128593
3


1
66747467
‘C/T’
−0.68
9.75E−04


RS499899
3


6
20109726
‘C/T’
−0.51
9.80E−04


RS11695594
3
ERBB4
2066
2
212035677
‘C/T’
0.50
9.80E−04


RS6961441
3
LOC401398
401398
7
124378107
‘A/G’
−0.46
9.88E−04


RS1871770
3
LOC401398
401398
7
124418075
‘G/T’
−0.46
9.88E−04


RS7787605
3
LOC401398
401398
7
124447218
‘A/G’
0.46
9.88E−04


RS1893833
3


18
73221461
‘C/T’
−0.51
9.97E−04


RS7625913
3


3
76167310
‘A/C’
0.67
9.98E−04





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Priority_date: SNP listed in 1: US 11/245,248 2: US 60/819,014 3: US 60/867,454


Sequence_ID: Sequence identification number


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


Minor Allele: SNP allele or its complementary nucleotide that is less common in the control population.


Allele_X2: Chi-squared test based on allele frequencies


Coefficient: Coefficient w of the model glm(z~w + r, family = binomial(link = logit)) in R where z is hypertension status, w is genotype (0, 1, 2) and r is T2D status


P value: P value of the coefficient w


Gene_content: Genes positioned within 100 Kbp up and downstream from the physical position of the SNPs based on NCBI Human Genome Build 36.1













