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

Authors: Yu, Bing; Pulit, Sara L; Hwang, Shih-Jen; Brody, Jennifer A; Amin, Najaf; Auer, Paul L; Bis, Joshua C; Boerwinkle, Eric; Burke, Gregory L; Chakravarti, Aravinda; Correa, Adolfo; Dreisbach, Albert W; Franco, Oscar H; Ehret, Georg B; Franceschini, Nora; Hofman, Albert; Lin, Dan-Yu; Metcalf, Ginger A; Musani, Solomon K; Muzny, Donna; Palmas, Walter; Raffel, Leslie; Reiner, Alex; Rice, Ken; Rotter, Jerome I; Veeraraghavan, Narayanan; Fox, Ervin; Guo, Xiuqing; North, Kari E; Gibbs, Richard A; van Duijn, Cornelia M; Psaty, Bruce M; Levy, Daniel; Newton-Cheh, Christopher; Morrison, Alanna C; CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*

Published In Circ Cardiovasc Genet, (2016 Feb)

Abstract: Rare genetic variants influence blood pressure (BP).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%; β=-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 (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-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%; β=-3.30; P=5.0×10(-7)).These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

PubMed ID: 26658788

MeSH Terms: No MeSH terms associated with this publication