Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Circulation. Cardiovascular genetics, 2016-02, Vol.9 (1), p.64-70

Ort / Verlag

United States

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.