TABLE 7







SNP markers with the strongest association with hypertension


in the regression analysis with a recessive genotype model and T2D


as a covariate. The analysis is based on the combined data of 110


HT cases and 110 healthy controls from the Ashkenazi Jew population,


114 HT cases and 114 healthy controls from the East Finnish population,


41 HT cases and 41 healthy controls from the German population and


28 HT cases and 28 healthy controls from the English population.
















Gene locus









and




P


dbSNP rs ID
Priority date
Gene ID
Chromosome
Position
Variats
Coefficient
value


















RS10509557
3
STAMBPL1
57559
10
90653819
‘C/T’
−1.70
1.34E−06


RS11088668
3


21
18448920
‘C/T’
−1.00
1.15E−05


RS1568447
3


17
70348607
‘A/G’
−1.11
1.41E−05


RS2458291
3
ATP6V1C1
528
8
104138327
‘C/T’
−0.93
1.92E−05


RS8043993
3
TMC7
79905
16
18956879
‘A/G’
−0.85
1.96E−05


RS1425531
3


4
143645481
‘C/T’
0.85
2.10E−05


RS261988
3


5
95866641
‘A/G’
1.11
2.35E−05


RS6474131
3
LOC651362
651362
8
39344125
‘A/C’
0.99
2.53E−05


RS6934805
3


6
168581640
‘A/G’
0.84
3.79E−05


RS10088400
3
ADAM5
255926
8
39350791
‘A/C’
0.96
4.07E−05


RS2723167
3


2
113337681
‘C/T’
−0.90
4.37E−05


RS4481638
3
LOC286094
286094
8
136363511
‘A/G’
−1.22
5.48E−05


RS717576
3
STAMBPL1
57559
10
90657573
‘C/T’
−1.30
5.69E−05


RS7213057
3
FLJ22222
79701
17
77972228
‘C/T’
1.78
6.70E−05


RS12513906
3


5
80267341
‘G/T’
−3.07
7.24E−05


RS6435367
3


2
207804849
‘A/G’
−1.11
7.94E−05


RS1163665
3
LIN7A
8825
12
79813991
‘C/T’
0.86
8.03E−05


RS11650418
3
ABR
29
17
1025021
‘G/T’
0.79
8.18E−05


RS7539199
3


1
34855853
‘A/G’
0.92
8.19E−05


RS1953352
3


14
55266912
‘A/G’
1.03
8.48E−05


RS11690643
3


2
228500725
‘C/T’
−0.78
8.65E−05


RS1425533
3


4
143640625
‘C/T’
0.79
9.37E−05


RS6128804
3


20
58403830
‘A/G’
0.81
1.08E−04


RS10962917
3


9
17220086
‘A/G’
0.82
1.12E−04


RS1335579
3
TCEA2
6919
20
62161757
‘A/G’
−0.78
1.24E−04


RS4447608
3


2
113322428
‘C/T’
−0.83
1.35E−04


RS827228
3
ARHGAP15
55843
2
143626189
‘C/T’
0.76
1.41E−04


RS599367
3


1
20306989
‘C/T’
−1.31
1.47E−04


RS3127084
3
NRAP
4892
10
115366641
‘A/G’
−0.94
1.51E−04


RS7252391
3
IGSF4C
199731
19
48834611
‘A/G’
1.70
1.52E−04


RS9533785
3


13
43661038
‘A/G’
−0.80
1.56E−04


RS17699211
3


12
3903752
‘C/T’
0.91
1.62E−04


RS10954695
3
PCLO
27445
7
82395164
‘A/G’
0.75
1.62E−04


RS12960602
3


18
501960
‘C/T’
0.75
1.69E−04


RS1524909
3


2
156090205
‘A/G’
−1.29
1.72E−04


RS521331
3


10
8264856
‘C/T’
0.74
1.79E−04


RS883509
3
TSPAN5
10098
4
99782699
‘C/T’
1.06
1.87E−04


RS1009283
3


2
240842754
‘A/G’
0.73
1.87E−04


RS976714
3
PCLO
27445
7
82419795
‘C/T’
0.74
1.88E−04


RS9863894
3
NLGN1
22871
3
174960398
‘C/T’
0.73
1.90E−04


RS6595959
3
LOC649922
649922
5
97938006
‘C/T’
0.82
1.90E−04


RS6474169
3
ADAM18
8749
8
39697120
‘G/T’
0.78
2.02E−04


RS7147000
3


14
104078860
‘A/G’
−1.24
2.02E−04


RS990060
3


6
89131055
‘C/T’
0.96
2.03E−04


RS9344790
3


6
89116996
‘A/G’
0.96
2.03E−04


RS10954696
3
PCLO
27445
7
82420782
‘C/T’
0.74
2.05E−04


RS2523647
3


6
31557757
‘C/T’
−1.62
2.05E−04


RS2256182
3


8
93637241
‘C/T’
0.72
2.09E−04


RS7081359
3
MGMT
4255
10
131402923
‘C/T’
−0.72
2.11E−04


RS873833
3
CABIN1
23523
22
22757878
‘C/T’
1.64
2.15E−04


RS2267064
3
LOC648941
648941
22
22874632
‘G/T’
1.64
2.15E−04


RS7334289
3


13
37000990
‘C/T’
0.81
2.19E−04


RS6823763
3


4
77945322
‘A/G’
2.01
2.19E−04


RS204505
3


9
117927770
‘C/T’
−0.73
2.19E−04


RS6074018
3
MANBAL
63905
20
35358710
‘A/G’
−0.73
2.27E−04


RS3863537
3


X
13030051
‘C/T’
−0.94
2.28E−04


RS7059239
3
PPEF1
5475
X
18622368
‘A/G’
−0.75
2.34E−04


RS5909201
3
PPEF1
5475
X
18623637
‘C/T’
−0.75
2.34E−04


RS2260849
3
ABR
29
17
943785
‘C/T’
0.77
2.38E−04


RS1871164
3


5
152771658
‘C/T’
−0.84
2.41E−04


RS1158717
3


6
115901074
‘C/T’
−0.77
2.42E−04


RS2025245
3


13
37001577
‘A/G’
0.80
2.50E−04


RS10116548
3


9
12224642
‘C/T’
−0.76
2.66E−04


RS4471434
3
KIRREL3
84623
11
125892601
‘C/T’
0.97
2.73E−04


RS10978931
3


9
109386549
‘A/G’
−0.90
2.74E−04


RS1017035
3
PSCD3
9265
7
6174894
‘A/G’
−1.33
2.78E−04


RS12581363
3


12
86455427
‘C/T’
0.72
2.80E−04


RS2377098
3
ESRRG
2104
1
214782137
‘G/T’
0.76
2.91E−04


RS276855
3


15
37318605
‘A/G’
−0.89
2.93E−04


RS798646
3


7
23586259
‘C/T’
−0.75
2.96E−04


RS758439
3
AFF2
2334
X
147872587
‘A/G’
−0.94
2.98E−04


RS6912194
3


6
115923850
‘A/G’
−0.76
3.01E−04


RS12599856
3
TMC7
79905
16
18929949
‘A/G’
−0.71
3.02E−04


RS7463107
3
ST18
9705
8
53350840
‘C/T’
−1.42
3.08E−04


RS2306245
3
LOC653983
653983
4
852156
‘A/G’
0.93
3.18E−04


RS6870276
3


5
85590471
‘A/G’
−0.83
3.19E−04


RS7805656
3
LOC392670
392670
7
50148762
‘C/T’
−0.89
3.34E−04


RS17523117
3


5
124691426
‘A/G’
−0.71
3.34E−04


RS2359682
3
LOC391475
391475
2
207288554
‘A/G’
0.71
3.40E−04


RS6467917
3
PCLO
27445
7
82407593
‘A/G’
0.79
3.50E−04


RS527713
3


6
94863650
‘C/T’
−1.03
3.51E−04


RS4432885
3
LOC649120
649120
5
84156628
‘C/T’
−1.09
3.55E−04


RS857160
3
C1orf168
199920
1
57014455
‘A/G’
−1.36
3.58E−04


RS2158232
3


16
17862049
‘G/T’
−0.88
3.59E−04


RS3130559
3
PSORS1C1
170679
6
31205280
‘C/T’
−0.71
3.62E−04


RS1833036
3
ESRRG
2104
1
214773635
‘A/C’
0.75
3.63E−04


RS4844078
3
AFF2
2334
X
147873742
‘A/G’
−0.93
3.63E−04


RS10245474
3
ATXN7L4
222255
7
105249944
‘A/C’
0.71
3.64E−04


RS456509
3


5
98022934
‘A/G’
0.77
3.71E−04


RS2409472
3


21
33421296
‘A/G’
0.98
3.74E−04


RS11618001
3


13
66975757
‘A/G’
−0.89
3.84E−04


RS288193
3
FBXL17
64839
5
107346510
‘A/G’
−0.71
3.92E−04


RS7557557
3
BARD1
580
2
215342872
‘C/T’
0.84
3.93E−04


RS4807030
3


19
5340941
‘A/G’
0.69
3.93E−04


RS2062960
3
LOC647489
647489
18
67533577
‘A/G’
−0.77
3.95E−04


RS2011050
3


5
151077474
‘A/G’
1.12
3.95E−04


RS351211
3


15
72363918
‘G/T’
−2.11
3.99E−04


RS2341919
3
AFF2
2334
X
147870833
‘G/T’
−0.92
3.99E−04


RS2055598
3
CNTN5
53942
11
98794981
‘A/G’
1.32
4.00E−04


RS6561018
3
MGC40178
122046
13
30433891
‘A/G’
−0.73
4.02E−04


RS4245178
3
TMPRSS13
84000
11
117293523
‘C/T’
1.12
4.12E−04


RS3816272
3
IMP-1
10642
17
44475466
‘C/T’
−1.10
4.28E−04


RS10831742
3
MICAL2
9645
11
12126901
‘A/G’
2.34
4.30E−04


RS9937539
3
TMC7
79905
16
18941493
‘A/C’
−0.70
4.35E−04


RS6677410
3
BLZF1
8548
1
167619919
‘C/T’
−0.71
4.44E−04


RS10464988
3
LOC286094
286094
8
136363842
‘C/T’
−0.94
4.51E−04


RS942233
3


13
79599849
‘A/G’
0.84
4.55E−04


RS9309828
3


3
79843464
‘A/G’
0.68
4.59E−04


RS8063120
3


16
80352553
‘A/G’
−0.70
4.59E−04


RS725613
3
KIAA0350
23274
16
11077184
‘A/C’
−0.94
4.64E−04


RS3816599
3
TSPAN13
27075
7
16782067
‘A/G’
