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Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.


ABSTRACT: 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 ?170 000 common variants (minor allele frequency, ?1%; statistical significance, P?2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ?17 000 genes; statistical significance, P?1.5×10(-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%; ?=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (?=-4.11; P=2.8×10(-4)), mean arterial pressure (?=-3.50; P=8.9×10(-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%; ?=-3.30; P=5.0×10(-7)). CONCLUSIONS:These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

PROVIDER: S-EPMC4771070 | BioStudies |

REPOSITORIES: biostudies

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