Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.
Mitchell GF., Verwoert GC., Tarasov KV., Isaacs A., Smith AV., Yasmin None., Rietzschel ER., Tanaka T., Liu Y., Parsa A., Najjar SS., O'Shaughnessy KM., Sigurdsson S., De Buyzere ML., Larson MG., Sie MPS., Andrews JS., Post WS., Mattace-Raso FUS., McEniery CM., Eiriksdottir G., Segers P., Vasan RS., van Rijn MJE., Howard TD., McArdle PF., Dehghan A., Jewell ES., Newhouse SJ., Bekaert S., Hamburg NM., Newman AB., Hofman A., Scuteri A., De Bacquer D., Ikram MA., Psaty BM., Fuchsberger C., Olden M., Wain LV., Elliott P., Smith NL., Felix JF., Erdmann J., Vita JA., Sutton-Tyrrell K., Sijbrands EJG., Sanna S., Launer LJ., De Meyer T., Johnson AD., Schut AFC., Herrington DM., Rivadeneira F., Uda M., Wilkinson IB., Aspelund T., Gillebert TC., Van Bortel L., Benjamin EJ., Oostra BA., Ding J., Gibson Q., Uitterlinden AG., Abecasis GR., Cockcroft JR., Gudnason V., De Backer GG., Ferrucci L., Harris TB., Shuldiner AR., van Duijn CM., Levy D., Lakatta EG., Witteman JCM.
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.