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Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.

AbstractIMPORTANCE:
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.
AuthorsJ Gustav Smith, Kevin Luk, Christina-Alexandra Schulz, James C Engert, Ron Do, George Hindy, Gull Rukh, Line Dufresne, Peter Almgren, David S Owens, Tamara B Harris, Gina M Peloso, Kathleen F Kerr, Quenna Wong, Albert V Smith, Matthew J Budoff, Jerome I Rotter, L Adrienne Cupples, Stephen Rich, Sekar Kathiresan, Marju Orho-Melander, Vilmundur Gudnason, Christopher J O'Donnell, Wendy S Post, George Thanassoulis, Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Extracoronary Calcium Working Group
JournalJAMA (JAMA) Vol. 312 Issue 17 Pg. 1764-71 (Nov 05 2014) ISSN: 1538-3598 [Electronic] United States
PMID25344734 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cholesterol, LDL
  • Calcium
Topics
  • Aged
  • Aortic Valve (chemistry)
  • Aortic Valve Stenosis (epidemiology, genetics)
  • Atherosclerosis (epidemiology, genetics)
  • Bicuspid Aortic Valve Disease
  • Calcium (analysis)
  • Causality
  • Cholesterol, LDL (blood, genetics)
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Heart Defects, Congenital (epidemiology, genetics)
  • Heart Valve Diseases (epidemiology, genetics)
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • United States (epidemiology)

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