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Genetic Associations With Valvular Calcification and Aortic Stenosis
Study Questions:
Is there a genetic basis for aortic valve calcification and for mitral annular calcification?
Methods:
Among a population of participants of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population), genome-wide associations were determined for the computed tomographic (CT) scanning-based presence of aortic valve calcification (among 6,942 participants) and for mitral annular calcification (among 3,795 participants). Findings were then tested in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
Results:
One single nucleotide polymorphism (SNP) in the lipoprotein(a) (LPA) locus (rs10455872) reached genome-wide significance for the presence of aortic valve calcification (odds ratio per allele, 2.05; p = 9.0 x 10-10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (p < 0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, also were associated with aortic valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval, 1.32-2.15) and aortic valve replacement (hazard ratio, 1.54; 95% confidence interval, 1.05-2.27) in a large Swedish cohort. The association with incident aortic stenosis also was replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genome-wide significance for mitral annular calcification (p = 1.5 x 10-8 and 1.8 x 10-8, respectively), but the findings were not replicated consistently.
Conclusions:
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic valve calcification across multiple ethnic groups and with incident clinical aortic stenosis.
Perspective:
Limited information is available regarding genetic contributions to valvular calcification. This study demonstrates that genetic variation in the LPA locus is associated with both aortic valve calcification and with clinical aortic stenosis. Mediation by Lp(a) is further evidence that aortic valve calcification and stenosis are atherosclerotic lesions. This work could have important implications in the identification of patients at risk of aortic stenosis, and raises the question of whether early intervention, targeted at Lp(a), might be able to affect the progression of aortic calcification and delay or prevent clinical aortic stenosis.
Keywords: Heart Valve Prosthesis, Ethnic Groups, Lipoprotein(a), Polymorphism, Single Nucleotide, Genome-Wide Association Study, Calcinosis, Constriction, Pathologic, Hispanic Americans, United States
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