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

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posted on 05.04.2021, 16:25 by Kyeezu Kim, Brian T. Joyce, Yinan Zheng, Pamela J. Schreiner, David R. Jacobs Jr., 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
DNA methylation-based biological age (epigenetic 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 one-year increase of GrimAge was associated with higher 10-year (Y15 to Y25) incidence of T2D (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 conclusion, 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 DNA methylation can potentially be utilized as a risk factor or biomarker associated with T2D development.


The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201800005I & 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, PI: Dr. Erica P. Gunderson), laboratory work and analytical components were funded by American Heart Association (17SFRN33700278 & 14SFRN20790000, Northwestern University, PI: Dr. Lifang Hou).