−0.77
4.69E−04


RS4260345
3
THRB
7068
3
24231702
‘C/T’
0.88
4.71E−04


RS744651
3


17
56918030
‘C/T’
−0.69
4.72E−04


RS6547369
3


2
81477485
‘A/C’
−1.01
4.75E−04


RS578130
3
ARRB1
408
11
74681211
‘C/T’
−0.68
4.80E−04


RS2173086
3
KIAA1040
23041
12
61165237
‘A/G’
0.74
4.86E−04


RS896169
3


7
131500210
‘A/C’
−1.20
4.89E−04


RS1447549
3


2
133334690
‘C/T’
1.58
4.89E−04


RS39617
3
TRIO
7204
5
14263897
‘G/T’
0.68
4.95E−04


RS6579891
3


5
151054802
‘C/T’
1.54
5.01E−04


RS6461076
3
DGKB
1607
7
14225771
‘G/T’
0.96
5.01E−04


RS890027
3


8
5844762
‘A/G’
−1.47
5.06E−04


RS1582029
3


9
17233746
‘A/G’
0.77
5.10E−04


RS6504593
3
IMP-1
10642
17
44487818
‘C/T’
−0.79
5.17E−04


RS1010032
3


3
59531242
‘C/T’
1.15
5.19E−04


RS6806589
3


3
76231050
‘C/T’
1.04
5.19E−04


RS1110968
3


4
165711289
‘A/C’
−0.94
5.21E−04


RS1895391
3
SV2C
22987
5
75481681
‘A/G’
−0.73
5.32E−04


RS1500106
3


12
124315518
‘C/T’
0.71
5.33E−04


RS1488547
3
NLGN1
22871
3
175008462
‘C/T’
0.67
5.35E−04


RS3091629
3
PKIG
11142
20
42598785
‘G/T’
0.79
5.38E−04


RS7909235
3
CTNNA3
29119
10
68044090
‘G/T’
−0.68
5.45E−04


RS2243512
3


12
103343237
‘C/T’
0.71
5.45E−04


RS725027
3
ATP2B2
491
3
10402190
‘A/G’
0.71
5.47E−04


RS10906855
3


10
15277222
‘A/G’
0.70
5.58E−04


RS582447
3
GRB14
2888
2
165074838
‘G/T’
0.70
5.59E−04


RS6633148
3
PPEF1
5475
X
18734999
‘C/T’
−0.77
5.63E−04


RS13029963
3


2
122601190
‘A/G’
0.71
5.71E−04


RS6659761
3


1
173450562
‘C/T’
−0.71
5.73E−04


RS12495441
3


3
86459666
‘C/T’
−0.70
5.76E−04


RS51774234
3


10
30257521
‘C/T’
2.00
6.11E−04


RS1998957
3
TPP2
7174
13
102064784
‘A/G’
−0.69
6.18E−04


RS4955834
3


3
55198023
‘C/T’
−0.72
6.27E−04


RS7359067
3


14
55464946
‘C/T’
−1.54
6.35E−04


RS2901483
3


2
62618776
‘A/G’
0.76
6.47E−04


RS939543
3
TMEM104
54868
17
70303779
‘A/G’
−0.76
6.61E−04


RS10872824
3


10
133356838
‘A/G’
0.71
6.62E−04


RS984923
3


8
24690660
‘A/G’
1.00
6.68E−04


RS2072954
3
PLCB4
5332
20
9388840
‘C/T’
1.10
6.72E−04


RS7318557
3
LHFP
10186
13
38818286
‘C/T’
−0.67
6.75E−04


RS1073768
3


20
35310424
‘A/G’
0.72
6.78E−04


RS873634
3
HCN2
610
19
539305
‘G/T’
1.22
6.79E−04


RS6663840
3
GlyBP
9731
1
3733179
‘A/G’
−0.67
6.88E−04


RS4585212
3


3
175925548
‘A/G’
0.73
6.93E−04


RS12141192
3
KIF1B
23095
1
10353719
‘C/T’
0.69
6.95E−04


RS983789
3


1
157862306
‘G/T’
−0.72
6.97E−04


RS9391970
3


6
2765877
‘A/G’
0.66
7.06E−04


RS2595042
3


8
29979947
‘A/G’
−0.80
7.07E−04


RS5917222
3


X
38509735
‘C/T’
−0.66
7.11E−04


RS4237333
3


10
73307232
‘C/T’
0.75
7.16E−04


RS7646664
3
ATP2B2
491
3
10404108
‘C/T’
0.68
7.25E−04


RS4481619
3
ST18
9705
8
53335359
‘C/T’
−1.55
7.39E−04


RS959678
3
ZPBP
11055
7
50031156
‘A/G’
−0.68
7.40E−04


RS2697144
3
SLC6A1
6529
3
11026099
‘A/G’
1.41
7.43E−04


RS1673130
3


19
9996687
‘C/T’
−0.67
7.51E−04


RS26999
3
MCTP1
79772
5
94261262
‘C/T’
−0.73
7.56E−04


RS354286
3
TRIO
7204
5
14288406
‘A/G’
0.65
7.57E−04


RS1366315
3


5
67292325
‘A/G’
−0.67
7.57E−04


RS5908660
3


X
142334080
‘A/G’
−1.06
7.58E−04


RS2925725
3
LOC651419
651419
5
6313651
‘A/C’
−0.71
7.62E−04


RS2838808
3
ADARB1
104
21
45445534
‘C/T’
1.17
7.65E−04


RS5934075
3


X
13077796
‘A/G’
−0.87
7.67E−04


RS244120
3
PKIG
11142
20
42629119
‘A/G’
0.77
7.68E−04


RS7169075
3
LRRC28
123355
15
97694447
‘A/G’
1.54
7.77E−04


RS9804335
3


10
130137163
‘A/G’
−0.67
7.85E−04


RS9292501
3
ADAMTS12
81792
5
33639167
‘A/G’
0.79
7.94E−04


RS6710189
3


2
112506263
‘A/G’
1.42
7.96E−04


RS32549
3
TRIO
7204
5
14266135
‘A/G’
0.66
8.03E−04


RS9695286
3


9
109812888
‘C/T’
−0.73
8.12E−04


RS6500316
3


16
49108242
‘A/G’
−0.99
8.35E−04


RS570657
3
GRB14
2888
2
165064589
‘C/T’
0.68
8.35E−04


RS7406978
3
ABR
29
17
983909
‘C/T’
−0.71
8.41E−04


RS1928863
3


9
12240170
‘A/G’
−0.69
8.43E−04


RS6073964
3


20
35342708
‘A/G’
−0.66
8.43E−04


RS532040
3


11
129081186
‘C/T’
−0.67
8.43E−04


RS6121666
3
CDH4
1002
20
59535349
‘A/G’
−0.80
8.45E−04


RS2068259
3
C20orf74
57186
20
20341219
‘A/C’
−0.66
8.47E−04


RS1838733
3
PDE4D
5144
5
58569149
‘A/G’
−0.65
8.52E−04


RS4107736
3


8
29995506
‘A/G’
−0.84
8.59E−04


RS5911500
3


X
115726187
‘C/T’
−0.85
8.60E−04


RS1022790
3


20
10678759
‘A/G’
0.79
8.61E−04


RS11733672
3


4
4653806
‘C/T’
−0.66
8.83E−04


RS9342944
3
RIMS1
22999
6
73131044
‘C/T’
−0.65
8.85E−04


RS901538
3


11
98312568
‘C/T’
−0.88
8.86E−04


RS462769
3
MGC26885
124044
16
88290764
‘A/G’
−0.68
8.95E−04


RS4952002
3
LYCAT
253558
2
30713511
‘A/G’
−0.68
8.97E−04


RS10494494
3


1
174140762
‘C/T’
−0.67
9.15E−04


RS13149290
3
LOC152485
152485
4
146970416
‘C/T’
−0.66
9.17E−04


RS4709122
3
RPS6KA2
6196
6
166907733
‘C/T’
−0.67
9.21E−04


RS7393306
3
C10orf92
54777
10
134483343
‘A/G’
−0.74
9.26E−04


RS7571570
3
DTNB
1838
2
25475034
‘C/T’
0.65
9.29E−04


RS917684
3


4
10961129
‘A/G’
1.96
9.30E−04


RS7560587
3
KIAA1679
80731
2
138118624
‘C/T’
−1.13
9.32E−04


RS3027363
3
GLRA2
2742
X
14519924
‘A/G’
−0.85
9.37E−04


RS4846217
3


1
10374386
‘C/T’
0.66
9.52E−04


RS893911
3


15
64715542
‘C/T’
−0.68
9.56E−04


RS1880832
3


17
36137258
‘A/G’
0.78
9.74E−04


RS1559621
3


2
59994112
‘A/G’
1.31
9.77E−04


RS9819838
3
LOC344595
344595
3
108418493
‘A/C’
−1.10
9.79E−04


RS6902101
3


6
140626077
‘A/G’
−0.71
9.87E−04


RS921449
3


8
35086721
‘C/T’
−0.96
9.96E−04


RS4478858
3


1
31656512
‘A/G’
−0.77
9.97E−04





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Priority_date: SNP listed in 1: US 11/245,248 2: US 60/819,014 3: US 60/867,454


Sequence_ID: Sequence identification number


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


Minor Allele: SNP allele or its complementary nucleotide that is less common in the control population.


Allele_X2: Chi-squared test based on allele frequencies


Coefficient: Coefficient w of the model g1m(z~w + r, family = binomial(link = logit)) in R where z is hypertension status, w is genotype (0, 1, 1<--2) and r is T2D status


P value: P value of the coefficient w


Gene_content: Genes positioned within 100 Kbp up and downstream from the physical position of the SNPs based on NCBI Human Genome Build 36.1













TABLE 8







SNP markers with the strongest association with hypertension


in the regression analysis with a dominant genotype model and T2D as


a covariate. The analysis is based on the combined data of 110 HT


cases and 110 healthy controls from the Ashkenazi Jew population,


114 HT cases and 114 healthy controls from the East Finnish population,


41 HT cases and 41 healthy controls from the German population


and 28 HT cases and 28 healthy controls from the English population.
















