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

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.

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.

Figure 1. Mendelian Randomization of LDL-C and Risk of Aortic Stenosis in the Malmö Diet and Cancer Study

The aim of Mendelian randomization is to provide a robust test of the association between low-density lipoprotein cholesterol (LDL-C) and aortic stenosis (association 3). Association 3 can be tested simply using standard epidemiologic methods, but these methods may be biased (eg, confounding, reverse causality, etc). To overcome this bias, Mendelian randomization indirectly tests association 3 by first establishing via linear regression that LDL-C-related single-nucleotide polymorphisms (SNPs) increase LDL-C (association 1). These LDL-C SNPs are then tested for an association with aortic stenosis (association 2). Under the assumption that the entire effect of the LDL-C SNPs on aortic stenosis (association 2) is mediated by their effect on increasing LDL-C (association 1), an unconfounded assessment of association 3 can be obtained (ie, instrumental variable estimate).

Figure 2. Magnitude of Genetic Increase in LDL-C and Odds of Aortic Valve Calcium Across All LDL-C SNPs in CHARGE Participants

Each dot represents a single low-density lipoprotein cholesterol (LDL-C) single-nucleotide polymorphism (SNP). Across all 57 LDL-C-associated SNPs, a given genetic increase in LDL-C is correlated with a concomitant increase in the odds of aortic valve calcium (AVC). The solid line represents the best line of fit, and the dashed lines represent the 95% CI for this relationship. P value reported is for the linear association.