Renalase Gene And Vascular Smooth Muscle Cells Contraction Pathway Related Gene Polymorphism And Essential Hypertension

It is widely believed that essential hypertension(EH) is a complex disease influenced by multiple factors including genetic and environmental element.It is,however,still unclear how the genetic factors contributes to this kind of disease.In our study,we use large hypertensive case-control samples to test associations between renalase,a novel blood pressure regulation related gene,and the interaction among genetic variants from contractile pathway of vascular smooth muscle cell(VSMC) and EH in Chinese Han population,respectively.We designed a two-stage case-control study to investigate whether the renalase gene harbored any genetic variants associated with EH in the northern Han Chinese population.1,317 hypertensive cases and 1,269 normotensive controls were recruited. These total 2,586 subjects were taken as the main study population in this study.In stage-1,all the eight selected single nucleotide polymorphisms(SNPs) of renalase gene were genotyped and tested within a subsample(503 cases and 490 controls) of the main study population.By single locus analyses,three SNPs,rs2576178, rs2296545,and rs2114406,showed significant associations with EH in stage-1 (P＜0.05) and were further genotypied among the remained sample.After Bonferroni correction for multiple comparisons,the associations of rs2576178 and rs2296545 with EH were still significant in stage-2.The cases had higher frequency of rs2576178 G allele and rs2296545 C allele than the controls(0.55 versus 0.49, P＜0.0001;0.61 versus 0.55,P＜0.0001).Particularly,under the codominant model,the adjusted odds ratios(ORs) for rs2576178 GG genotype and rs2296545 CC genotype were 1.58(95%CI,1.25 to 2.00;P=0.0002) and 1.61(95%CI,1.26 to 2.04; P=0.0002),respectively.We also found risk-associated haplotypes and diplotypes, which further confirmed the significant association between the renalase gene and EH.These findings may provide novel genetic susceptibility markers for EH and lead to a better understanding of EH pathophysiology.In addition,further replications in other populations and functional studies would be warranted.We selected five genes from the contractile pathway of VSMC,KCNMB1,RGS2, PRKG,ROCK2,and MYLK,to test their individual and interactive effects on the risk of EH.Potential functional polymorphisms of the five genes were analyzed in a large, representative Chinese Han sample of 4759 individuals,including 2411 hypertensive patients and 2348 age- and gender-matched healthy controls.Single locus analyses showed significant association of the alleles of RGS2-rs34717272 with hypertension (original P ofχ~2-test=0.005;P value of permutation=0.019).After the adjustment for covariates,the carriers of minor D allele of RGS2-rs34717272 had an increased hypertension risk(DD+ID vs.Ⅱ;OR=1.19;95%CI,1.04-1.35;P value after the Bonferroni correction=0.009×5=0.045).We also found that the carriers of minor T allele of KCNMB1-rs11739136 had a significantly decreased risk for hypertension (TT+CT vs.CC;OR=0.83;95%CI,0.72-0.95;P value after the Bonferroni correction=0.008×5=0.040).Final interaction models were selected and evaluated by permutation test and/or cross-validation test.Both the multifactor-dimensionality reduction(MDR) and classification and regression trees(CART) methods revealed a high-order gene-gene interaction among KCNMB1,RGS2,PRKG,and MYLK genes (P value of permutation in MDR=0.012).The overall results supported that the genetic variants in the contractile pathway of VSMC could contribute to hypertension risk independently or in an interactive manner.