Gene locus









and


dbSNP rs ID
Priority date
Gene ID
Chromosome
Position
Variats
Coefficient
P value


















RS165774
3
COMT
1312
22
18332561
‘A/G’
1.80
2.45E−06


RS6444191
3
ST6GAL1
6480
3
188182304
‘A/G’
−0.98
6.23E−06


RS4813231
3


20
16551596
‘A/G’
−1.13
1.61E−05


RS10241873
3
ZNF212
7988
7
148571806
‘A/C’
1.14
2.06E−05


RS934083
3
CACNA2D3
55799
3
54765419
‘C/T’
0.94
3.47E−05


RS2242278
3
SPON2
10417
4
1155516
‘A/G’
−1.53
4.59E−05


RS711129
3


12
76568088
‘C/T’
−0.96
5.54E−05


RS4891635
3


18
63741526
‘C/T’
1.10
6.50E−05


RS2245192
3


7
113789771
‘C/T’
−0.86
6.58E−05


RS1795502
3
LIN7A
8825
12
79791804
‘A/C’
−0.86
8.03E−05


RS4760980
3


12
126628924
‘A/C’
−0.80
8.25E−05


RS4865755
3
ITGA2
3673
5
52326944
‘C/T’
−0.76
8.69E−05


RS3900775
3
SMOC2
64094
6
168613353
‘C/T’
−0.84
9.57E−05


RS6980380
3
PRKAG2
51422
7
151018453
‘C/T’
0.83
9.85E−05


RS6604634
3
ESRRG
2104
1
214787878
‘A/G’
−0.91
1.24E−04


RS7008482
3
C8orf36
286053
8
126336812
‘G/T’
0.75
1.29E−04


RS6038092
3


20
5137472
‘A/G’
−0.96
1.38E−04


RS7305776
3


12
76122239
‘A/G’
0.75
1.47E−04


RS827226
3
ARHGAP15
55843
2
143639083
‘C/T’
−0.76
1.48E−04


RS10119193
3


9
109336507
‘C/T’
0.87
1.53E−04


RS4723924
3
CDC2L5
8621
7
39997013
‘C/T’
0.76
1.57E−04


RS720295
3
PSAP
5660
10
73267358
‘C/T’
−0.78
1.62E−04


RS290048
3


2
77381720
‘A/G’
−1.45
1.69E−04


RS6726521
3


2
236019083
‘A/G’
−1.00
1.71E−04


RS2329727
3


7
51368212
‘A/G’
1.05
1.76E−04


RS3827256
3
PFKL
5211
21
44565251
‘A/G’
−1.02
1.86E−04


RS2216374
3


2
207798149
‘A/G’
1.07
1.91E−04


RS10506851
3
PPFIA2
8499
12
80662290
‘A/G’
−0.79
2.05E−04


RS7406978
3
ABR
29
17
983909
‘C/T’
−0.86
2.11E−04


RS11652097
3
LOC649173
649173
17
42671716
‘C/T’
−1.20
2.11E−04


RS2675494
3
EPHB2
2048
1
23099753
‘C/T’
−0.89
2.17E−04


RS7335400
3


13
37001152
‘A/C’
−0.81
2.19E−04


RS10495026
3
ESRRG
2104
1
214767553
‘C/T’
−0.74
2.21E−04


RS7141
3
EFNB3
1949
17
7555326
‘A/G’
0.72
2.22E−04


RS897407
3


8
136498130
‘A/G’
1.30
2.26E−04


RS2182703
3


1
22899076
‘A/G’
−0.71
2.27E−04


RS11861084
3
FANCA
2175
16
88403211
‘A/C’
0.97
2.59E−04


RS1369704
3
DTNB
1838
2
25477094
‘A/G’
−0.71
2.61E−04


RS11791609
3


9
12246453
‘A/G’
0.74
2.67E−04


RS583190
3
CACNA2D3
55799
3
54702117
‘A/C’
0.82
2.75E−04


RS6816464
3


4
19537700
‘C/T’
0.71
2.76E−04


RS10008492
3


4
38442115
‘C/T’
−0.83
2.79E−04


RS846491
3
KATNAL1
84056
13
29743131
‘C/T’
0.89
2.99E−04


RS6890771
3


5
180014372
‘C/T’
0.86
3.06E−04


RS2852217
3
GRIK4
2900
11
120152436
‘C/T’
0.70
3.08E−04


RS149999
3


3
139027068
‘C/T’
−1.03
3.10E−04


RS9564765
3


13
70431786
‘A/G’
0.69
3.10E−04


RS3780087
3
AGPAT5
55326
8
6555609
‘C/T’
0.91
3.11E−04


RS1880845
3


12
104377662
‘A/G’
−1.38
3.14E−04


RS1384634
3
ZPBP
11055
7
50035023
‘C/T’
0.86
3.14E−04


RS1874622
3
CRISPLD2
83716
16
83455234
‘A/G’
−0.90
3.17E−04


RS549065
3


6
94860908
‘G/T’
1.03
3.18E−04


RS16956762
3


15
29539275
‘A/G’
−1.17
3.21E−04


RS9616080
3


22
45396830
‘C/T’
−1.78
3.22E−04


RS2137490
3


3
86393288
‘A/C’
0.74
3.39E−04


RS1322280
3


9
10572246
‘C/T’
−1.70
3.43E−04


RS7590833
3
HDAC4
9759
2
239948271
‘A/G’
0.70
3.45E−04


RS6038010
3
SLC23A2
9962
20
4811786
‘C/T’
0.73
3.45E−04


RS7237611
3
CD226
10666
18
65700586
‘A/G’
−0.70
3.47E−04


RS2072824
3
JARID2
3720
6
15616089
‘C/T’
0.77
3.48E−04


RS4900672
3


14
44967080
‘A/G’
−0.93
3.53E−04


RS7601055
3
KIAA1486
57624
2
226028326
‘C/T’
−1.02
3.55E−04


RS2703833
3
KCTD8
386617
4
44036287
‘C/T’
0.74
3.57E−04


RS189816
3
ARHGAP15
55843
2
143607496
‘C/T’
−0.70
3.74E−04


RS246107
3
P4HA2
8974
5
131574567
‘A/G’
−0.69
3.90E−04


RS3848521
3


19
62264525
‘A/G’
0.69
3.94E−04


RS4422314
3


3
166030858
‘A/G’
−0.90
4.03E−04


RS12128593
3


1
66747467
‘C/T’
−0.82
4.03E−04


RS320379
3


1
211743714
‘A/G’
0.70
4.14E−04


RS1110277
3
SLC23A2
9962
20
4802682
‘A/G’
0.69
4.28E−04


RS5936438
3
AFF2
2334
X
147694315
‘A/G’
0.92
4.29E−04


RS4855268
3


3
166063217
‘C/T’
−0.90
4.30E−04


RS6436553
3
KIAA1486
57624
2
226002129
‘A/G’
−1.00
4.34E−04


RS2637988
3
IL1RN
3557
2
113593250
‘A/G’
−0.74
4.60E−04


RS2051089
3


6
7569571
‘C/T’
−0.68
4.61E−04


RS921924
3


12
123787936
‘A/G’
0.78
4.62E−04


RS12038863
3


1
178843066
‘A/C’
−0.94
4.64E−04


RS4663588
3


2
236042298
‘A/G’
−0.99
4.67E−04


RS767460
3
CNTN4
152330
3
2716787
‘A/G’
−0.68
4.74E−04


RS9321194
3
C6orf191
253582
6
130216831
‘C/T’
−0.67
4.74E−04


RS10120248
3


9
109897328
‘A/G’
1.53
4.75E−04


RS1412435
3


9
109904257
‘C/T’
1.53
4.75E−04


RS7991284
3


13
20584944
‘A/G’
−0.82
4.78E−04


RS2041670
3
KIAA0350
23274
16
11082153
‘C/T’
1.02
4.79E−04


RS1399333
3


4
10878977
‘C/T’
0.69
4.91E−04


RS2305913
3
FBF1
85302
17
71434536
‘A/G’
−0.69
4.92E−04


RS7624656
3
PCOLCE2
26577
3
144068492
‘C/T’
0.94
4.96E−04


RS4626202
3


4
19592202
‘C/T’
0.73
4.98E−04


RS10515283
1


5
98121571
‘C/T’
−0.69
5.06E−04


RS1348530
3


4
162413018
‘C/T’
0.78
5.10E−04


RS460879
3
PCOLN3
5119
16
88240390
‘C/T’
0.78
5.10E−04


RS11985201
3


8
39558078
‘A/G’
−0.92
5.10E−04


RS2283712
3
PPEF1
5475
X
18752705
‘A/G’
0.87
5.12E−04


RS9514497
3


13
105569397
‘A/G’
−0.74
5.14E−04


RS1449994
3


3
36136098
‘G/T’
−0.68
5.18E−04


RS1332855
3


9
82827607
‘G/T’
−0.79
5.18E−04


RS10521767
3


X
130284232
‘C/T’
0.88
5.20E−04


RS477558
3


1
18092414
‘A/G’
−0.73
5.23E−04


RS5930664
3


X
125213018
‘A/G’
0.97
5.34E−04


RS1387389
3
PBX1
5087
1
162956386
‘C/T’
−1.13
5.47E−04


RS6075078
3


20
16519466
‘G/T’
−0.77
5.52E−04


RS1721355
3
WDR69
164781
2
228491220
‘A/G’
−0.70
5.55E−04


RS3743024
3
MAPKBP1
23005
15
39906263
‘C/T’
−0.68
5.55E−04


RS12487554
3
SEC22L2
26984
3
124425472
‘A/G’
0.69
5.56E−04


RS183007
3
PPEF1
5475
X
18746756
‘C/T’
0.77
5.63E−04


RS263350
3


5
95885359
‘C/T’
−0.69
5.64E−04


RS1641394
3
LOC649004
649004
2
150315150
‘A/G’
−1.19
5.69E−04


RS2773857
3


9
12362356
‘A/G’
0.79
5.71E−04


RS2655074
3


11
11157434
‘G/T’
−1.05
5.72E−04


RS11199496
3


10
122439906
‘C/T’
−0.68
5.74E−04


RS4143444
3


6
91103018
‘C/T’
−0.84
5.76E−04


RS11025056
3


11
19186741
‘A/G’
−0.93
5.78E−04


RS6984551
3
LOC648814
648814
8
9148232
‘C/T’
0.68
5.80E−04


RS2167644
3
LRRN6C
158038
9
28076344
‘A/G’
−0.68
5.86E−04


RS9639874
3
HECW1
23072
7
43381531
‘A/G’
−1.07
5.88E−04


RS9558678
3


13
105554332
‘C/T’
−0.76
5.89E−04


RS7148858
3
CLMN
79789
14
94818468
‘C/T’
−0.69
5.90E−04


RS2191031
3


3
45885874
‘C/T’
−0.97
5.95E−04


RS261966
3


5
95875343
‘A/G’
−0.75
5.96E−04


RS7835480
3


8
131593803
‘A/G’
−0.66
5.97E−04


RS1544452
3


7
124168925
‘A/G’
−0.68
5.98E−04


RS2838817
3
ADARB1
104
21
45456126
‘C/T’
−1.26
6.01E−04


RS12359135
3


10
94833525
‘C/T’
−0.79
6.01E−04


RS4873814
3


8
144793335
‘A/G’
0.76
6.03E−04


RS7991184
3
LOC642172
642172
13
86898647
‘A/C’
−0.88
6.11E−04


RS152439
3


5
141904579
‘C/T’
0.94
6.13E−04


RS9518797
3
TPP2
7174
13
102060880
‘C/T’
0.69
6.18E−04


RS2303518
3
MAPKBP1
23005
15
39897267
‘A/C’
−0.67
6.20E−04


RS6520049
3


22
45374973
‘C/T’
−1.54
6.23E−04


RS6604632
3
ESRRG
2104
1
214774201
‘A/G’
−0.67
6.44E−04


RS5979317
3
MID1
4281
X
10462458
‘C/T’
0.83
6.47E−04


RS1398882
3


17
39103977
‘C/T’
−0.79
6.52E−04


RS2327935
3
HECA
51696
6
139532786
‘A/G’
−1.04
6.63E−04


RS9945206
3


18
11222515
‘C/T’
−0.95
6.65E−04


RS9545836
3


13
81171954
‘A/G’
−1.28
6.73E−04


RS4399918
3
NLGN1
22871
3
175087027
‘C/T’
−0.86
6.76E−04


RS10492519
3
FLJ30707
220108
13
50722329
‘A/G’
0.68
6.77E−04


RS25890
3


5
131465461
‘A/G’
−0.67
6.87E−04


RS10513560
3
PPM1L
151742
3
162193492
‘A/G’
0.96
7.04E−04


RS6517708
3


21
16972413
‘A/G’
1.07
7.19E−04


RS1406076
3
HS3ST1
9957
4
11012802
‘C/T’
−1.23
7.19E−04


RS288649
3


16
61163939
‘C/T’
0.67
7.29E−04


RS9922975
3


16
26847848
‘A/G’
0.78
7.38E−04


RS13074723
3
NLGN1
22871
3
175004791
‘A/G’
−0.66
7.43E−04


RS7565864
3


2
44135829
‘A/G’
0.81
7.45E−04


RS1873773
3


4
54894535
‘A/G’
−0.66
7.56E−04


RS10738168
3


9
10570326
‘G/T’
−1.36
7.61E−04


RS11095604
3


X
13053820
‘C/T’
0.87
7.67E−04


RS11794056
3
SNX30
401548
9
114644464
‘A/G’
−0.66
7.68E−04


RS6843684
3


4
174859417
‘A/G’
−0.71
7.71E−04


RS4651073
3
XPR1
9213
1
178867222
‘A/G’
−0.66
7.72E−04


RS4412655
3
PLEKHA6
22874
1
202477373
‘A/C’
0.89
7.79E−04


RS2391335
3
EFNB2
1948
13
105969986
‘G/T’
−0.82
7.87E−04


RS1293427
3
ZNF218
128553
20
51171008
‘A/G’
0.97
7.88E−04


RS6885761
3


5
154595473
‘A/G’
0.99
7.90E−04


RS592048
3
TNS3
64759
7
47544477
‘C/T’
0.67
8.01E−04


RS2246815
3
DPYS
1807
8
105509638
‘A/G’
−1.17
8.06E−04


RS987848
3


13
38779740
‘C/T’
0.67
8.11E−04


RS6083269
3


20
23733807
‘A/G’
−0.97
8.13E−04


RS10494301
3
KCNN3
3782
1
152967842
‘A/G’
−0.96
8.19E−04


RS4242670
3
TEK
7010
9
27190738
‘A/C’
−1.69
8.24E−04


RS11651563
3
FOXK2
3607
17
78106672
‘C/T’
1.25
8.33E−04


RS2097585
3


8
18063184
‘C/T’
0.84
8.37E−04


RS1921931
3


X
13079476
‘A/G’
0.86
8.42E−04


RS6041592
3


20
12673486
‘A/G’
−0.66
8.44E−04


RS11199460
3


10
122402920
‘A/G’
−0.76
8.59E−04


RS306364
3


4
131871491
‘A/G’
−0.88
8.59E−04


RS2183869
3
APTX
54840
9
32973442
‘A/G’
−0.81
8.61E−04


RS189947
3


21
17556641
‘A/C’
1.09
8.63E−04


RS193762
3


16
11219674
‘A/C’
1.07
8.67E−04


RS8084310
3


18
8940504
‘A/G’
0.72
8.70E−04


RS894911
3
CDH12
1010
5
22467224
‘C/T’
−0.65
8.71E−04


RS945864
3


9
1248905
‘C/T’
−0.67
8.78E−04


RS1476240
3
ZPBP
11055
7
50003183
‘A/G’
0.66
8.83E−04


RS1531812
3


X
5712016
‘C/T’
1.07
8.86E−04


RS10082730
3


12
44288969
‘C/T’
0.79
8.86E−04


RS6534677
3


4
129441351
‘C/T’
−0.84
8.96E−04


RS10491285
3
LOC648089
648089
5
126367985
‘A/G’
0.64
9.06E−04


RS354694
3
ARHGAP15
55843
2
143641987
‘C/T’
−0.65
9.11E−04


RS4657284
3


1
161707341
‘A/G’
−0.74
9.18E−04


RS4669621
3
ATP6V1C2
245973
2
10803549
‘C/T’
−0.70
9.20E−04


RS7190823
3
FANCA
2175
16
88393544
‘C/T’
0.67
9.23E−04


RS4476727
3


5
3340958
‘A/G’
1.17
9.24E−04


RS1250126
3


4
1181042
‘C/T’
−1.18
9.24E−04


RS1822454
3
PTPRM
5797
18
7848157
‘A/G’
0.69
9.34E−04


RS926073
3


21
35778797
‘A/G’
0.74
9.36E−04


RS2447523
3


11
33418920
‘A/G’
−0.68
9.42E−04


RS7905355
3


10
125914585
‘A/G’
−0.65
9.56E−04


RS4680
3
COMT
1312
22
18331271
‘A/G’
0.74
9.67E−04


RS9298628
3


8
42725148
‘C/T’
1.79
9.71E−04


RS4313076
3


7
9351828
‘A/C’
1.17
9.72E−04


RS688630
3
TCTEX1D1
200132
1
66995554
‘A/G’
0.67
9.73E−04


RS10810351
3


9
1510510
‘A/G’
−0.97
9.91E−04


RS9495378
3


6
139564988
‘A/G’
−1.03
9.96E−04


RS6632802
3


X
16260152
‘C/T’
0.68
9.96E−04


RS6882366
3


5
95890449
‘C/T’
−1.03
9.98E−04


RS1715843
3


2
228511974
‘C/T’
0.65
9.99E−04





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Priority_date: SNP listed in 1: US 11/245,248 2: US 60/819,014 3: US 60/867,454


Sequence_ID: Sequence identification number


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


Minor Allele: SNP allele or its complementary nucleotide that is less common in the control population.


Allele_x2: Chi-squared test based on allele frequencies


Coefficient: Coefficient w of the model glm(z~w + r, family = binomial (link = logit)) in R where z is hypertension status, w is genotype (0, 0<--1, 1<--2) and r is T2D status


P value: P value of the coefficient w


Gene_content: Genes positioned within 100 Kbp up and downstream from the physical position of the SNPs based on NCBI Human Genome Build 36.1













TABLE 9







Haplotype genomic regions with the strongest association


with hypertension in the haplotype sharing analysis (HaploRec + HPM)


with 5 SNPs. The analysis is based on the combined data of 110 HT


cases and 110 healthy controls from the Ashkenazi Jew population,


114 HT cases and 114 healthy controls from the East Finnish population,


41 HT cases and 41 healthy controls from the German population


and 28 HT cases and 28 healthy controls from the English population.















