Abstract 14241: A Meta-Analysis of Genome Wide Association Studies Identifies Novel Loci for Aortic Valvular and Mitral Annular Calcium and Implicates LPA in the Development of Aortic Stenosis
Background: Valvular calcification precedes valve stenosis and may represent an important intermediate phenotype for valve disease. Although several cardiovascular risk factors are known to be associated with aortic valve calcification (AVC) and mitral annular calcification (MAC), there is limited data regarding the genetic contributions to valve calcification.
Methods: We performed separate genome-wide association studies for the presence of AVC or MAC identified by cardiac computed tomography across 3 cohorts (Framingham Heart Study, Multi-Ethnic Study of Atherosclerosis, and Age Gene/Environment Susceptibility Study). A total of 6942 individuals of European descent contributed data for AVC and 3795 individuals for MAC. Individual study results were combined using fixed effects meta-analysis by inverse probability weighting.
Results: For presence of AVC, we identified one genome-wide significant SNP (rs10455872) in the LPA locus (p= 9.0 x 10-10) with a similar effect in all three cohorts. A consistent association between rs10455872 and AVC was also identified in African Americans and Hispanics in MESA; and in White Europeans in the Heinz-Nixdorf Recall study, providing independent evidence for replication of the AVC GWAS finding (p<0.05 for all). Additional instrumental variable analyses demonstrated strong associations between rs10455872 and plasma Lp(a) levels and between Lp(a) levels and AVC suggesting a possible causal role for Lp(a) in AVC. In an independent study to examine associations with clinically apparent aortic valve disease, we found a consistent association between rs10455872 and incident aortic stenosis (n=308) in 28,193 participants of the Malmö Diet and Cancer Study (HR=1.68 per allele, 95%CI=1.32-2.15; p=3x10-5). For MAC, we identified two SNPs that achieved genome-wide significance near the proinflammatory IL1F9 gene in the IL1 superfamily gene cluster (rs17659543 and rs13415097; p-value p= 1.5 x 10-8 and 1.8 x 10-8, respectively).
Conclusions: The LPA locus appears to be associated with AVC and the IL1F9 locus with MAC. Our results suggest that Lp(a) and inflammation may play important roles in AVC and MAC, respectively, and that LPA is strongly implicated in the development of aortic valve disease.
- © 2011 by American Heart Association, Inc.