Home > Journal Club, Valvular heart disease > Journal Club 13 February 2013

Journal Club 13 February 2013

Paper

Genetic Associations with Valvular Calcification and Aortic Stenosis

Presenter

CC

Summary

Background

Limited information is available regarding genetic contributions to valvular calcification,
which is an important precursor of clinical valve disease.

Methods

We determined genomewide associations with the presence of aortic-valve calcification
(among 6942 participants) and mitral annular calcification (among 3795 participants),
as detected by computed tomographic (CT) scanning; the study population
for this analysis included persons of white European ancestry from three cohorts
participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology
consortium (discovery population). Findings were replicated in independent
cohorts of persons with either CT-detected valvular calcification or clinical aortic
stenosis.

Results

One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance
for the presence of aortic-valve calcification (odds ratio per allele, 2.05;
P = 9.0×10-10), 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, were also 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 [CI], 1.32 to 2.15) and aortic-valve replacement (hazard
ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident
aortic stenosis was also replicated in an independent Danish cohort. Two SNPs
(rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide
significance for mitral annular calcification (P = 1.5×10-8 and P = 1.8×10-8,
respectively), but the findings were not replicated consistently.

Conclusions

Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve
calcification across multiple ethnic groups and with incident clinical aortic
stenosis.

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