Effects of rare and common blood pressure gene variants on essential hypertension: results from the Family Blood Pressure Program, CLUE, and Atherosclerosis Risk in Communities studies

Abstract

Rationale: Hypertension affects ≈30% of adults in industrialized countries and is the major risk factor for cardiovascular disease.

Objective: We sought to study the genetic effect of coding and conserved noncoding variants in syndromic hypertension genes on systolic blood pressure (BP) and diastolic BP to assess their overall impact on essential hypertension.

Methods and results: We resequenced 11 genes (AGT, CYP11B1, CYP17A1, HSD11B2, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1, and WNK4) in 560 European American (EA) and African American ancestry GenNet participants with extreme systolic BP. We investigated genetic associations of 2535 variants with BP in 19997 EAs and in 6069 African Americans in 3 types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9747 EA and 3207 African American Atherosclerosis Risk in Communities subjects. Finally, we genotyped 37 missense and common noncoding variants in 6591 EAs and in 6521 individuals (3659 EA/2862 African American) from the CLUE and Family Blood Pressure Program studies, respectively. None of the variants individually reached significant false-discovery rates ≤0.05 for systolic BP and diastolic BP. However, on pooling all coding and noncoding variants, we identified at least 5 loci (AGT, CYP11B1, NR3C2, SCNN1G, and WNK1) with higher association at evolutionary conserved sites.

Conclusions: Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units), and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.

Figure 1

Distribution of systolic blood pressure (SBP) residuals in GenNet participants: (a) 705 unrelated European Americans (EA), and (b) 521 unrelated African Americans (AA). Residual SBP for the 280 EA and 280 AA individuals chosen for sequencing are highlighted in blue.

Figure 1

Distribution of systolic blood pressure (SBP) residuals in GenNet participants: (a) 705 unrelated European Americans (EA), and (b) 521 unrelated African Americans (AA). Residual SBP for the 280 EA and 280 AA individuals chosen for sequencing are highlighted in blue.

Figure 2

The classification of all 1,277 and 1,972 sequence variants observed, by functional category and relative abundance, in the 11 genes we examined.