학술논문
Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study
Document Type
article
Author
Chen, Hao Yu; Dina, Christian; Small, Aeron M; Shaffer, Christian M; Levinson, Rebecca T; Helgadóttir, Anna; Capoulade, Romain; Munter, Hans Markus; Martinsson, Andreas; Cairns, Benjamin J; Trudsø, Linea C; Hoekstra, Mary; Burr, Hannah A; Marsh, Thomas W; Damrauer, Scott M; Dufresne, Line; Le Scouarnec, Solena; Messika-Zeitoun, David; Ranatunga, Dilrini K; Whitmer, Rachel A; Bonnefond, Amélie; Sveinbjornsson, Garðar; Daníelsen, Ragnar; Arnar, David O; Thorgeirsson, Gudmundur; Thorsteinsdottir, Unnur; Gudbjartsson, Daníel F; Hólm, Hilma; Ghouse, Jonas; Olesen, Morten Salling; Christensen, Alex H; Mikkelsen, Susan; Jacobsen, Rikke Louise; Dowsett, Joseph; Pedersen, Ole Birger Vesterager; Erikstrup, Christian; Ostrowski, Sisse R; Center, Regeneron Genetics; O’Donnell, Christopher J; Budoff, Matthew J; Gudnason, Vilmundur; Post, Wendy S; Rotter, Jerome I; Lathrop, Mark; Bundgaard, Henning; Johansson, Bengt; Ljungberg, Johan; Näslund, Ulf; Le Tourneau, Thierry; Smith, J Gustav; Wells, Quinn S; Söderberg, Stefan; Stefánsson, Kári; Schott, Jean-Jacques; Rader, Daniel J; Clarke, Robert; Engert, James C; Thanassoulis, George
Source
European Heart Journal. 44(21)
Subject
Language
Abstract
AimsAlthough highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS.Methods and resultsA genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.ConclusionDyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.