Gene locus








and


dbSNP rs ID
Priority date
Gene ID
Chromosome
Position
Variats
P value

















RS2122952
3


2
195004717
‘A/G’
0.0002


RS2060798
3


2
195008975
‘G/T’
<0.0001


RS1451703
3


2
195009566
‘A/G’
0.0009


RS2128663
3
ZPBP
11055
7
50023480
‘C/T’
0.0008


RS959678
3
ZPBP
11055
7
50031156
‘A/G’
<0.0001


RS1384634
3
ZPBP
11055
7
50035023
‘C/T’
<0.0001


RS12718237
3
ZPBP
11055
7
50081500
‘C/T’
<0.0001


RS1870029
3
LOC392670
392670
7
50114262
‘C/T’
0.0005


RS2249963
3


8
11512635
‘C/T’
<0.0001


RS1017804
3


8
11515365
‘A/C’
0.0003


RS7028628
3


9
137223172
‘G/T’
0.0006


RS1891999
3


9
137226410
‘G/T’
0.0001


RS11794621
3


9
137231415
‘C/T’
<0.0001


RS1891996
3


9
137233596
‘A/G’
0.0003


RS10506851
3
PPFIA2
8499
12
80662290
‘A/G’
<0.0001


RS4519318
3


15
96252471
‘A/G’
<0.0001


RS1075440
3
FTO
79068
16
52348407
‘A/G’
0.0003


RS8050136
3
FTO
79068
16
52373776
‘A/C’
<0.0001


RS3751812
3
FTO
79068
16
52375961
‘G/T’
0.0002


RS9319757
3


18
64003719
‘C/T’
<0.0001


RS8139003
3


22
47590619
‘A/G’
0.0007


RS7288568
3
LOC648551
648551
22
47595366
‘C/T’
<0.0001


RS1531812
3


X
5712016
‘C/T’
0.0004


RS5961851
3


X
5722793
‘A/G’
<0.0001


RS5961861
3


X
5738176
‘C/T’
<0.0001


RS6529882
3


X
5746495
‘A/G’
<0.0001


RS5961868
3


X
5750117
‘G/T’
<0.0001


RS3788776
3
ODZ1
10178
X
123512044
‘A/G’
<0.0001


RS2843518
3
ODZ1
10178
X
123515881
‘C/T’
0.0003


RS11260476
3
ODZ1
10178
X
123517696
‘C/T’
<0.0001


RS2858438
3
ODZ1
10178
X
123529425
‘C/T’
0.0004


RS2283740
3
CXorf6
10046
X
149387455
‘C/T’
0.0005


RS2073043
3
CXorf6
10046
X
149392677
‘A/G’
<0.0001


RS547771
3
CXorf6
10046
X
149394072
‘A/G’
<0.0001


RS731426
3
CXorf6
10046
X
149395757
‘C/T’
<0.0001


RS523773
3
CXorf6
10046
X
149396625
‘A/G’
<0.0001


RS477252
3
CXorf6
10046
X
149398941
‘A/G’
0.0001


RS10915318
3


1
4004999
‘A/G’
0.0001


RS12749761
3


1
4011047
‘A/G’
0.0004


RS3820742
3
ACVR1
90
2
158344587
‘C/T’
0.0001


RS10497190
1
ACVR1
90
2
158347486
‘C/T’
0.0006


RS2160871
3
ATP2B2
491
3
10421826
‘A/G’
0.0006


RS34904
3
ATP2B2
491
3
10426267
‘A/G’
0.0001


RS34914
3
ATP2B2
491
3
10432314
‘A/G’
0.0001


RS11719939
3
ATP2B2
491
3
10432572
‘A/G’
0.0003


RS9849596
3


3
79839174
‘A/G’
0.0001


RS9309828
3


3
79843464
‘A/G’
0.0001


RS6803083
3


3
79852274
‘G/T’
0.0002


RS6548651
3


3
79867106
‘A/G’
0.0005


RS7639547
3


3
104505765
‘A/G’
0.0001


RS159977
3


5
152708309
‘A/C’
0.0001


RS159978
3


5
152717768
‘A/G’
0.0006


RS1337420
3
GRIK2
2898
6
102203016
‘C/T’
0.0001


RS12193068
3
GRIK2
2898
6
102208930
‘A/C’
0.0006


RS217510
3
CREB5
9586
7
28484580
‘C/T’
0.0007


RS217517
3
CREB5
9586
7
28488170
‘A/G’
0.0001


RS6988809
3


8
40925672
‘C/T’
0.0006


RS17571033
3


8
40929479
‘A/G’
0.0001


RS884540
3


9
8250902
‘A/G’
0.0001


RS1027584
3


9
8258051
‘A/G’
0.0009


RS7910196
3
FRMD4A
55691
10
13850065
‘A/G’
0.0004


RS2049745
3
FRMD4A
55691
10
13857950
‘A/G’
0.0001


RS2042707
3


13
22146799
‘C/T’
0.0001


RS9506903
3


13
22150146
‘C/T’
0.0003


RS2258026
3
ABR
29
17
957228
‘A/G’
0.001


RS7406978
3
ABR
29
17
983909
‘C/T’
0.0001


RS2440766
3
ABR
29
17
989709
‘A/G’
0.0003


RS7207116
3
ABR
29
17
1015143
‘A/G’
0.0005


RS11655015
3
ABR
29
17
1018374
‘C/T’
0.0009


RS11088668
3


21
18448920
‘C/T’
0.0001


RS2824664
3


21
18450015
‘C/T’
0.0001


RS2284006
3
CACNG2
10369
22
35399975
‘C/T’
0.0001


RS3850163
3


X
28355558
‘G/T’
0.0001


RS878007
3
DMD
1756
X
31760187
‘A/G’
0.0001


RS206061
3


X
41841584
‘A/G’
0.0006


RS432284
3


X
41846701
‘A/G’
0.0003


RS206056
3


X
41846775
‘C/T’
0.0001


RS5918294
3


X
41854429
‘C/T’
0.0001


RS12853682
3
CXorf43
139324
X
83570446
‘C/T’
0.0001


RS5924105
3


X
86889097
‘A/G’
0.001


RS12557304
3


X
86910552
‘C/T’
0.0001


RS2208908
3


X
86915504
‘A/G’
0.0003


RS7051454
3


X
120029242
‘A/C’
0.0001


RS596987
3


X
144193420
‘A/G’
0.0001


RS580628
3


X
144250244
‘A/C’
0.0002


RS481091
3


X
144251889
‘A/G’
0.0003


RS995895
3


X
144258291
‘A/G’
0.0001


RS13100475
3


3
192637284
‘A/G’
0.0002


RS4863179
3


4
190635394
‘A/C’
0.0002


RS386936
3
LOC442237
442237
6
97264417
‘C/T’
0.0002


RS1334327
3
LOC442237
442237
6
97269908
‘A/G’
0.001


RS38557
3
CACNA2D1
781
7
81720845
‘A/G’
0.0002


RS4518686
3


8
126539999
‘A/G’
0.0002


RS10490913
3


10
120144426
‘C/T’
0.0004


RS853925
3


10
120144856
‘A/G’
0.0005


RS853943
3


10
120154241
‘C/T’
0.0004


RS10886243
3


10
120171437
‘G/T’
0.0002


RS1013620
3


10
120177712
‘A/G’
0.0002


RS10886244
3


10
120182316
‘A/G’
0.0007


RS220838
3
IGSF4
23705
11
114819312
‘A/G’
0.0005


RS314474
3
IGSF4
23705
11
114826343
‘A/G’
0.0005


RS10502202
3
IGSF4
23705
11
114829700
‘A/G’
0.0002


RS10047420
3
IGSF4
23705
11
114834362
‘A/G’
0.0002


RS10891859
3
IGSF4
23705
11
114840831
‘A/G’
0.0002


RS314494
3
IGSF4
23705
11
114841812
‘A/G’
0.0003


RS7983414
3


13
26355842
‘A/G’
0.0005


RS7994792
3


13
26356054
‘G/T’
0.0002


RS1950771
3


14
94334655
‘A/G’
0.0002


RS10136233
3


14
94334883
‘A/G’
0.0002


RS2691239
3


19
56243624
‘A/G’
0.0006


RS1880413
3
KLK13
26085
19
56252279
‘C/T’
0.0002


RS7059234
3


X
24948077
‘C/T’
0.001


RS5986723
3


X
24965806
‘A/G’
0.0002


RS2188616
3


X
24975597
‘C/T’
0.0003


RS6673711
3
LOC126917
126917
1
19108104
‘C/T’
0.0003


RS1513089
2
LOC642216
642216
5
17965365
‘A/C’
0.0003


RS7014552
3
TSNARE1
203062
8
143408330
‘A/G’
0.0003


RS3858054
3


9
8243589
‘C/T’
0.0003


RS10976882
3


9
8247948
‘A/G’
0.0005


RS2167644
3
LRRN6C
158038
9
28076344
‘A/G’
0.0005


RS10968337
3
LRRN6C
158038
9
28076683
‘C/T’
0.0003


RS4305993
3
LRRN6C
158038
9
28078526
‘C/T’
0.0003


RS4611181
3
ZNF195
7748
11
3349321
‘C/T’
0.0003


RS1150935
3


12
27493452
‘C/T’
0.0003


RS306594
3


12
27500523
‘G/T’
0.0005


RS1000703
3


12
93780350
‘A/G’
0.0008


RS892492
3


12
93784834
‘C/T’
0.0005


RS7961204
3


12
93801511
‘C/T’
0.0003


RS10777647
3


12
93804844
‘C/T’
0.0003


RS12588192
3
MAMDC1
161357
14
46651013
‘G/T’
0.0003


RS8037284
3


15
58176069
‘C/T’
0.0009


RS10048054
3


15
58185128
‘C/T’
0.0003


RS8063120
3


16
80352553
‘A/G’
0.0003


RS10445097
3


16
80357386
‘G/T’
0.0009


RS873634
3
HCN2
610
19
539305
‘G/T’
0.0003


RS2047373
3
DMD
1756
X
31676566
‘C/T’
0.0003


RS2061426
3


X
124373041
‘A/G’
0.0003


RS5904833
3
FMR1NB
158521
X
146892840
‘A/G’
0.0003


RS764631
3
FMR1NB
158521
X
146895941
‘C/T’
0.0003


RS12499689
3


4
13879456
‘C/T’
0.0005


RS3111813
3


4
13884425
‘A/C’
0.0004


RS7034341
3
SUSD1
64420
9
113854649
‘C/T’
0.0004


RS220836
3
IGSF4
23705
11
114807081
‘A/G’
0.0004


RS10488707
3
IGSF4
23705
11
114807162
‘A/G’
0.0007


RS1749704
2
TTC7B
145567
14
90239107
‘G/T’
0.0007


RS1535321
2
TTC7B
145567
14
90240579
‘C/T’
0.0004


RS1749718
2
TTC7B
145567
14
90253080
‘C/T’
0.0005


RS1742083
2
TTC7B
145567
14
90256423
‘C/T’
0.0008


RS8047519
3


16
49026539
‘C/T’
0.0004


RS1548914
3


16
