Association of Cardiovascular Health Through Young Adulthood with Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study

Yinan Zheng, Brian T. Joyce, Shih Jen Hwang, Jiantao Ma, Lei Liu, Norrina B. Allen, Amy E. Krefman, Jun Wang, Tao Gao, Drew R. Nannini, Haixiang Zhang, David R. Jacobs, Myron D. Gross, Myriam Fornage, Cora E. Lewis, Pamela J. Schreiner, Stephen Sidney, Dongquan Chen, Philip Greenland, Daniel LevyLifang Hou, Donald M. Lloyd-Jones

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)94-109
Number of pages16
Issue number2
StatePublished - Jul 12 2022

Bibliographical note

Funding Information:
The CARDIA study (Coronary Artery Risk Development in Young Adults Study) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201800005I AND HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). CARDIA was also supported in part by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). The DNA methylation laboratory work and analytic component were funded by the American Heart Association (17SFRN33700278 and 14SFRN20790000, Northwestern University, to Dr Hou) and NIA R21AG068955 (to Drs Liu and Zheng). The FHS (Framingham Heart Study) is funded by National Institutes of Health (NIH) contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, Bethesda, MD. The analytic component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This manuscript has been reviewed by CARDIA for the scientific content.

Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.


  • cardiovascular diseases
  • cardiovascular risk factors
  • DNA methylation
  • Risk Assessment
  • Humans
  • Middle Aged
  • Risk Factors
  • Coronary Artery Disease
  • Incidence
  • Young Adult
  • DNA Methylation
  • Biomarkers
  • Adult
  • Health Status
  • Cardiovascular Diseases/diagnosis

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural
  • Journal Article
  • Research Support, N.I.H., Extramural


Dive into the research topics of 'Association of Cardiovascular Health Through Young Adulthood with Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study'. Together they form a unique fingerprint.

Cite this