Analysis of associations of hypertension with 16 genetic markers selected according to genome-wide studies

Abstract

The multifactorial genesis of hypertension (HTN) enforced the investigation of genetically determined component of its etiopathogenesis in various populations.The aim of present work is to assess the associations between blood pressure (BP) and HTN and polymorphism of a number of genetic markers identified according to GWAS data, in a case-control study based on Siberian population cohort. Design and methods. Design of the work—case-control study in the groups aged 45–69 years old based on a caucasoid population cohort (Novosibirsk). The group of cases included HTN subjects with established diagnosis of HTN under the age of 50 (n = 346)). The control included subjects matched by sex and age to cases, and having at least 2 examinations (6 months apart) with BP levels not exceeding “normal” BP by ESH, 2018 (n = 168). A total of 514 people were included in the analysis. We used standardized epidemiological methods to assess HTN and cardiovascular diseases. Single nucleotide polymorphisms (SNPs) were tested using real-time PCR (ABI 7900HT). The analysis included 16 markers identified in GWAS studies (rs11646213, rs17367504, rs11191548, rs12946454, rs16998073, rs1530440, rs653178, rs1378942, rs1004467, rs381815, rs2681492, rs2681472, rs3184504, rs2384550, rs6495122, rs6773957).Results. For the polymorphism rs1378942 of cytoplasmic tyrosine kinase gene (CSK), in a multivariable-adjusted logistic regression, the carriers of the AC/CC vs. AA genotypes had odds ratio (OR) of HTN of 1,51 (p = 0,043) independent of age and sex; this excess risk was partly explained by the impact of body mass index (BMI). With respect to the quantitative phenotype, women carrying the AA genotype had diastolic BP (DBP) value 5 mm Hg lower than carriers of AC/CC genotypes (p = 0,026). In a multivariable-adjusted analysis, the polymorphism rs653178 of ataxin 2 gene (ATXN2) was associated with HTN independent of age and BMI (СС vs ТТ/ТС; OR = 0,61; p = 0,022); this relationship was realized due to the contribution of men (p = 0,027). With respect to the quantitative phenotype, in the multivariable analysis, the carriers of СС genotype had DBP value lower than those with ТТ/ТС (p = 0,022) independent of age and BMI, and due to the contribution of men. In a multivariableadjusted analysis, the polymorphism rs6773957 of adiponectin gene (ADIPOQ) was associated with HTN in women regardless of age and BMI (GG v. AA/AG; OR = 0,29; p = 0,001). In unadjusted analysis, we found the association between polymorphism rs2384550 of T box transcription factor gene (TBX3) and the level of systolic BP (SBP) in men (p = 0,043); when comparing homozygous groups, the level of SBP was significantly higher among carriers of the AA genotype versus GG (p = 0,013), but this association was attenuated to insignificant in in a multivariate analysis.Conclusions. In a case-control study based on Siberian population sample, we found the associations between qualitative and quantitative phenotypes of BP/HTN and polymorphism of 4 SNPs (CSK, ATXN2, ADIPOQ, TBX3 genes). Our data replicated a number of positive results obtained in genomewide studies, and we obtained the evidence of new associations not previously convincingly shown, and of the context dependency of the association between HTN and a number of molecular markers.