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Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.
- Source :
-
JAMA [JAMA] 2014 Nov 05; Vol. 312 (17), pp. 1764-71. - Publication Year :
- 2014
-
Abstract
- 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.<br />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.<br />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 Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461).<br />Main Outcomes and Measures: Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.<br />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).<br />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.
- Subjects :
- Aged
Aortic Valve chemistry
Aortic Valve Stenosis epidemiology
Atherosclerosis epidemiology
Atherosclerosis genetics
Bicuspid Aortic Valve Disease
Causality
Cohort Studies
Female
Genome-Wide Association Study
Heart Defects, Congenital epidemiology
Heart Valve Diseases epidemiology
Humans
Incidence
Male
Middle Aged
Risk Factors
United States epidemiology
Aortic Valve Stenosis genetics
Calcium analysis
Cholesterol, LDL blood
Cholesterol, LDL genetics
Genetic Predisposition to Disease
Heart Defects, Congenital genetics
Heart Valve Diseases genetics
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 1538-3598
- Volume :
- 312
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- JAMA
- Publication Type :
- Academic Journal
- Accession number :
- 25344734
- Full Text :
- https://doi.org/10.1001/jama.2014.13959