Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.
Yu 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., CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP* None.
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.