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Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis
Study Questions:
Is there an association between low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or triglycerides (TGs) and aortic valve disease?
Methods:
Weighted genetic risk scores (GRSs, a measure of the genetic predisposition to elevations in plasma lipids) were constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids. Using a Mendelian randomization study design, GRSs then were evaluated for an association with aortic valve disease. The population included community-based cohorts participating in the CHARGE consortium (n = 6,942); including the Framingham Heart Study (inception to last follow-up, 1971-2013; n = 1,295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2,527), Age Gene/Environment Study–Reykjavik (2000-2012; n = 3,120), and the Malmö Diet and Cancer Study (MDCS; 1991-2010; n = 28,461). Aortic valve calcium was quantified by computed tomography in the CHARGE consortium, and by incident aortic stenosis in the MDCS.
Results:
The prevalence of aortic valve calcium across the three CHARGE cohorts was 32% (n = 2,245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1,000 participants (n = 473), and aortic valve replacement for aortic stenosis occurred in 7 per 1,000 (n = 205). Plasma LDL-C, but not HDL-C or TGs, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% confidence interval [CI], 1.04-1.57; p = 0.02; 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 the presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; p = 0.007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; p = 0.02; 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 TGs, the LDL-C GRS remained associated with aortic valve calcium (p = 0.03) and aortic stenosis (p = 0.009). 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 = 0.02).
Conclusions:
Genetic predisposition to elevated LDL-C was associated with the presence of aortic valve calcium and the 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.
Perspective:
Elevated plasma LDL-C has been associated with aortic stenosis in observational studies. However, randomized trials with cholesterol-lowering therapies in patients with established aortic valve disease have failed to demonstrate reduced disease progression. Those studies included patients with advanced valve disease, witnessed by high rates of intervention during relatively short follow-up intervals, suggesting that pharmacotherapy probably came too late to make a clinical difference. This study used genetic risk scores, which have been shown to be strongly associated with their corresponding lipid levels in children and adults, rather than direct measurement of lipids; however, the study design afforded truly long-term follow-up and patient inclusion before the advent of clinical aortic valve disease. These data support a causative role for elevated LDL-C in aortic valve calcification and the development of clinical aortic stenosis, and beg the question of whether earlier pharmacotherapy would delay or prevent clinically significant aortic stenosis.
Keywords: Atherosclerosis, Cholesterol, LDL, Heart Defects, Congenital, Genome-Wide Association Study, Lipids, Calcinosis, Tomography, Genetic Predisposition to Disease, Aortic Valve Stenosis, Heart Valve Diseases, Diet, Triglycerides, Disease Progression
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