49036872
‘A/C’
0.0006


RS1232143
3


X
8798982
‘A/G’
0.0004


RS1458368
3
DMD
1756
X
31730435
‘A/G’
0.0004


RS5928121
3
DMD
1756
X
32862842
‘A/G’
0.0004


RS5931268
2


X
136893265
‘G/T’
0.0004


RS962429
3
C1orf125
126859
1
177719318
‘C/T’
0.0005


RS3748971
3
ECEL1P2
347694
2
232958927
‘A/G’
0.0005


RS1873038
3
NLGN1
22871
3
175020335
‘A/G’
0.0005


RS13105217
3


4
65064629
‘C/T’
0.0005


RS10962912
3


9
17209242
‘C/T’
0.0005


RS11046835
3


12
23211061
‘C/T’
0.0005


RS1870943
3


12
88192283
‘C/T’
0.0005


RS9936750
3


16
53729375
‘C/T’
0.0005


RS1486735
3


16
53737593
‘A/G’
0.0009


RS8072734
3


17
14642128
‘A/G’
0.0005


RS9622650
3


22
36315673
‘C/T’
0.0005


RS7291493
3


22
47615371
‘A/G’
0.0005


RS812452
3


X
7123308
‘C/T’
0.0005


RS12861247
3
STS
412
X
7184199
‘A/G’
0.0009


RS4825236
3
PPEF1
5475
X
18642674
‘C/T’
0.0008


RS2269584
3
PPEF1
5475
X
18689642
‘A/G’
0.0007


RS2269586
3
PPEF1
5475
X
18690101
‘A/G’
0.0005


RS5925675
3


X
22742435
‘A/G’
0.0005


RS1935074
3


X
80063759
‘C/T’
0.0005


RS10482585
3
LOC648118
648118
X
80073549
‘C/T’
0.0007


RS592807
2
GRIA3
2892
X
122419337
‘C/T’
0.0006


RS503118
2
GRIA3
2892
X
122421904
‘C/T’
0.0005


RS585602
2


X
137025064
‘A/G’
0.0005


RS5919819
3


X
144161129
‘G/T’
0.0005


RS1488547
3
NLGN1
22871
3
175008462
‘C/T’
0.0006


RS9290481
3
NLGN1
22871
3
175013923
‘A/G’
0.0009


RS9296444
3


6
44728485
‘C/T’
0.0008


RS1021129
3


6
44735522
‘C/T’
0.0006


RS1377050
3
LRRN6C
158038
9
28090836
‘A/G’
0.0006


RS1416836
3


9
109806784
‘C/T’
0.0009


RS9695286
3


9
109812888
‘C/T’
0.0006


RS1747839
3
LOC650079
650079
9
138155232
‘G/T’
0.0006


RS2767431
3
LOC647525
647525
10
134472497
‘C/T’
0.0006


RS2387069
3
C10orf92
54777
10
134475893
‘A/G’
0.0006


RS12818362
3


12
92915037
‘C/T’
0.0006


RS984429
3


18
47941339
‘A/C’
0.0006


RS2837705
3
DSCAM
1826
21
40852671
‘C/T’
0.0007


RS2837709
3
DSCAM
1826
21
40861610
‘A/C’
0.0006


RS2837713
3
DSCAM
1826
21
40873626
‘A/C’
0.001


RS2837716
3
DSCAM
1826
21
40875564
‘A/G’
0.001


RS2007215
3
PTCHD2
57540
1
11460564
‘A/G’
0.0007


RS4846012
3
PTCHD2
57540
1
11480513
‘G/T’
0.0007


RS2053671
3
KCNJ3
3760
2
155345484
‘G/T’
0.0007


RS6433574
3


2
176806772
‘A/G’
0.0007


RS6816464
3


4
19537700
‘C/T’
0.0007


RS4464568
3


4
19542167
‘C/T’
0.0007


RS2086735
3


4
65006948
‘G/T’
0.0007


RS4865755
3
ITGA2
3673
5
52326944
‘C/T’
0.0007


RS17237251
3


5
67447959
‘C/T’
0.0007


RS2888306
3


5
67448240
‘C/T’
0.001


RS6890771
3


5
180014372
‘C/T’
0.001


RS7705017
3


5
180026648
‘C/T’
0.0007


RS9405675
3


6
389600
‘A/G’
0.0007


RS7755154
3


6
2558943
‘C/T’
0.0007


RS10215999
3


7
13640063
‘C/T’
0.0007


RS10513402
1


9
124204757
‘C/T’
0.0007


RS10899922
3
C10orf136
414260
10
43661970
‘A/G’
0.0007


RS1463632
3


16
53741402
‘A/G’
0.0007


RS1734920
3


21
40266781
‘G/T’
0.0007


RS8131179
3
PDE9A
5152
21
42955270
‘C/T’
0.0009


RS2284958
3
PDE9A
5152
21
42961700
‘C/T’
0.0007


RS373747
3


22
18535192
‘C/T’
0.0007


RS5955922
3


X
17970012
‘C/T’
0.001


RS6527831
3


X
18015188
‘A/C’
0.0007


RS5955936
3


X
18046471
‘A/G’
0.0008


RS2050909
3


X
137313831
‘A/G’
0.0007


RS10187702
3
LOC652214
652214
2
58723279
‘C/T’
0.0008


RS7591633
3
LOC400955
400955
2
58725562
‘A/G’
0.0008


RS6715162
3
LOC400955
400955
2
58740811
‘C/T’
0.0009


RS2166512
3


2
176779427
‘A/G’
0.0008


RS6931600
3


6
130140464
‘C/T’
0.0008


RS1871400
3


6
153580911
‘A/G’
0.0008


RS2732744
3


7
84680820
‘A/G’
0.0008


RS4242499
3


8
4867155
‘G/T’
0.0008


RS6990880
3


8
4868194
‘C/T’
0.0008


RS4873814
3


8
144793335
‘A/G’
0.0008


RS716064
3
NRXN3
9369
14
78753709
‘A/C’
0.0008


RS10853007
3
GJA7
10052
17
40248321
‘A/G’
0.001


RS1071682
3
HIGD1B
51751
17
40283247
‘C/T’
0.0008


RS2267064
3
LOC648941
648941
22
22874632
‘G/T’
0.0008


RS5927001
3
DMD
1756
X
31161215
‘C/T’
0.0008


RS5953392
3


X
44137384
‘A/G’
0.0008


RS1831116
3


X
83811301
‘C/T’
0.0008


RS17036947
3
PTCHD2
57540
1
11497847
‘G/T’
0.001


RS2072996
3
PTCHD2
57540
1
11501560
‘A/G’
0.0009


RS2817632
3
PTCHD2
57540
1
11510818
‘A/G’
0.0009


RS2076468
3
PTCHD2
57540
1
11512498
‘C/T’
0.001


RS561264
3


2
238994718
‘A/C’
0.0009


RS11128372
3


3
74096334
‘A/G’
0.0009


RS4315784
3


4
19551691
‘A/G’
0.0009


RS6826691
3


4
164821659
‘C/T’
0.0009


RS6897616
3
LOC642216
642216
5
17884426
‘A/G’
0.0009


RS2607605
3


8
24700639
‘C/T’
0.0009


RS1879188
2
PTK2B
2185
8
27249840
‘G/T’
0.0009


RS10283134
3
C8orf36
286053
8
126341828
‘A/G’
0.0009


RS10773557
3


12
127638497
‘A/C’
0.0009


RS1926005
3


13
45731151
‘A/C’
0.0009


RS2239975
3
SYT17
51760
16
19104701
‘G/T’
0.0009


RS12450029
3
ABR
29
17
949596
‘C/T’
0.0009


RS5905269
2


X
115402180
‘A/C’
0.0009


RS1293468
3


X
122036209
‘C/T’
0.0009


RS644210
3
SPANX-N1
494118
X
144142532
‘G/T’
0.0009


RS150571
3


1
37430550
‘C/T’
0.001


RS803441
3


1
162450455
‘C/T’
0.001


RS2881507
3


1
162492876
‘A/G’
0.001


RS12133017
3
C1orf125
126859
1
177708960
‘C/T’
0.001


RS4686599
2


3
193327806
‘C/T’
0.001


RS1511776
3


4
164801907
‘C/T’
0.001


RS2391671
3
CREB5
9586
7
28518902
‘A/G’
0.001


RS2284218
3
CRHR2
1395
7
30680858
‘C/T’
0.001


RS2245192
3


7
113789771
‘C/T’
0.001


RS419490
3


9
106836369
‘A/C’
0.001


RS888219
3


9
127968844
‘G/T’
0.001


RS7644
3
PARVA
55742
11
12508420
‘C/T’
0.001


RS10892358
3


11
118761005
‘A/G’
0.001


RS1793566
3


11
130636689
‘C/T’
0.001


RS9506776
3
LOC650912
650912
13
21518850
‘C/T’
0.001


RS1561942
3
AK7
122481
14
95955212
‘A/G’
0.001


RS8015440
3
AK7
122481
14
95961302
‘A/C’
0.001


RS2068259
3
C20orf74
57186
20
20341219
‘A/C’
0.001


RS133519
2


22
46955392
‘G/T’
0.001


RS1999925
3


X
93215057
‘A/G’
0.001


RS5949848
3


X
95623109
‘C/T’
0.001





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Sequence_ID: Sequence identification number


Priority_date: SNP listed in 1: US 11/245,248 2: US 60/819,014 3: US 60/867,454


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


P-value: P-value based on permutation test


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Gene_content: Genes positioned within 100 Kbp up and downstream (End) from the physical position of the SNPs bordering the haplotype genomic region based on NCBI Human Genome Build 36.













TABLE 10







Haplotypes with the strongest association with hypertension


based on HaploRec + HPM analysis with 5 SNPs. The analysis is based


on the combined data of 110 HT cases and 110 healthy controls from


the Ashkenazi Jew population, 114 HT cases and 114 healthy controls


from the East Finnish population, 41 HT cases and 41 healthy controls


from the German population and 28 HT cases and 28 healthy controls


from the English population.
















Gene locus









and


dbSNP rs ID
Priority date
Gene ID
Chromosome
Position
Variats
Risk Allele
Chi square


















