Mehdi Afshar1, Kevin Luk1, Ron Do2, Line Dufresne1, David S Owens3, Tamara B Harris4, Gina M Peloso5, Kathleen F Kerr6, Quenna Wong6, Albert V Smith7, Mathew J Budoff8, Jerome I Rotter8, L Adrienne Cupples9, Stephen S Rich10, James C Engert1, Vilmundur Gudnason7, Christopher J O'Donnell11, Wendy S Post12, George Thanassoulis13. 1. Department of Medicine, McGill University, Montreal, Quebec, Canada; Preventive and Genomic Cardiology, McGill University Health Center and Research Institute, Montreal, Quebec, Canada. 2. The Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Department of Medicine, University of Washington, Seattle, Washington. 4. National Institute on Aging, Bethesda, Maryland. 5. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. 6. Department of Biostatistics, University of Washington, Seattle, Washington. 7. Icelandic Heart Association, Kopavogur, Iceland; 2 Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 8. Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles, Los Angeles, California. 9. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts; Framingham Heart Study, Framingham, Massachusetts. 10. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. 11. Framingham Heart Study, Framingham, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts; NHLBI Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland. 12. Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. 13. Department of Medicine, McGill University, Montreal, Quebec, Canada; Preventive and Genomic Cardiology, McGill University Health Center and Research Institute, Montreal, Quebec, Canada. Electronic address: george.thanassoulis@mcgill.ca.
Abstract
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.
RCT Entities:
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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