03283nas a2200565 4500008004100000022001400041245009400055210006900149260001300218300001000231490000600241520164500247100001301892700001901905700002001924700002301944700001601967700001801983700001902001700002102020700002202041700002602063700001902089700002502108700002102133700002002154700002302174700001902197700001602216700002302232700002302255700001702278700001902295700001902314700001702333700001402350700002202364700002902386700001502415700001702430700001902447700002202466700002302488700002002511700001702531700002902548700002402577710008002601856003602681 2016 eng d a1942-326800aRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.0 aRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Leve c2016 Feb a64-700 v93 a
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.
1 aYu, Bing1 aPulit, Sara, L1 aHwang, Shih-Jen1 aBrody, Jennifer, A1 aAmin, Najaf1 aAuer, Paul, L1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBurke, Gregory, L1 aChakravarti, Aravinda1 aCorrea, Adolfo1 aDreisbach, Albert, W1 aFranco, Oscar, H1 aEhret, Georg, B1 aFranceschini, Nora1 aHofman, Albert1 aLin, Dan-Yu1 aMetcalf, Ginger, A1 aMusani, Solomon, K1 aMuzny, Donna1 aPalmas, Walter1 aRaffel, Leslie1 aReiner, Alex1 aRice, Ken1 aRotter, Jerome, I1 aVeeraraghavan, Narayanan1 aFox, Ervin1 aGuo, Xiuqing1 aNorth, Kari, E1 aGibbs, Richard, A1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aLevy, Daniel1 aNewton-Cheh, Christopher1 aMorrison, Alanna, C1 aCHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP* uhttps://chs-nhlbi.org/node/6937