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Background-: Rare genetic variants influence blood pressure (BP).

Methods and Results-: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of [almost equal to]170 000 common variants (minor allele frequency, >=1%; statistical significance, P<=2.9x10-7) and gene-based tests of rare variants (minor allele frequency, <1%; [almost equal to]17 000 genes; statistical significance, P<=1.5x10-6) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; [beta]=-3.20; P=4.1x10-6) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP ([beta]=-4.11; P=2.8x10-4), mean arterial pressure ([beta]=-3.50; P=8.9x10-6), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; [beta]=-3.30; P=5.0x10-7).

Conclusions-: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

(C) 2016 American Heart Association, Inc.