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

Tuesday,2016-01-12 12:30 America/Los_Angeles — zdrager
TitleRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.
Publication TypeJournal Article
Year of Publication2016
AuthorsYu, B, Pulit, SL, Hwang, S-J, Brody, JA, Amin, N, Auer, PL, Bis, JC, Boerwinkle, E, Burke, GL, Chakravarti, A, Correa, A, Dreisbach, AW, Franco, OH, Ehret, GB, Franceschini, N, Hofman, A, Lin, D-Y, Metcalf, GA, Musani, SK, Muzny, D, Palmas, W, Raffel, L, Reiner, A, Rice, K, Rotter, JI, Veeraraghavan, N, Fox, E, Guo, X, North, KE, Gibbs, RA, van Duijn, CM, Psaty, BM, Levy, D, Newton-Cheh, C, Morrison, AC
Corporate/Institutional AuthorsCHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*
JournalCirc Cardiovasc Genet
Volume9
Issue1
Pagination64-70
Date Published2016 Feb
ISSN1942-3268
Abstract<p><b>BACKGROUND: </b>Rare genetic variants influence blood pressure (BP).</p><p><b>METHODS AND RESULTS: </b>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)).</p><p><b>CONCLUSIONS: </b>These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.</p>
DOI10.1161/CIRCGENETICS.115.001215
Alternate JournalCirc Cardiovasc Genet
PubMed ID26658788
PubMed Central IDPMC4771070
Grant List5RC2HL102419 / HL / NHLBI NIH HHS / United States
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