Common Genetic Variation in the 3′- BCL11B Gene Desert Is Associated With Carotid-Femoral Pulse Wave Velocity and Excess Cardiovascular Disease Risk

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 5,306 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 = 2.8 x 10−10; replication beta=−0.086±0.020 SD/allele, P = 1.4 x 10−6). 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 = 1.0 x 10−11). Results were consistent in younger (<55 years, 6 cohorts, N=13,914, beta=−0.081±0.014 SD/allele, P = 2.3 x 10−9) 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 [HR]=1.05, confidence interval [CI]=1.02 to 1.08, P=0.0013) and heart failure (HR=1.10, CI=1.03 to 1.16, P=0.004). Conclusions Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor one 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.

Association of Cross-Sectional and Longitudinal Change in Arterial Stiffness With Gene Expression in the Twins UK Cohort

“…COL4A1 has previously been implicated in arterial stiffness in a GWAS performed in 4221 participants from the SardiNIA study and replicated in a further 1828 individuals 14 but not in a large meta-analysis that included >20 000 individuals. 15 The findings in this study support the role of COL4A1 in age-related arterial stiffening. Although the functional role of COL4A1 in arterial stiffness remains to be determined, degradation of type IV collagen may permit migration of VSMC into the internal elastic membrane and subendothelial space.…”

“…Fifty-two genes (Table S1 in the online-only Data Supplement) were selected from previously published studies examining genetic variants associated with arterial stiffness, 24 including GWAS 14,15 and the association of arterial phenotypes with expression levels of these genes in LCLs examined.…”

“…3 Candidate gene and genome-wide association studies (GWAS) have identified genes potentially implicated in this process. [4][5][6][7][8][9][10][11][12][13][14][15] However, genetic variants described to date account for small amounts of variance in arterial phenotypes and often do not replicate, presumably because of the difficulty in identifying rare variants, epigenetic modification, limited influence of common variants on gene expression and type 1 statistical error. 16,17 Epigenetic modification, in particular, is likely to be an important regulator of gene expression and cardiovascular phenotype.…”

Arterial Stiffness and Decline in Kidney Function

“…We selected single-nucelotide polymorphisms (SNPs) reported in genome-wide association studies (GWAS) to be associated with pulse pressure and PWV (22,23). There is no GWAS available on carotid stiffness.…”

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

“…We evaluated the contribution of common genetic variation at the N‐WASP locus (gene symbol WASL ) to aortic stiffness in humans by interrogating results of the CFPWV genome‐wide association study performed by the AortaGen Consortium 31. The standardized phenotype in the AortaGen analysis was 1/CFPWV, which was adjusted for age, 2 height, and weight and then transformed to standardized Z‐values (mean=0 and SD=1).…”