RS9564765
3


13
70431786
‘A/G’
G
22.83


RS803815
3


13
70434610
‘C/T’
G


RS2202564
3


13
70430344
‘A/G’
A
22.25


RS9564765
3


13
70431786
‘A/G’
G


RS803815
3


13
70434610
‘C/T’
G


RS2265326
3


13
64959554
‘C/T’
A
21.68


RS2067741
3


13
64966931
‘A/G’
A


RS9540461
3


13
64989389
‘A/G’
G


RS9540464
3


13
65000270
‘A/G’
A


RS9598990
3


13
65001632
‘A/C’
A


RS950942
3


13
70429810
‘C/T’
A
21.67


RS2202564
3


13
70430344
‘A/G’
A


RS9564765
3


13
70431786
‘A/G’
G


RS803815
3


13
70434610
‘C/T’
G


RS2067741
3


13
64966931
‘A/G’
A
21.40


RS9540461
3


13
64989389
‘A/G’
G


RS9540464
3


13
65000270
‘A/G’
A


RS9598990
3


13
65001632
‘A/C’
A


RS9571419
3


13
65001891
‘A/C’
C


RS2067741
3


13
64966931
‘A/G’
A
21.40


RS9540461
3


13
64989389
‘A/G’
G


RS9540464
3


13
65000270
‘A/G’
A


RS9598990
3


13
65001632
‘A/C’
A


RS2067741
3


13
64966931
‘A/G’
A
20.82


RS9540461
3


13
64989389
‘A/G’
G


RS9540464
3


13
65000270
‘A/G’
A


RS9317509
3


13
64943251
‘C/T’
A
19.89


RS2265326
3


13
64959554
‘C/T’
A


RS2067741
3


13
64966931
‘A/G’
A


RS9540461
3


13
64989389
‘A/G’
G


RS9540464
3


13
65000270
‘A/G’
A


RS2806939
3


13
52648971
‘C/T’
G
19.88


RS2806947
3


13
52666026
‘A/G’
A


RS1322949
3
LOC647339
647339
13
52671659
‘C/T’
G


RS2806957
3


13
52688480
‘C/T’
G


RS1923773
3


13
52648355
‘C/T’
A
19.88


RS2806939
3


13
52648971
‘C/T’
G


RS2806947
3


13
52666026
‘A/G’
A


RS1322949
3
LOC647339
647339
13
52671659
‘C/T’
G


RS2806957
3


13
52688480
‘C/T’
G


RS2806947
3


13
52666026
‘A/G’
A
19.82


RS1322949
3
LOC647339
647339
13
52671659
‘C/T’
G


RS2806957
3


13
52688480
‘C/T’
G


RS2265326
3


13
64959554
‘C/T’
A
19.77


RS2067741
3


13
64966931
‘A/G’
A


RS9540461
3


13
64989389
‘A/G’
G


RS9540464
3


13
65000270
‘A/G’
A


RS1849067
3


2
195675318
‘A/G’
G
20.71


RS715200
3


2
195677764
‘A/G’
G


RS1599755
3


2
195682608
‘A/G’
G


RS4047462
3


2
16222221
‘A/G’
A
20.23


RS7422511
3


2
16224996
‘A/G’
G


RS12995942
3


2
16226902
‘A/G’
A


RS7559122
2


2
16229611
‘A/G’
A


RS7560874
2


2
16233209
‘A/G’
G


RS11845875
3
AK7
122481
14
96002882
‘A/G’
A
20.47


RS3809425
3
PAPOLA
10914
14
96055906
‘A/G’
A


RS2274795
3
PAPOLA
10914
14
96064435
‘C/T’
A


RS8013517
3
PAPOLA
10914
14
96082661
‘A/G’
G


RS11160342
3


14
96104107
‘C/T’
A


RS10858385
3


9
137335350
‘C/T’
G
20.49


RS3884535
3


9
137337030
‘C/T’
A


RS4842247
3


9
137339138
‘A/G’
G


RS4775234
3


15
58117938
‘A/C’
A
20.33


RS713469
3


15
58121920
‘A/G’
G


RS335787
3


15
58124590
‘A/G’
G


RS193097
3
LOC651082
651082
15
58134744
‘A/G’
A


RS4775234
3


15
58117938
‘A/C’
A
20.33


RS713469
3


15
58121920
‘A/G’
G


RS335787
3


15
58124590
‘A/G’
G


RS193097
3
LOC651082
651082
15
58134744
‘A/G’
A


RS6494166
3


15
58140408
‘A/G’
G


RS713469
3


15
58121920
‘A/G’
G
20.33


RS335787
3


15
58124590
‘A/G’
G


RS193097
3
LOC651082
651082
15
58134744
‘A/G’
A


RS713469
3


15
58121920
‘A/G’
G
20.33


RS335787
3


15
58124590
‘A/G’
G


RS193097
3
LOC651082
651082
15
58134744
‘A/G’
A


RS6494166
3


15
58140408
‘A/G’
G


RS335787
3


15
58124590
‘A/G’
G
20.03


RS193097
3
LOC651082
651082
15
58134744
‘A/G’
A


RS11084402
3
ZNF579
163033
19
60785177
‘C/T’
G
19.87


RS693289
3
ZNF524
147807
19
60802848
‘A/G’
G


RS310465
3
LOC388565
388565
19
60815558
‘A/G’
G


RS4750957
3


10
130151665
‘C/T’
A
20.25


RS7096455
3


10
130162023
‘G/T’
C


RS7901182
3


10
130168169
‘A/G’
G


RS7915794
3


10
130179509
‘A/G’
A


RS7893667
3


10
130181728
‘A/G’
G


RS11150469
3


16
81114803
‘C/T’
A
22.48


RS7198864
3


16
81119203
‘C/T’
G


RS9931462
3


16
81119956
‘C/T’
G


RS766291
3


16
81125471
‘C/T’
A


RS7406978
3
ABR
29
17
983909
‘C/T’
A
21.30


RS2440766
3
ABR
29
17
989709
‘A/G’
A


RS6502048
3


17
77598217
‘A/G’
G
19.56


RS9915228
3
RFNG
5986
17
77601176
‘A/G’
A


RS228039
3
PDE9A
5152
21
42945262
‘C/T’
G
22.75


RS2269127
3
PDE9A
5152
21
42950306
‘A/G’
G


RS8131179
3
PDE9A
5152
21
42955270
‘C/T’
A


RS228038
3
PDE9A
5152
21
42945008
‘A/G’
G
19.75


RS228039
3
PDE9A
5152
21
42945262
‘C/T’
G


RS2269127
3
PDE9A
5152
21
42950306
‘A/G’
G


RS8131179
3
PDE9A
5152
21
42955270
‘C/T’
A


RS2825172
3


21
19119089
‘A/G’
A
19.58


RS2825180
3


21
19124203
‘C/T’
A


RS481091
3


X
144251889
‘A/G’
G
24.81


RS995895
3


X
144258291
‘A/G’
A


RS17244441
3


X
144270169
‘C/T’
A


RS11094472
3


X
144273211
‘A/G’
G


RS481091
3


X
144251889
‘A/G’
G
24.81


RS995895
3


X
144258291
‘A/G’
A


RS17244441
3


X
144270169
‘C/T’
A


RS481091
3


X
144251889
‘A/G’
G
24.81


RS995895
3


X
144258291
‘A/G’
A


RS1924476
3
SMARCA1
6594
X
128441964
‘A/G’
G
23.20


RS3131274
3
SMARCA1
6594
X
128486023
‘C/T’
A


RS3118108
3


X
128496148
‘G/T’
A


RS5977112
3
OCRL
4952
X
128545248
‘A/G’
G


RS2071706
3
OCRL
4952
X
128552206
‘A/G’
G


RS5955898
3
RPS6KA3
6197
X
20185233
‘A/G’
A
22.55


RS6418738
3


X
20198804
‘A/G’
G


RS5990883
3


X
20241006
‘C/T’
A


RS7886043
3


X
20246948
‘A/C’
C


RS12689240
3


X
20252714
‘C/T’
A


RS549580
3
GRIA3
2892
X
122405634
‘C/T’
A
21.88


RS10521721
3
GRIA3
2892
X
122405854
‘C/T’
A


RS687577
3
GRIA3
2892
X
122406785
‘G/T’
C


RS625074
3
GRIA3
2892
X
122403594
‘A/G’
G
21.88


RS545958
3
GRIA3
2892
X
122405251
‘A/G’
A


RS549580
3
GRIA3
2892
X
122405634
‘C/T’
A


RS10521721
3
GRIA3
2892
X
122405854
‘C/T’
A


RS687577
3
GRIA3
2892
X
122406785
‘G/T’
C


RS545958
3
GRIA3
2892
X
122405251
‘A/G’
A
21.88


RS549580
3
GRIA3
2892
X
122405634
‘C/T’
A


RS10521721
3
GRIA3
2892
X
122405854
‘C/T’
A


RS687577
3
GRIA3
2892
X
122406785
‘G/T’
C


RS5990883
3


X
20241006
‘C/T’
A
21.86


RS7886043
3


X
20246948
‘A/C’
C


RS12689240
3


X
20252714
‘C/T’
A


RS6653648
3


X
20265327
‘C/T’
G


RS5950381
3


X
20267586
‘C/T’
A


RS1924476
3
SMARCA1
6594
X
128441964
‘A/G’
G
21.25


RS3131274
3
SMARCA1
6594
X
128486023
‘C/T’
A


RS3118108
3


X
128496148
‘G/T’
A


RS5977112
3
OCRL
4952
X
128545248
‘A/G’
G


RS1324150
3
SMARCA1
6594
X
128412541
‘C/T’
A
21.25


RS1924476
3
SMARCA1
6594
X
128441964
‘A/G’
G


RS3131274
3
SMARCA1
6594
X
128486023
‘C/T’
A


RS3118108
3


X
128496148
‘G/T’
A


RS5977112
3
OCRL
4952
X
128545248
‘A/G’
G


RS580628
3


X
144250244
‘A/C’
C
21.02


RS481091
3


X
144251889
‘A/G’
G


RS995895
3


X
144258291
‘A/G’
A


RS580628
3


X
144250244
‘A/C’
C
21.02


RS481091
3


X
144251889
‘A/G’
G


RS995895
3


X
144258291
‘A/G’
A


RS17244441
3


X
144270169
‘C/T’
A


RS11094472
3


X
144273211
‘A/G’
G


RS580628
3


X
144250244
‘A/C’
C
21.02


RS481091
3


X
144251889
‘A/G’
G


RS995895
3


X
144258291
‘A/G’
A


RS17244441
3


X
144270169
‘C/T’
A


RS9405986
3


6
6859406
‘C/T’
A
20.83


RS2768999
3


6
6863125
‘C/T’
A


RS2769006
3


6
6868881
‘C/T’
G


RS2876048
3


6
6871409
‘C/T’
G


RS1536242
3


6
6876009
‘C/T’
G


RS7954232
3
LOC651534
651534
12
91963517
‘C/T’
G
19.76


RS4760381
3
LOC651534
651534
12
91972190
‘A/G’
G


RS4584620
3
LOC651534
651534
12
91978954
‘C/T’
G


RS1542481
3
LOC651534
651534
12
91982962
‘A/G’
G





dbSNP_rs_ID: SNP identification number in NCBI dbSNP database


Sequence_ID: Sequence identification number


Priority date: SNP listed in 1: US 11/245,248 2: US 60/819,014 3: US 60/867,454


Gene_locus: Gene locus and gene id as reported by NCBI dbSNP database build 126


Position: Basepair Position, SNP physical position according to NCBI Human Genome Build 36.1


Variants: Alternate SNP alleles or their complementary nucleotides in the position indicated by dbSNP RS ID and basepair position


Risk_allele: Allele in at-risk haplotype


Chi_square: Chi-squared test based on allele frequencies


P-value: P-value based on the chi-square test






REFERENCES



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  • Binder A 2007. A review of the genetics of essential hypertension. Curr Opin Cardiol 22:176-184.

  • Cusi D et al. 1997. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet 349:1353-1357

  • Eronen L et al. 2004. A Markov chain approach to reconstruction of long haplotypes. Pac Symp Biocomput: 104-115.

  • Fuentes R 2003. Familial aggregation and tracking of blood pressure, body mass index and serum total cholesterol during childhood. A prospective family study in eastern Finland. Doctoral Dissertation. Kuopio University Publications D. Medical Sciences 296: 139 p. ISBN 951-781-896-3; ISSN 1235-0303.

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  • Hunt S C, Geleijnse J M, Wu L L, Witteman J C, Williams R R, Grobbee D E. 1999. Enhanced blood pressure response to mild sodium reduction in subjects with the 235T variant of the angiotensinogen gene. Am J Hypertens 12:460-466.

  • Koivukoski L et al. 2004. Meta-analysis of genome-wide scans for hypertension and blood pressure in Caucasians shows evidence of susceptibility regions on chromosomes 2 and 3. Hum Mol Genet 13:2325-2332.

  • Kokubo Y et al. 2005. Association analysis between hypertension and CYBA, CLCNKB, and KCNMB1 functional polymorphisms in the Japanese population—the Suita Study. Circ J 69:138-142.

  • Kwok P-Y 2001. Methods for genotyping single nucleotide polymorphisms. Ann Rev Genomics Hum Genet 2:235-258.

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  • Luft F 2003. Mendelian forms of human hypertension and mechanisms of disease. Clin Med Res 1:291-300.

  • Luedemann J et al. 2002. The association between behavior dependent cardiovascular risk factors and asymptomatic carotid atherosclerosis in a general population. Stroke 33: 2929-2935.

  • Moreno M U et al. 2006. The C242T CYBA polymorphism of NADPH oxidase is associated with essential hypertension. J Hypertens 24:1299-1306.

  • Nielsen P E et al. 1991. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 254:1497-500.

  • Rabbitt P et al. 2004. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1983 through 2003. Aging, Neuropsychol. Cogn. 11: 245-270.

  • Shimkets R A, Warnock D G, Bositis C M, Nelson-Williams C, Hansson J H, Schambelan M, Gill J R Jr, Ulick S, Milora R V, Findling J W, et al. 1994. Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 79:407-414.

  • Staessen J A et al. 2001. Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens 19:1349-1358.

  • Syvanen A-C 2001. Accessing genetic variation: Genotyping single nucleotide polymorphisms. Nature Reviews Genetics 2:930-942.

  • Toivonen H T et al. 2000. Data mining applied to linkage disequilibrium mapping. Am. J. Hum. Genet. 67:133-45.

  • Turner S T et al. 2001. C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic. Hypertension 37:739-743.

  • Weder A B 2007. Genetics and Hypertension. J Clin Hypertens 9:217-223

  • Yamamoto M et al. 2006. Interaction between serotonin 2A receptor and endothelin-1 variants in association with hypertension in Japanese. Hypertens Res 29:227-232.

  • Zintzaras E et al. 2006. Endothelial NO synthase gene polymorphisms and hypertension: a meta-analysis. Hypertension 48:700-710.


