Bing Yu, Sara L Pulit, Shih-Jen Hwang, Jennifer A Brody, Najaf Amin, Paul L Auer, Joshua C Bis, Eric Boerwinkle, Gregory L Burke, Aravinda Chakravarti, Adolfo Correa, Albert W Dreisbach, Oscar H Franco, Georg B Ehret, Nora Franceschini, Albert Hofman, Dan-Yu Lin, Ginger A Metcalf, Solomon K Musani, Donna Muzny, Walter Palmas, Leslie Raffel, Alex Reiner, Ken Rice, Jerome I Rotter, Narayanan Veeraraghavan, Ervin Fox, Xiuqing Guo, Kari E North, Richard A Gibbs, Cornelia M van Duijn, Bruce M Psaty, Daniel Levy, Christopher Newton-Cheh, Alanna C Morrison
{"title":"Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.","authors":"Bing Yu, Sara L Pulit, Shih-Jen Hwang, Jennifer A Brody, Najaf Amin, Paul L Auer, Joshua C Bis, Eric Boerwinkle, Gregory L Burke, Aravinda Chakravarti, Adolfo Correa, Albert W Dreisbach, Oscar H Franco, Georg B Ehret, Nora Franceschini, Albert Hofman, Dan-Yu Lin, Ginger A Metcalf, Solomon K Musani, Donna Muzny, Walter Palmas, Leslie Raffel, Alex Reiner, Ken Rice, Jerome I Rotter, Narayanan Veeraraghavan, Ervin Fox, Xiuqing Guo, Kari E North, Richard A Gibbs, Cornelia M van Duijn, Bruce M Psaty, Daniel Levy, Christopher Newton-Cheh, Alanna C Morrison","doi":"10.1161/CIRCGENETICS.115.001215","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Rare genetic variants influence blood pressure (BP).</p><p><strong>Methods and results: </strong>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)).</p><p><strong>Conclusions: </strong>These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.</p>","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2016-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771070/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation-Cardiovascular Genetics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1161/CIRCGENETICS.115.001215","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2015/12/11 0:00:00","PubModel":"Epub","JCR":"Q","JCRName":"Medicine","Score":null,"Total":0}
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.
期刊介绍:
Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease. Manuscripts are examined by the editorial staff and usually evaluated by expert reviewers assigned by the editors. Both clinical and basic articles will also be subject to statistical review, when appropriate. Provisional or final acceptance is based on originality, scientific content, and topical balance of the journal. Decisions are communicated by email, generally within six weeks. The editors will not discuss a decision about a manuscript over the phone. All rebuttals must be submitted in writing to the editorial office.