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DNA methylation trajectories and accelerated epigenetic aging in incident type 2 diabetes

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Abstract

DNA methylation (DNAm) patterns across the genome changes during aging and development of complex diseases including type 2 diabetes (T2D). Our study aimed to estimate DNAm trajectories of CpG sites associated with T2D, epigenetic age (DNAmAge), and age acceleration based on four epigenetic clocks (GrimAge, Hannum, Horvath, phenoAge) in the period 10 years prior to and up to T2D onset. In this nested case–control study within Doetinchem Cohort Study, we included 132 incident T2D cases and 132 age- and sex-matched controls. DNAm was measured in blood using the Illumina Infinium Methylation EPIC array. From 107 CpG sites associated with T2D, 10 CpG sites (9%) showed different slopes of DNAm trajectories over time (p < 0.05) and an additional 8 CpG sites (8%) showed significant differences in DNAm levels (at least 1%, p-value per time point < 0.05) at all three time points with nearly parallel trajectories between incident T2D cases and controls. In controls, age acceleration levels were negative (slower epigenetic aging), while in incident T2D cases, levels were positive, suggesting accelerated aging in the case group. We showed that DNAm levels at specific CpG sites, up to 10 years before T2D onset, are different between incident T2D cases and healthy controls and distinct patterns of clinical traits over time may have an impact on those DNAm profiles. Up to 10 years before T2D diagnosis, cases manifested accelerated epigenetic aging. Markers of biological aging including age acceleration estimates based on Horvath need further investigation to assess their utility for predicting age-related diseases including T2D.

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Acknowledgements

We thank the participants of the Doetinchem Cohort Study, as well as the field workers of the Municipal Health Services in Doetinchem (C. te Boekhorst, I. Hengeveld, L. de Klerk, I. Thus, and C. de Rover) for their contribution to the data collection of this study. We are grateful to P. Vissink for logistic management and A. Blokstra for data management (both from the National Institute for Public Health and the Environment).

Funding

This work was supported by the Ministry of Health, Welfare and Sport of the Netherlands, the National Institute for Public Health and the Environment (RIVM; grant number S/132005), and by Biobanking and Biomolecular Resources Research Infrastructure-NL (grant number CP2011-27).

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  1. Chris H.L. Thio, Paul Wackers, Harold Snieder, Annemieke M. W. Spijkerman, and Mirjam Luijten contributed equally to this work.

Authors and Affiliations

  1. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Eliza Fraszczyk, Chris H. L. Thio & Harold Snieder

  2. Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

    Eliza Fraszczyk, Paul Wackers, Martijn E. T. Dollé, Hennie Hodemaekers, Marjolein Stynenbosch & Mirjam Luijten

  3. Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Vincent W. Bloks

  4. Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

    H. Susan Picavet, W. M. Monique Verschuren & Annemieke M. W. Spijkerman

  5. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    W. M. Monique Verschuren

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Fraszczyk, E., Thio, C.H.L., Wackers, P. et al. DNA methylation trajectories and accelerated epigenetic aging in incident type 2 diabetes. GeroScience 44, 2671–2684 (2022). https://doi.org/10.1007/s11357-022-00626-z

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