DNA Methylation GrimAge and Incident Diabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Kyeezu Kim, Brian T. Joyce, Yinan Zheng, Pamela J. Schreiner, David R. Jacobs, Janet M. Catov, James M. Shikany, Mercedes R. Carnethon, Philip Greenland, Linda V. Van Horn, Norrina B. Allen, Donald M. Lloyd-Jones, Erica P. Gunderson, Lifang Hou

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


DNA methylation (DNAm)-based biological age (epige-netic age) has been suggested as a useful biomarker of age-related conditions including type 2 diabetes (T2D), and its newest iterations (GrimAge measurements) have shown early promise. In this study, we explored the association between epigenetic age and incident T2D in the context of their relationships with obesity. A total of 1,057 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were included in the current analyses. We stratified the participants into three groups: normal weight, overweight, and obese. A 1-year increase of GrimAge was associated with higher 10-year (study years 15–25) incidence of T2D (odds ratio [OR] 1.06, 95% CI 1.01–1.11). GrimAge acceleration, which represents the deviation of GrimAge from chronological age, was derived from the residuals of a model of GrimAge and chronological age, and any GrimAge acceleration (positive GrimAA: having GrimAge older than chronological age) was associated with significantly higher odds of 10-year incidence of T2D in obese participants (OR 2.57, 95% CI 1.61–4.11). Cumulative obesity was estimated by years since obesity onset, and GrimAge partially mediated the statistical association between cumulative obesity and incident diabetes or prediabetes (proportion mediated = 8.0%). In conclu-sion, both older and accelerated GrimAge were associated with higher risk of T2D, particularly among obese participants. GrimAge also statistically mediated the associations between cumulative obesity and T2D. Our findings suggest that epigenetic age measurements with DNAm can potentially be used as a risk factor or biomarker associated with T2D development.

Original languageEnglish (US)
Pages (from-to)1404-1413
Number of pages10
Issue number6
StatePublished - Jun 2021

Bibliographical note

Funding Information:
Funding. The Coronary Artery Risk Development in Young Adults (CARDIA) study is conducted and supported by the 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 is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). The data collection was supported by the National Institute of Digestive Diseases and Diabetes (R01 DK106201 [Kaiser Permanente Northern California; Principal Investigator, E.P.G.]), and laboratory work and analytical components were funded by the American Heart Association (17SFRN33700278 and 14SFRN20790000 [Northwestern University; Principal Investigator, L.H.]). The manuscript was reviewed by CARDIA for scientific content. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. P.J.S., J.M.S., and E.P.G. collected data. K.K., B.T.J., and Y.Z. developed an analysis plan, interpreted data, and prepared the manuscript. E.P.G. and L.H. designed the study. K.K. generated study hypotheses, performed data analysis, and wrote the manuscript. P.J.S., D.R.J., J.M.C., J.M.S., M.R.C., P.G., L.V.V.H., E.P.G., and L.H. participated in analysis and manuscript writing. N.B.A. and D.M.L.-J. participated in manuscript preparation. L.H. developed the conceptual framework and laboratory component and oversaw manuscript preparation. All authors participated in editing the manuscript and approved the final version. L.H. and E.P.G. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Publisher Copyright:
© 2021 by the American Diabetes Association..


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