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Original Investigation
November 5, 2014

Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis

Author Affiliations
  • 1Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
  • 2Department of Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden
  • 3Department of Clinical Sciences, Lund University, Malmö, Sweden
  • 4Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
  • 5McGill University Health Center, Preventive and Genomic Cardiology, Montreal, Quebec, Canada
  • 6McGill University Health Center and Research Institute, Department of Medicine, Montreal, Quebec, Canada
  • 7Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston
  • 8Department of Medicine, University of Washington, Seattle
  • 9National Institute on Aging, Bethesda, Maryland
  • 10Department of Biostatistics, University of Washington, Seattle
  • 11Icelandic Heart Association Research Institute, Kopavogur, Iceland
  • 12Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  • 13Los Angeles Biomedical Research Institute at Harbor–UCLA, Los Angeles, California
  • 14Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  • 15Framingham Heart Study, Framingham, Massachusetts
  • 16University of Virginia, Charlottesville
  • 17Cardiology Division, Massachusetts General Hospital, Boston
  • 18NHLBI Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
  • 19Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
JAMA. 2014;312(17):1764-1771. doi:10.1001/jama.2014.13959

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 Malmö 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.