Triglyceride-Related Genetic Variants and Mitral Annular Calcification

Study Questions:

Is a genetic predisposition to elevations in plasma lipids associated with the presence of mitral annular calcification (MAC)?

Methods:

Three separate Mendelian randomization techniques were used to evaluate the associations of lipid genetic risk scores (GRS) with MAC in three large patient cohorts: the Framingham Health Study, MESA (Multiethnic European Study of Atherosclerosis), and the AGE-RS (Age, Gene/Environment Susceptibility-Reykjavik Study). The investigators provided cross-ethnicity replication in the MESA Hispanic-American participants.

Results:

MAC was present in 1,149 participants (20.4%) of the 5,651 individuals who underwent a computed tomography (CT) scan. In pooled analyses across all three cohorts, a triglyceride GRS was significantly associated with the presence of MAC (odds ratio [OR] per triglyceride GRS unit, 1.73; p = 0.0013). Neither low-density lipoprotein nor high-density lipoprotein cholesterol GRS was significantly associated with MAC. Results were consistent in cross-ethnicity analyses among the MESA Hispanic-American cohort (OR per triglyceride GRS unit, 2.04; p = 0.04). In joint meta-analysis across all included cohorts, the triglyceride GRS was associated with MAC (OR per triglyceride GRS unit, 1.79; p = 0.0001). The results were robust to several sensitivity analyses that limit both known and unknown forms of genetic pleiotropy.

Conclusions:

Genetic predisposition to elevated triglyceride levels was associated with the presence of MAC, a risk factor for clinically significant mitral valve (MV) disease, suggesting a causal association. Whether reducing triglyceride levels can lower the incidence of clinically significant MV disease requires further study.

Perspective:

MAC is an independent risk marker for cardiovascular events and can be associated with significant MV stenosis and insufficiency. It is associated with age, dyslipidemia, diabetes, and hypertension. While the study demonstrated that MAC is related to gene-regulated lifelong elevation of triglycerides and not low-density lipoprotein cholesterol, the relative contribution of diabetes and hypertension is not known.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Valvular Heart Disease, Lipid Metabolism, Nonstatins, Computed Tomography, Nuclear Imaging, Hypertension

Keywords: Atherosclerosis, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Genetic Pleiotropy, Genetic Predisposition to Disease, Heart Valve Diseases, Hypertension, Hispanic Americans, Lipids, Metabolic Syndrome X, Mitral Valve, Primary Prevention, Risk Factors, Tomography, X-Ray Computed, Triglycerides


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