Abstract
DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women’s Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Δage, at each timepoint. We fit linear mixed models to characterize how Δage contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Δage remained constant, indicating that age acceleration is generally stable over time. We found that Δage associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes.
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Funding
We gratefully acknowledge funding from “Longitudinal study of DNA methylation as a mediator between age and cardiovascular risk” (National Heart, Lung, and Blood Institute (NHLBI) Contract #HHSN268201100046C, to K.C.) and “Epigenetic Mechanisms of PM-Mediated CVD Risk” (National Institute of Environmental Health Sciences (NIEHS) R01-ES020836, to E.W.), P30ES009089 to A.B., National Institute on Aging (NIA) U34-AG051418 to K.C. and A.B., and DGE-1444932 (National Science Foundation Graduate Research Fellowships Program (NSF GRFP), to C.G.). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. (DGE-1444932). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. All contributors to WHI science are listed at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf.
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Grant, C.D., Jafari, N., Hou, L. et al. A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk. GeroScience 39, 475–489 (2017). https://doi.org/10.1007/s11357-017-0001-z
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DOI: https://doi.org/10.1007/s11357-017-0001-z