Claims
  • 1. A method for risk assessment, molecular diagnosis or prognosis assessment of hypertension (HT) or a HT related condition in a mammalian subject using a biological sample obtained from the subject comprising: a) detecting one or more HT associated biomarkers in said sample, wherein the biomarkers are related to one or more genes set forth in table 1, or said biomarkers are related to one or more polypeptides encoded by said genes, and;c) comparing the biomarker data from the subject to biomarker data from healthy and diseased people to make risk assessment, molecular diagnosis or prognosis of HT.
  • 2. The method according to claim 1, wherein said HT related condition comprises cerebrovascular disease, arterial aneurysm, left ventricular hypertrophy, congestive heart failure, other congestive heart disease, coronary heart disease, other ischemic arterial disease, other arteriosclerotic disease, hypertensive renal disease or hypertensive retinal disease.
  • 3. The method according to claim 1, wherein at least one biomarker is a HT associated polymorphic site residing in a genomic region containing a gene set forth in table 1.
  • 4. The method according to claim 1, wherein at least one biomarker is selected from the SNP markers set forth in tables 2 to 10.
  • 5. The method according to claim 1, wherein at least one biomarker is a HT associated polymorphic site associated with one or more of the SNP markers set forth in tables 2 to 10.
  • 6. The method according to claim 1, wherein at least one biomarker is a HT associated polymorphic site being in complete linkage disequilibrium with one or more of the SNP markers set forth in tables 2 to 10.
  • 7. The method according to claim 1, wherein at least one biomarker is an expression product of a gene set forth in table 1.
  • 8. The method according to claim 1, wherein at least one biomarker is related to biological activity or function of a polypeptide encoded by a gene set forth in table 1.
  • 9. The method according to claim 1, wherein at least one biomarker is a metabolite of a polypeptide encoded by a gene set forth in table 1.
  • 10. The method according to claim 1, wherein at least one biomarker is an antibody specific to a polypeptide encoded by a gene set forth in table 1.
  • 11. The method according to claim 1, wherein said method is for identifying subjects having altered risk for developing HT or a HT related condition.
  • 12. The method according to claim 1, wherein said method is for selecting efficient and/or safe therapy to prevent HT or a HT related condition in a subject having increased risk of HT or a HT related condition.
  • 13. The method according to claim 1, wherein said method is for predicting efficiency or monitoring the effect of a therapy used to prevent HT or a HT related condition in a subject having increased risk of HT or a HT related condition.
  • 14. The method according to claim 1, wherein said method is for diagnosing a subtype of HT in a subject having HT or a HT related condition.
  • 15. The method according to claim 1, wherein said method is for selecting efficient and safe therapy to treat HT or a HT related condition in a subject having HT or a HT related condition.
  • 16. The method according to claim 1, wherein said method is for predicting efficiency or monitoring the effect of a therapy used to treat HT or a HT related condition in a subject having HT or a HT related condition.
  • 17. The method according to claim 1 further comprising a SNP marker set or a microsatellite marker set to assess the ancestry of a subject.
  • 18. The method according to claim 1 further comprising a step of combining non-genetic information with the biomarker data to make risk assessment, diagnosis or prognosis of HT or a HT related condition for a subject.
  • 19. The method according to claim 18, wherein the non-genetic information comprises age, gender, ethnicity, socioeconomic status, medical history of the subject, psychological traits and states, behavior patterns and habits, biochemical measurements, clinical measurements and family history of HT and relevant conditions.
  • 20. The method according to claim 19, wherein the medical history of the subject comprises cerebrovascular disease, other cardiovascular disease, hypercholesterolemia, obesity, diabetes and the metabolic syndrome.
  • 21. The method according to claim 19, wherein the relevant family history information comprises HT, cerebrovascular disease, other cardiovascular disease, hypercholesterolemia, obesity, diabetes and the metabolic syndrome.
  • 22. The method according to claim 19, wherein the biochemical measurements comprise the measurements of determining blood, serum or plasma concentration or urinary excretion of VLDL, LDL, HDL, total cholesterol, triglycerides, apolipoprotein (a), fibrinogen, ferritin, transferrin receptor, C-reactive protein, glucose, insulin, vasoactive peptides, sodium, potassium, magnesium, calcium, selenium, saturated and unsaturated fatty acids, amino acids, dietary antioxidants such as vitamin C and E and biomarkers of alcohol intake such as gamma-glutamyltransaminase.
  • 23. The method according to claim 19, wherein the clinical measurements comprise systolic and diastolic blood pressure measurements and measurements of obesity and adiposity comprising height, weight, body-mass index (kg/m2), waist circumference, waist-to-hip circumference ratio, skinfold thickness measurements, adipose tissue thickness measurements and measurements of amount and proportion of adipose tissue of the body.
  • 24. The method according to claim 19, wherein the behaviour patterns and habits include tobacco smoking, physical activity, dietary intakes of nutrients, salt intake, alcohol intake and consumption patterns and coffee consumption and quality.
  • 25. The method according to claim 1 further comprising a step of calculating the risk of HT or a HT related condition using a logistic regression equation as follows: Risk of HT=[1+e−(a+Σ(bi*Xi)]−1, where e is Napier's constant, Xi are variables associated with the risk of HT, bi are coefficients of these variables in the logistic function, and a is the constant term in the logistic function.
  • 26. The method according to claim 25, wherein subject's short term, median term, and/or long term risk of HT or a HT related condition is predicted.
  • 27. A test kit for risk assessment, molecular diagnosis or prognosis assessment of HT or a HT related condition from biological samples taken from mammalian subjects comprising: a) reagents, materials and protocols for assessing type and/or level of one or more HT associated biomarkers in a biological sample, wherein the biomarkers are related to one or more genes set forth in table 1, or said biomarkers are related to one or more polypeptides encoded by said genes, and;b) instructions and software for comparing the biomarker data from a subject to biomarker data from healthy and diseased people to make risk assessment, molecular diagnosis or prognosis of HT or a HT related condition.
  • 28. The test kit according to claim 27, wherein said HT related condition comprises cerebrovascular disease, arterial aneurysm, left ventricular hypertrophy, congestive heart failure, other congestive heart disease, coronary heart disease, other ischemic arterial disease, other arteriosclerotic disease, hypertensive renal disease or hypertensive retinal disease.
  • 29. The test kit according to claim 27, wherein at least one biomarker is a HT associated polymorphic site residing in a genomic region containing a gene set forth in table 1.
  • 30. The test kit according to claim 27, wherein at least one biomarker is selected from the SNP markers set forth in tables 1 to 10.
  • 31. The test kit according to claim 27, wherein at least one biomarker is a HT associated polymorphic site associated with one or more of the SNP markers set forth in tables 2 to 10.
  • 32. The test kit according to claim 27, wherein at least one biomarker is a HT associated polymorphic site being in complete linkage disequilibrium with one or more of the SNP markers set forth in tables 2 to 10.
  • 33. The test kit according to claim 27, wherein at least one biomarker is an expression product of a gene set forth in table 1.
  • 34. The test kit according to claim 27, wherein at least one biomarker is related to biological activity or function of a polypeptide encoded by a gene set forth in table 1.
  • 35. The test kit according to claim 27, wherein at least one biomarker is a metabolite of a polypeptide encoded by a gene set forth in table 1.
  • 36. The test kit according to claim 27, wherein at least one biomarker is an antibody specific to a polypeptide encoded by a gene set forth in table 1.
  • 37. The test kit according to claim 27, wherein said test kit is for identifying subjects having altered risk for developing HT or a HT related condition.
  • 38. The test kit according to claim 27, wherein said test kit is for selecting efficient and safe therapy to prevent HT or a HT related condition in a subject having increased risk of HT or a HT related condition.
  • 39. The test kit according to claim 27, wherein said test kit is for predicting efficiency or monitoring the effect of a therapy used to prevent HT or a HT related condition in a subject having increased risk of HT or a HT related condition.
  • 40. The test kit according to claim 27, wherein said test kit is for diagnosing a subtype of HT in a subject having HT or a HT related condition.
  • 41. The test kit according to claim 27, wherein said test kit is for selecting efficient and safe therapy to treat HT or a HT related condition in a subject having HT or a HT related condition.
  • 42. The test kit according to claim 27, wherein said test kit is for predicting efficiency or monitoring the effect of a therapy used to treat HT or a HT related condition in a subject having HT or a HT related condition.
  • 43. The test kit according to claim 27 further comprising a SNP marker set or microsatellite marker set to assess the ancestry of a subject.
  • 44. The test kit according to claim 27 further comprising a questionnaire and instructions for collecting personal and clinical information from the subject, and software and instructions for combining personal and clinical information with biomarker data to make risk assessment, diagnosis or prognosis of HT or a HT related condition.
  • 45. The test kit according to claim 44, wherein the non-genetic information comprises age, gender, ethnicity, socioeconomic status, medical history of the subject, psychological traits and states, behavior patterns and habits, biochemical measurements, clinical measurements and family history of HT and relevant conditions.
  • 46. The test kit according to claim 45, wherein the medical history of the subject comprises cerebrovascular disease, other cardiovascular disease, hypercholesterolemia, obesity, diabetes and the metabolic syndrome.
  • 47. The test kit according to claim 45, wherein the relevant family history information comprises cerebrovascular disease, other cardiovascular disease, hypercholesterolemia, obesity, diabetes and the metabolic syndrome.
  • 48. The test kit according to claim 45, wherein the biochemical measurements comprise the measurements of determining blood, serum or plasma concentration or urinary excretion of VLDL, LDL, HDL, total cholesterol, triglycerides, apolipoprotein (a), fibrinogen, ferritin, transferrin receptor, C-reactive protein, glucose, insulin, vasoactive peptides, sodium, potassium, magnesium, calcium, selenium, saturated and unsaturated fatty acids, amino acids, dietary antioxidants such as vitamin C and E and biomarkers of alcohol intake such as gamma-glutamyltransaminase.
  • 49. The test kit according to claim 45, wherein the clinical measurements comprise systolic and diastolic blood pressure measurements and measurements of obesity and adiposity comprising height, weight, body-mass index (kg/m2), waist circumference, waist-to-hip circumference ratio, skinfold thickness measurements, adipose tissue thickness measurements and measurements of amount and proportion of adipose tissue of the body.
  • 50. The test kit according to claim 45, wherein the behaviour patterns and habits include tobacco smoking, physical activity, dietary intakes of nutrients, salt intake, alcohol intake and consumption patterns and coffee consumption and quality.
  • 51. The test kit according to claim 27 further comprising a step of calculating the risk of HT or a HT related condition using a logistic regression equation as follows: Risk of HT=[1+e−(a+Σ(bi*Xi)]−1, where e is Napier's constant, Xi are variables associated with the risk of HT, bi are coefficients of these variables in the logistic function, and a is the constant term in the logistic function.
  • 52. The test kit according to claim 27, wherein subject's short term, median term, and/or long term risk of HT or a HT related condition is predicted.
  • 53. The test kit according to claim 27 comprising a PCR primer set for amplifying at least one of said biomarkers.
  • 54. The test kit according to claim 27 comprising a capturing nucleic acid probe set specifically binding to at least one of said biomarkers.
  • 55. The test kit according to claim 27 comprising a microarray or multiwell plate to assess said biomarkers.
  • 56. Use of an agent modulating biological activity or function of a polypeptide encoded by a HT associated gene set forth in table 1 for manufacturing of a pharmaceutical composition for prevention or treatment of HT or a HT related condition in a mammalian subject
  • 57. The use according to claim 56, wherein said HT related condition comprises cerebrovascular disease, arterial aneurysm, left ventricular hypertrophy, congestive heart failure, other congestive heart disease, coronary heart disease, other ischemic arterial disease, other arteriosclerotic disease, hypertensive renal disease or hypertensive retinal disease.
  • 58. The use according to claim 56, wherein said agent enhances or reduces expression of a HT associated gene set forth in table 1.
  • 59. The use according to claim 56, wherein said agent enhances or reduces biological activity or function of a metabolic pathway related to a HT associated gene set forth in table 1, or its encoded polypeptide.
  • 60. The use according to claim 56, wherein said agent enhances or reduces activity of a pathophysiological pathway involved in HT or a HT related condition and related to a HT associated gene set forth in table 1, or its encoded polypeptide.
  • 61. The use according to claim 56, wherein said agent is a recombinant polypeptide encoded by a HT associated gene set forth in table 1, or a variant, a fragment or a derivative thereof.
  • 62. The use according to claim 56, wherein said agent is an antibody binding to a polypeptide encoded by a HT associated gene set forth in table 1.
  • 63. The use according to claim 56, wherein said agent binds to a polypeptide encoded by a HT associated gene set forth in table 1.
  • 64. The use according to claim 56, wherein said agent is a sequence specific gene silencing agent such as a siRNA hybridising to a RNA encoded by a HT associated gene set forth in table 1.
  • 65. A method for preventing, treating or reducing the risk of HT or a HT related condition in a mammalian subject comprising a therapy modulating biological activity or function of a polypeptide encoded by a HT associated gene set forth in table 1.
  • 66. The method according to claim 65, wherein said HT related condition comprises cerebrovascular disease, arterial aneurysm, left ventricular hypertrophy, congestive heart failure, other congestive heart disease, coronary heart disease, other ischemic arterial disease, other arteriosclerotic disease, hypertensive renal disease or hypertensive retinal disease.
  • 67. The method according to claim 65 comprising administering to a mammalian subject in need of such treatment an effective amount of a therapeutic agent enhancing or reducing expression of a HT associated gene set forth in table 1.
  • 68. The method according to claim 65 comprising administering to a mammalian subject in need of such treatment an effective amount of a therapeutic agent enhancing or reducing biological activity or function of a metabolic pathway related to a HT associated gene set forth in table 1, or its encoded polypeptide.
  • 69. The method according to claim 65 comprising administering to a mammalian subject in need of such treatment an effective amount of a therapeutic agent enhancing or reducing activity of a pathophysiological pathway involved in HT or a HT related condition and related to a HT associated gene set forth in table 1, or its encoded polypeptide.
  • 70. The method according to claim 65, wherein said therapy comprises a recombinant polypeptide encoded by a HT associated gene set forth in table 1, or a variant, a fragment or a derivative thereof.
  • 71. The method according to claim 65, wherein said therapy comprises an antibody binding to a polypeptide encoded by a HT associated gene set forth in table 1.
  • 72. The method according to claim 65, wherein said therapy comprises an agent binding to a polypeptide encoded by a HT associated gene set forth in table 1.
  • 73. The method according to claim 65, wherein said therapy comprises a sequence specific gene silencing agent such as a siRNA hybridising to a RNA encoded by a HT associated gene set forth in table 1.
  • 74. The method according to claim 65 comprising gene therapy, gene transfer, dietary treatment or a vaccination.
  • 75. The method according to claim 74, wherein said therapy comprises the transfer of a HT associated gene set forth in table 1, or a variant, a fragment or a derivative thereof in somatic cells, in stem cells, or in affected tissues of said subject.
  • 76. A pharmaceutical composition for preventing, treating or reducing the risk of HT or a HT related condition in a mammalian subject comprising an agent modulating biological activity or function of a polypeptide encoded by a HT associated gene set forth in table 1.
  • 77. The pharmaceutical composition according to claim 76, wherein said HT related condition comprises cerebrovascular disease, arterial aneurysm, left ventricular hypertrophy, congestive heart failure, other congestive heart disease, coronary heart disease, other ischemic arterial disease, other arteriosclerotic disease, hypertensive renal disease or hypertensive retinal disease.
  • 78. The pharmaceutical composition according to claim 76, wherein said agent enhances or reduces expression of a HT associated gene set forth in table 1.
  • 79. The pharmaceutical composition according to claim 76, wherein said agent enhances or reduces biological activity or function of a metabolic pathway related to a HT associated gene set forth in table 1, or its encoded polypeptide.
  • 80. The pharmaceutical composition according to claim 76, wherein said agent enhances or reduces activity of a pathophysiological pathway involved in HT or a HT related condition and related to a HT associated gene set forth in table 1, or its encoded polypeptide.
  • 81. The pharmaceutical composition according to claim 76, wherein said agent is a recombinant polypeptide encoded by a HT associated gene set forth in table 1, or a variant, a fragment or a derivative thereof.
  • 82. The pharmaceutical composition according to claim 76, wherein said agent is an antibody binding to a polypeptide encoded by a HT associated gene set forth in table 1.
  • 83. The pharmaceutical composition according to claim 76, wherein said agent binds to a polypeptide encoded by a HT associated gene set forth in table 1.
  • 84. The pharmaceutical composition according to claim 76, wherein said agent is a sequence specific gene silencing agent such as a siRNA hybridising to a RNA encoded by a HT associated gene set forth in table 1.
  • 85. A method for screening agents for preventing or treating HT or a HT related condition in a mammal comprising determining the effect of an agent either on a metabolic pathway related to a polypeptide or a RNA molecule encoded by a HT associated gene set forth in table 1 in living cells; wherein an agent altering activity of a metabolic pathway is considered useful in prevention or treatment of HT or a HT related condition.
  • 86. The method according to claim 85, wherein said agent is administered to a model system or organism, and wherein an agent altering or modulating expression, biological activity or function of a HT associated gene set forth in table 1, or its encoded polypeptide is considered useful in prevention or treatment of HT or a HT related condition.
  • 87. The method according to claim 86, wherein the model system or organism comprises cultured microbial, insect or mammalian cells, mammalian tissues, organs or organ systems or non-human transgenic animals expressing a HT associated gene set forth in table 1.
RELATED APPLICATIONS

This application claims the benefit of U.S. provisional Application No. 60/819,014, filed on Jul. 7, 2006 and U.S. provisional Application No. 60/867,454 filed on Nov. 28, 2006. The entire teachings of the above applications are incorporated herein by reference.

Provisional Applications (2)
Number Date Country
60819014 Jul 2006 US
60867454 Nov 2006 US