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.
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.
Mitchell, GF; Verwoert, GC; Tarasov, KV; Isaacs, A; Smith, AV; Yasmin, ; 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
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