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

Publication Type:

Journal Article

Source:

Circulation. Cardiovascular genetics (2015)

Abstract:

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 and African ancestry (14,497 first stage and 3,459 second stage discovery) to examine the impact of rare variants on hypertension and four BP traits: systolic and diastolic BP (SBP, DBP), pulse pressure (PP), and mean arterial pressure (MAP). Tests of ~170,000 common variants (minor allele frequency, MAF, ≥1%, statistical significance P≤2.9×10(-7)) and gene-based tests of rare variants (MAF<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 DBP (cumulative MAF=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 SBP (β=-4.11, P=2.8×10(-4)), MAP (β=-3.50, P=8.9×10(-6)), and reduced hypertension risk (odds ratio=0.72, P=0.017). Meta-analysis of the two-stage discovery samples showed that CLCN6 was associated with lower DBP at exome-wide significance (cumulative MAF=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.