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

  • Author(s): 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*
  • et al.

Published Web Location
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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)).


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

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