Genes encoding key elements of the renin-angiotensin-aldosterone system (RAAS) cascade have been previously but inconsistently associated with blood pressure. Sex-dependency might be important here and functional genetic polymorphisms might exhibit epistatic effects.Design and Method:
We assessed variation in the genes encoding renin (REN), angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1) and aldosterone synthase (CYP11B2). We determined whether individual SNPs, interactions between SNPs or sex-SNP interactions were associated with systolic blood pressure (SBP). 88 SNPs provided gene-wide coverage of the 5 RAAS genes for 2929 individuals (comprising over 800 2-generation white adult families) from the Victorian Family Heart Study. Variance components models were used that adjusted for measured covariates and within-family correlation.Results:
Initial analyses found that three SNPs (rs8075924 and rs4277404 in ACE and rs12721297 in AGTR1) were inversely associated with SBP with significant (p < 0.005) effect sizes around −1.7 mmHg to −2.5 mmHg. No association was observed for markers for well-known polymorphisms: ACE I/D, AGTR1 A1166C and AGT M235T. Significant sex-specific associations were seen for 3 SNPs in males (rs2468523 and rs2478544 in AGT and rs11658531 in ACE) and 1 SNP in females (rs12451328 in ACE). There were significant interactions between 3 pairs of SNPs (rs7079 in AGT with rs2004776 in AGT; rs4736360 in CYP11B with rs2478523 in AGT and rs4736360 in CYP11B with rs2478545 in AGT). The interaction effect estimates ranged from 2.9 to 5.5 mmHg.Conclusions:
Our analyses of SNPs in and around key RAAS genes for SBP reveal evidence of direct association, association dependent on sex and association dependent on epistasis. Variants dependent on epistasis or sex were not obvious in direct tests of association with SBP. Analyses that incorporate sex-dependent and epistatic effects could help account for the missing heritability of blood pressure.