Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 5, Issue 1, Pages 81-90Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.111.959817
Keywords
aorta; arterial stiffness; pulse wave velocity; genetics; cardiovascular disease
Funding
- National Institutes of Health
- National Institute on Aging Intramural Research Program
- Hjartavernd (Icelandic Heart Association)
- Althingi (Icelandic Parliament)
- NIH, National Institute on Aging
- Netherlands Organization for Scientific Research
- Erasmus Medical Center
- Centre for Medical Systems Biology (CMSB)
- Netherlands Kidney Foundation
- National Heart, Lung, and Blood Institute's Framingham Heart Study
- Affymetrix, Inc
- National Heart, Lung, and Blood Institute
- National Institutes on Aging
- Donald W. Reynolds Foundation
- NIH National Institute on Aging
- National Center for Research Resources
- National Institute of Diabetes, Digestive, and Kidney Disease
- Erasmus University Rotterdam
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Heart Foundation
- Ministry of Education, Culture and Science
- Ministry of Health Welfare and Sports
- European Commission
- Municipality of Rotterdam
- Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging
- Netherlands Organization for Scientific Research (Vici grant)
- National Institute on Aging
- National Human Genome Research Institute
- British Heart Foundation
- Cambridge BioMedical Research Centre Award
- Addenbrooke's Charitable Trust
- Fonds voor Wetenschappelijk Onderzoek-Vlaanderen FWO
- British Heart Foundation [FS/07/001/21990] Funding Source: researchfish
- Medical Research Council [G0801056, G0801056B] Funding Source: researchfish
- MRC [G0801056] Funding Source: UKRI
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Background-Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. Methods and Results-We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, beta=-0.075 +/- 0.012 SD/allele, P=2.8x10(-10); replication beta=-0.086 +/- 0.020 SD/allele, P=1.4x10(-6)). Combined results for rs7152623 from 11 cohorts gave beta=-0.076 +/- 0.010 SD/allele, P=3.1x10(-15). The association persisted when adjusted for mean arterial pressure (beta=-0.060 +/- 0.009 SD/allele, P=1.0x10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, beta =-0.081 +/- 0.014 SD/allele, P=2.3x10(-9)) and older (9 cohorts, n=12 026, beta=-0.061 +/- 0.014 SD/allele, P=-9.4x10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004). Conclusions-Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events. (Circ Cardiovasc Genet. 2012;5:81-90.)
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