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Genetic associations with valvular calcification and aortic stenosis
- Source :
- The New England journal of medicine 368(6), 503-512 (2013). doi:10.1056/NEJMoa1109034
- Publication Year :
- 2013
-
Abstract
- Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.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.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 (P0.05 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.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. (Funded by the National Heart, Lung, and Blood Institute and others.).
- Subjects :
- Male
diagnostic imaging [Aortic Valve]
genetics [Calcinosis]
Heart Valve Diseases
Medizin
Genome-wide association study
030204 cardiovascular system & hematology
ethnology [Heart Valve Diseases]
ethnology [Aortic Valve Stenosis]
genetics [Aortic Valve Stenosis]
0302 clinical medicine
Epidemiology
diagnostic imaging [Mitral Valve]
0303 health sciences
education.field_of_study
Calcinosis
General Medicine
Middle Aged
3. Good health
Aortic Valve
cardiovascular system
Cardiology
Population study
Mitral Valve
Female
medicine.medical_specialty
Population
pathology [Mitral Valve]
Polymorphism, Single Nucleotide
Article
03 medical and health sciences
genetics [Lipoprotein(a)]
Internal medicine
medicine
diagnostic imaging [Aortic Valve Stenosis]
Humans
ddc:610
education
030304 developmental biology
Aged
business.industry
Calcific aortic valve stenosis
pathology [Aortic Valve]
Odds ratio
Aortic Valve Stenosis
Mendelian Randomization Analysis
diagnostic imaging [Heart Valve Diseases]
medicine.disease
Stenosis
Linear Models
genetics [Heart Valve Diseases]
business
Tomography, X-Ray Computed
Calcification
Genome-Wide Association Study
Lipoprotein(a)
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- The New England journal of medicine 368(6), 503-512 (2013). doi:10.1056/NEJMoa1109034
- Accession number :
- edsair.doi.dedup.....6968d6233127bc8d9e7fb31d4aac2d5b