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Association of Triglyceride-Related Genetic Variants With Mitral Annular Calcification
Mehdi Afshar1, Kevin Luk1, Ron Do2
1Department of Medicine, McGill University, Montreal, Quebec, Canada; Preventive and Genomic Cardiology, McGill University Health Center and Research Institute, Montreal, Quebec, Canada.
Insights
Genetic predisposition to high triglycerides is linked to mitral annular calcium (MAC). This finding suggests a potential causal relationship, warranting further investigation into triglyceride-lowering therapies for valvular heart disease prevention.
Area of Science:
- Cardiovascular Genetics
- Valvular Heart Disease Etiology
Background:
- Mitral annular calcium (MAC) is linked to cardiovascular events and significant mitral valve dysfunction.
- The biological underpinnings of MAC remain largely unexplored.
Purpose of the Study:
- To investigate the association between genetic predisposition to plasma lipid levels and the presence of MAC.
- To determine if genetic factors influencing lipids contribute to MAC development.
Main Methods:
- Employed three distinct Mendelian randomization techniques across three large cohorts (Framingham, MESA, AGE-RS).
- Utilized lipid genetic risk scores (GRS) to assess associations with MAC.
- Performed cross-ethnicity replication analysis in Hispanic-American participants of the MESA cohort.
Main Results:
- A genetic risk score for triglycerides was significantly associated with the presence of MAC (pooled OR 1.73, p=0.0013).
- This association was consistent in cross-ethnicity analyses (Hispanic-Americans: OR 2.04, p=0.04).
- No significant association was found between low- or high-density lipoprotein cholesterol GRS and MAC.
Conclusions:
- Genetic predisposition to elevated triglycerides is associated with MAC.
- This suggests a potential causal link between triglyceride metabolism and MAC development.
- Further research is needed to determine if triglyceride-lowering interventions can prevent mitral valve disease.
Background:
Mitral annular calcium (MAC), commonly identified by cardiac imaging, is associated with cardiovascular events and predisposes to the development of clinically important mitral valve regurgitation and mitral valve stenosis. However, its biological determinants remain largely unknown.
Objectives:
The authors sought to evaluate whether a genetic predisposition to elevations in plasma lipids is associated with the presence of MAC.
Methods:
The authors used 3 separate Mendelian randomization techniques to evaluate the associations of lipid genetic risk scores (GRS) with MAC in 3 large patient cohorts: the Framingham Health Study, MESA (Multiethnic European Study of Atherosclerosis), and the AGE-RS (Age, Gene/Environment Susceptibility-Reykjavik Study). The authors provided cross-ethnicity replication in the MESA Hispanic-American participants.
Results:
MAC was present in 1,149 participants (20.4%). In pooled analyses across all 3 cohorts, a triglyceride GRS was significantly associated with the presence of MAC (odds ratio [OR] per triglyceride GRS unit: 1.73; 95% confidence interval [CI]: 1.24 to 2.41; p = 0.0013). Neither low- nor high-density lipoprotein cholesterol GRS was significantly associated with MAC. Results were consistent in cross-ethnicity analyses among the MESA Hispanic-Americans cohort (OR per triglyceride GRS unit: 2.04; 95% CI: 1.03 to 4.03; 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; 95% CI: 1.32 to 2.41; 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 disease, suggesting a causal association. Whether reducing triglyceride levels can lower the incidence of clinically significant mitral valve disease requires further study.
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