期刊
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
卷 312, 期 17, 页码 1764-1771出版社
AMER MEDICAL ASSOC
DOI: 10.1001/jama.2014.13959
关键词
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资金
- Swedish Cancer Society
- Swedish Medical Research Council
- Swedish Dairy Association
- Albert Pahlsson Foundation
- Gunnar Nilsson Foundation
- Malmo city council
- Swedish Heart-Lung Foundation
- Swedish National Health Service
- Crafoord Foundation
- Skane University Hospital
- Thorsten Westerstrom Foundation
- National Institute on Aging [N01-AG-12100]
- National Eye Institute
- National Institute on Deafness and Other Communication Disorders
- National Heart, Lung, and Blood Institute (NHLBI)
- National Institute on Aging Intramural Research Program
- Hjartavernd (the Icelandic Heart Association)
- Althingi (Icelandic parliament)
- NHLBI [N02-HL-64278, UL1 RR024156, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, N01-HC-25195]
- American College of Cardiology Foundation/Merck Adult Cardiology Research Fellowship Award
- GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease Young Investigator Award
- Clinician-Scientist Salary Award from the Fonds de la Recherche du Quebec-Sante
- RI-MUHC/Merck Research Competition
- Canadian Institutes of Health Research [MOP-119380, MOP-126033]
- [N01-HC-95159]
- [N01-HC-95160]
- [N01-HC-95161]
- [N01-HC-95162]
- [N01-HC-95163]
- [N01-HC-95164]
- [N01-HC-95165]
- [N01-HC-95166]
- [N01-HC-95167]
- [N01-HC-95168]
- [N01-HC-95169]
- [N01-HC-65226]
- [R01 HL071739]
- Novo Nordisk Fonden [NNF14OC0011049] Funding Source: researchfish
IMPORTANCE Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmo Diet and Cancer Study (MDCS, 1991-2010; n = 28 461). MAIN OUTCOMES AND MEASURES Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02). CONCLUSIONS AND RELEVANCE Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation. Copyright 2014 American Medical Association. All rights reserved.
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