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Original Investigation
August 4, 2021

Blood DNA Methylation and Incident Coronary Heart Disease: Evidence From the Strong Heart Study

Author Affiliations
  • 1Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York
  • 2Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain
  • 3Department of Statistics and Operations Research, University of Valencia, Valencia, Spain
  • 4College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville
  • 5Vicerrectoría Académica, Universidad de La Frontera, Temuco, Chile
  • 6Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston
  • 7Population Health Program, Texas Biomedical Research Institute, San Antonio
  • 8Department of Biostatistics, Columbia University Mailman School of Public Health, New York, New York
  • 9MedStar Health Research Institute, Washington, DC
  • 10Missouri Breaks Industries Research Inc, Eagle Butte, South Dakota
  • 11Department of Medicine, Cornell University, New York, New York
  • 12Center for American Indian Health Research, Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City
  • 13Department of Epidemiology, University of Washington, Seattle
  • 14Department of Cardiology, Heart Center Clinic Floridsdorf, Vienna, Austria
  • 15National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, Massachusetts
  • 16Section of Preventive Medicine and Epidemiology and Section of Cardiovascular Medicine, Department of Medicine, Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 17Bioinformatics Unit, Institute for Biomedical Research INCLIVA, Valencia, Spain
  • 18Department of Occupational and Environmental Health, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 19Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston
  • 20Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC
  • 21Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland
  • 22Department of Mental Health, Johns Hopkins University, Baltimore, Maryland
JAMA Cardiol. 2021;6(11):1237-1246. doi:10.1001/jamacardio.2021.2704
Key Points

Question  Is blood DNA methylation (DNAm) associated with the development of coronary heart disease (CHD)?

Findings  In this multi-cohort study, a high-dimensional multi-adjusted model assessing blood DNAm in 2321 American Indian adults selected 505 differentially methylated positions (DMPs) associated with incident CHD in the Strong Heart Study. These DMPs were evaluated in the Women’s Health Initiative, the Framingham Heart Study, and the Atherosclerosis Risk in Communities Study, and several DMPs common across cohorts tagged genes with established associations with cardiovascular disease.

Meaning  In this study, blood DNAm was associated with CHD beyond traditional factors associated with cardiovascular disease, with a complex epigenomic signature across populations.


Importance  American Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.

Objective  To investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.

Design, Setting, and Participants  This prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women’s Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]–Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021.

Exposure  Blood DNA methylation.

Main Outcome and Measure  Using a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts.

Results  The median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts.

Conclusions and Relevance  In this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.

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