November 9, 2011Circulation Cardiovascular Genetics105 citationsOpen Access
Common Genetic Variation in the 3′- BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk
Key Result
The rs7152623 variant in the 3'-BCL11B gene desert was associated with carotid-femoral pulse wave velocity (β=-0.076 SD/allele; P=3.1×10(-15)) and increased risk for coronary artery disease.
Study Design
Type
Meta-Analysis (n=25,940)
Multicenter
Yes
Structured PICO
Is common genetic variation in the 3'-BCL11B gene desert associated with carotid-femoral pulse wave velocity and cardiovascular disease risk in individuals of European ancestry?
P
Population
25,940 participants of European ancestry from 11 community-based cohorts included in a meta-analysis of genome-wide association data for aortic stiffness.
E
Exposure
Common genetic variation in the 3'-BCL11B gene desert (rs7152623)
C
Comparator
Alternative alleles at rs7152623
O
Outcome
Carotid-femoral pulse wave velocity (CFPWV)surrogate
A novel genetic locus in the BCL11B gene desert is associated with increased aortic stiffness and higher risk of coronary artery disease and heart failure.
Main Result
Effect estimate: β=-0.076±0.010 SD/allele
p-value: p=3.1×10(-15)
Abstract
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, β=-0.075±0.012 SD/allele, P=2.8×10(-10); replication β=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave β=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (β=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, β=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, β=-0.061±0.014 SD/allele, P=9.4×10(-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.