Abstract
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.
Original language | English |
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Article number | 2581 |
Pages (from-to) | 1-11 |
Number of pages | 11 |
Journal | Nature Communications |
Volume | 10 |
DOIs | |
Publication status | Published - 13 Jun 2019 |
Funding
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. 1Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015GD, The Netherlands. 2Nuffield Department of Population Health, University of Oxford, Oxford OX3 7FL, UK. 3Center for Genomics and Oncological Research, GENYO, Pfizer/University of Granada/ Andalusian Government, PTS, Granada 18007, Spain. 4Department of Twin Research and Genetic Epidemiology, King’s College London, London WC2R 2LS, UK. 5Department of Biological Psychology, Amsterdam Public Health (APH) research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam 1081BT, The Netherlands. 6Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA. 7Department of Biomedical Sciences, Chang Gung University, Taoyuan 333, Taiwan. 8Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou 333, Taiwan. 9Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 10The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 11Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Erasmus University Medical Center, Rotterdam 3015GD, The Netherlands. 12Department of Psychiatry and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam 1081BT, The Netherlands. 13Division of Neonatology, Department of Pediatrics, Erasmus University Medical Center, Rotterdam 3015GD, The Netherlands. 14Division of Respiratory Medicine, Department of Pediatrics, Erasmus University Medical Center, Rotterdam 3015GD, The Netherlands. 15Department of Pediatrics, Erasmus University Medical Center, Rotterdam 3015GD, The Netherlands. 16Generation R Study Group, Erasmus University Medical Center, Rotterdam 3015GD, The Netherlands. 17Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam 3015GD, The Netherlands. 18Department of Social and Behavioral Science, Harvard TH Chan School of Public Health, Boston, MA 02115, USA. 19The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA. 20The Framingham Heart Study, National Heart, Lung and Blood Institute, National Institutes of Health, Framingham, MA 01702, USA. 21Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. 22Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA. 23Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. 24German Center for Diabetes Research (DZD), München-Neuherberg 85764, Germany. 25Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany. 26Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf 40225, Germany. 27Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA. 28Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA. 29Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA. 30Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA. 31Geriatric Unit, Azienda Sanitaria di Firenze, Florence 50137, Italy. 32School of Public Health, University of Kentucky, Lexington, KY 40536, USA. 33Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health, Neuherberg 85764, Germany. 34Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL 60611, USA. 35Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. 36Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. 37Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, NC 27516, USA. 38Department of Human Genetics, Leiden University Medical Center, Leiden 2333ZA, The Netherlands. 39Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden 2333ZA, The Netherlands. 40Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern 3012, Switzerland. 41Department of Epidemiology and Biostatistics, Imperial College London, London SW7 2AZ, UK. 42Department of Medicine, Université de Sherbrooke, Sherbrooke, QC J1K0A5, Canada. 43Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA.44Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA. 45The Institute for Translational Genomics and Population Sciences and Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA. 46Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. 47Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. 48Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. 49Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA. 50CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology (MaCSBio), and Departments of Biochemistry and Physiology, Maastricht University, Maastricht 6211LK, The Netherlands. 51Department of Genetics, University Medical Center Groningen, Groningen 9713GZ, The Netherlands. 52Section of Statistical Multi-Omics, Department of Experimental and Clinical Research, School of Bioscience and Medicine, Univeristy of Surrey, Guildford GU2 7XH, UK. 53Leiden Academic Center for Drug Research, Leiden University, Leiden 2311EZ, The Netherlands. 54These authors contributed equally: Jun Liu, Elena Carnero-Montoro. 55These authors jointly supervised this work: Ayşe Demirkan, Cornelia M. van Duijn
Funders | Funder number |
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Cardiovasculair Onderzoek Nederland | 733050814, U01-AG061359 |
National Institute on Aging | |
National Heart, Lung, and Blood Institute | K01 HL130609-02, ZIAHL006001 |
Horizon 2020 Framework Programme | 667375, 633595, K24 DK080140 |
Biotechnology and Biological Sciences Research Council | BB/S020845/1 |
Economic and Social Research Council | ES/N000404/1 |
European Research Council | ERC-2014-CoG-648916 |
ZonMw | CVON2012-03, VENI 91616165 |
Hartstichting | |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | VIDI 016.136.361 |
Cohort Studies
- Netherlands Twin Register (NTR)