%0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. %A Yu, Bing %A Pulit, Sara L %A Hwang, Shih-Jen %A Brody, Jennifer A %A Amin, Najaf %A Auer, Paul L %A Bis, Joshua C %A Eric Boerwinkle %A Burke, Gregory L %A Chakravarti, Aravinda %A Correa, Adolfo %A Dreisbach, Albert W %A Franco, Oscar H %A Ehret, Georg B %A Franceschini, Nora %A Hofman, Albert %A Lin, Dan-Yu %A Ginger A Metcalf %A Musani, Solomon K %A Donna M Muzny %A Palmas, Walter %A Raffel, Leslie %A Reiner, Alex %A Rice, Ken %A Rotter, Jerome I %A Veeraraghavan, Narayanan %A Fox, Ervin %A Guo, Xiuqing %A North, Kari E %A Richard A Gibbs %A van Duijn, Cornelia M %A Psaty, Bruce M %A Levy, Daniel %A Newton-Cheh, Christopher %A Morrison, Alanna C %K Alleles %K Black People %K Blood Pressure %K Chloride Channels %K Exome %K Female %K Gene Frequency %K Humans %K Hypertension %K Male %K Risk Factors %K White People %X

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%; 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)).

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

%B Circ Cardiovasc Genet %V 9 %P 64-70 %8 2016 Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26658788?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001215