Dataset Information

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

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 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%; ?=-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 (?=-4.11; P=2.8×10(-4)), mean arterial pressure (?=-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%; ?=-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.

SUBMITTER: Yu B

PROVIDER: S-EPMC4771070 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IMPORTANCE:Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. OBJECTIVE:To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. DESIGN, SETTING, AND PARTICIPANTS:The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed?approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. MAIN OUTCOMES AND MEASURES:Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). RESULTS:We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio,?2.15; P?=?2.63?×?10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio,?2.04; P?=?1.24?×?10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). CONCLUSIONS AND RELEVANCE:Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets