期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 368, 期 6, 页码 503-512出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1109034
关键词
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资金
- National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-25195, N02-HL-6-4278, N01-HC-95159, 95169, RR-024156, R01-HL-071739, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, N01-HC-65226]
- Affymetrix for genotyping services
- National Institute on Aging [N01-AG-12100]
- National Eye Institute
- National Institute on Deafness and Other Communication Disorders
- National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association)
- Althingi (Icelandic parliament)
- MESA
- MESA Family
- MESA CARe
- MESA SHARe project
- Heinz Nixdorf Recall Study
- Heinz Nixdorf Foundation
- German Foundation of Research (DFG)
- Malmo Diet and Cancer study
- Swedish Cancer Society
- Swedish Medical Research Council
- Swedish Dairy Association
- Albert Pahlsson Foundation
- Gunnar Nilsson Foundation
- Malmo city council
- Copenhagen City Heart Study
- Danish Heart Foundation
- MRC [MR/L003120/1] Funding Source: UKRI
- British Heart Foundation [RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [MR/L003120/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10165] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0005339] Funding Source: researchfish
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 = 9.0x10(-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 = 1.5x10(-8) and P = 1.8x10(-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. (Funded by the National Heart, Lung, and Blood Institute and others.)
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