Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.
Bibliographical noteFunding Information:
We gratefully acknowledge the BIOS consortium (https://www.bbmri.nl/?p=259) of Biobanking and BioMolecular resources Research Infrastructure of the Netherlands (BBMRI-NL) and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. This work is part of the CardioVasculair Onderzoek Nederland (CVON 2012-03), the Common mechanisms and pathways in Stroke and Alzheimer's disease (CoSTREAM) project (https://www.costream.eu, grant agreement No 667375), Memorabel program (project number 733050814), Netherlands X-omics Research Infrastructure and U01-AG061359 NIA. The full list of funding information of each cohort is found in Supplementary Note 2. J.L., C.M.v.D. and A.Demirkan have used exchange grants from the Personalized pREvention of Chronic DIseases consortium (PRECeDI) (H2020-MSCA-RISE-2014). A.Demirkan is supported by a Veni grant (2015) from ZonMw (VENI 91616165). C.M.v.D. received funding of CardioVasculair Onderzoek Nederland (CVON2012-03) of the Netherlands Heart Foundation. B.A.H. was supported by NHLBI K01 award (K01 HL130609-02). V.W.V.J. received a grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). J.F.F. has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633595 (Dyna-HEALTH). J.B.M. is supported by K24 DK080140. J.T.B. received funding support from the JPI ERA-HDHL DIMENSION project (BBSRC BB/S020845/1) and from the ESRC (ES/N000404/1). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
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