Genetic Associations with Valvular Calcification and Aortic Stenosis

Abstract

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 aorticvalve 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 aorticvalve 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 aorticvalve 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. (Funded by the National Heart, Lung, and Blood Institute and others.)

Ideal Cardiovascular Health and the Prevalence and Severity of Aortic Stenosis in Elderly Patients

“…Smoking, higher BMI, higher low‐density lipoprotein cholesterol levels, and the rate of progression in coronary artery calcification all predict the development of AV calcification 32. Traditional cardiovascular risk assessed in midlife predicts the presence and extent of AV calcification by cardiac computed tomography 3 decades later 33. These cardiovascular risk factors also predict the progression of calcific AV disease and the prevalence of AS 1, 34.…”

Lipoprotein(a) Interactions With Low‐Density Lipoprotein Cholesterol and Other Cardiovascular Risk Factors in Premature Acute Coronary Syndrome (ACS)

“…Lp(a) has also been shown to be a potential causal factor for valve calcification and aortic stenosis in a large genome‐wide association study,3 and in several subsequent reports 29, 30. Despite these important associations, Lp(a) screening remains controversial in general practice largely due to the limited therapeutic options for lowering Lp(a).…”

“…Lp(a) has recently been confirmed as a causal factor for cardiovascular disease including myocardial infarction (MI)2 and aortic stenosis 3. To date, the appropriate management of high Lp(a) is not known as there are limited therapeutic options to directly lower Lp(a) 4.…”

ApoB/ApoA‐I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study

“…However, there is now compelling evidence suggesting that AS is an active and multifactorial disease involving numerous pathophysiological processes, such as atherosclerotic‐like processes 1, 2, 3, 4, 5. In this regard, well‐known atherosclerotic risk factors, including age, male sex, smoking, hypertension, hypercholesterolemia, obesity, metabolic syndrome, diabetes mellitus, as well as elevated plasma level of lipoprotein(a) (Lp[a]) have been associated with the development and/or progression of AS 6, 7, 8, 9, 10, 11, 12, 13, 14. A recent Mendelian randomization study also suggests a causal association between elevated LDL‐C and incidence of AS 15.…”