Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.
Yu Chen H., Dina C., Small AM., Shaffer CM., Levinson RT., Helgadóttir A., Capoulade R., Munter HM., Martinsson A., Cairns BJ., Trudsø LC., Hoekstra M., Burr HA., Marsh TW., Damrauer SM., Dufresne L., Le Scouarnec S., Messika-Zeitoun D., Ranatunga DK., Whitmer RA., Bonnefond A., Sveinbjornsson G., Daníelsen R., Arnar DO., Thorgeirsson G., Thorsteinsdottir U., Gudbjartsson DF., Hólm H., Ghouse J., Olesen MS., Christensen AH., Mikkelsen S., Jacobsen RL., Dowsett J., Pedersen OBV., Erikstrup C., Ostrowski SR., Regeneron Genetics Center None., O'Donnell CJ., Budoff MJ., Gudnason V., Post WS., Rotter JI., Lathrop M., Bundgaard H., Johansson B., Ljungberg J., Näslund U., Le Tourneau T., Smith JG., Wells QS., Söderberg S., Stefánsson K., Schott J-J., Rader DJ., Clarke R., Engert JC., Thanassoulis G.
AIMS: Although 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 RESULTS: A 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. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.