Yinan Zheng1, Brian T Joyce1, Shih-Jen Hwang2, Jiantao Ma3, Lei Liu4, Norrina B Allen1, Amy E Krefman1, Jun Wang1, Tao Gao1, Drew R Nannini1, Haixiang Zhang5, David R Jacobs6, Myron D Gross7, Myriam Fornage8, Cora E Lewis9,10, Pamela J Schreiner6, Stephen Sidney11, Dongquan Chen12, Philip Greenland1, Daniel Levy2, Lifang Hou1, Donald M Lloyd-Jones1. 1. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (Y.Z., B.T.J., N.B.A., A.E.K., J.W., T.G., D.R.N., P.G., L.H., D.M.L.-J.). 2. Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (S.-J.H., D.L.). 3. Tufts University Friedman School of Nutrition Science and Policy, Boston, MA (J.M.). 4. Division of Biostatistics, Washington University, St. Louis, MO (L.L.). 5. Center for Applied Mathematics, Tianjin University, Tianjin, China (H.Z.). 6. Division of Epidemiology and Community Health, School of Public Health (D.R.J., P.J.S.), University of Minnesota, Minneapolis. 7. Department of Laboratory Medicine and Pathology, Medical School (M.D.G.), University of Minnesota, Minneapolis. 8. Institute of Molecular Medicine, University of Texas Health Science Center at Houston (M.F.). 9. Department of Epidemiology (C.E.L.), University of Alabama at Birmingham. 10. Division of Preventive Medicine (C.E.L.), University of Alabama at Birmingham. 11. Division of Research, Kaiser Permanente Northern California, Oakland, CA (S.S.). 12. Department of Medicine, School of Medicine (D.C.), University of Alabama at Birmingham.
Abstract
BACKGROUND: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. METHODS: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. RESULTS: We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05). CONCLUSIONS: Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.
BACKGROUND: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. METHODS: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. RESULTS: We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05). CONCLUSIONS: Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.
Entities:
Keywords:
DNA methylation; cardiovascular diseases; cardiovascular risk factors
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