Author:
Mitchell Gary F.,Verwoert Germaine C.,Tarasov Kirill V.,Isaacs Aaron,Smith Albert V.,Yasmin ,Rietzschel Ernst R.,Tanaka Toshiko,Liu Yongmei,Parsa Afshin,Najjar Samer S.,O'Shaughnessy Kevin M.,Sigurdsson Sigurdur,De Buyzere Marc L.,Larson Martin G.,Sie Mark P.S.,Andrews Jeanette S.,Post Wendy S.,Mattace-Raso Francesco U.S.,McEniery Carmel M.,Eiriksdottir Gudny,Segers Patrick,Vasan Ramachandran S.,van Rijn Marie Josee E.,Howard Timothy D.,McArdle Patrick F.,Dehghan Abbas,Jewell Elizabeth S.,Newhouse Stephen J.,Bekaert Sofie,Hamburg Naomi M.,Newman Anne B.,Hofman Albert,Scuteri Angelo,De Bacquer Dirk,Arfan Ikram Mohammad,Psaty Bruce M.,Fuchsberger Christian,Olden Matthias,Wain Louise V.,Elliott Paul,Smith Nicholas L.,Felix Janine F.,Erdmann Jeanette,Vita Joseph A.,Sutton-Tyrrell Kim,Sijbrands Eric J.G.,Sanna Serena,Launer Lenore J.,De Meyer Tim,Johnson Andrew D.,Schut Anna F.C.,Herrington David M.,Rivadeneira Fernando,Uda Manuela,Wilkinson Ian B.,Aspelund Thor,Gillebert Thierry C.,Van Bortel Luc,Benjamin Emelia J.,Oostra Ben A.,Ding Jingzhong,Gibson Quince,Uitterlinden André G.,Abecasis Gonçalo R.,Cockcroft John R.,Gudnason Vilmundur,De Backer Guy G.,Ferrucci Luigi,Harris Tamara B.,Shuldiner Alan R.,van Duijn Cornelia M.,Levy Daniel,Lakatta Edward G.,Witteman Jacqueline C.M.
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Genetics (clinical),Cardiology and Cardiovascular Medicine,Genetics