University of Oulu

Canouil, M., Khamis, A., Keikkala, E., Hummel, S., Lobbens, S., Bonnefond, A., Delahaye, F., Tzala, E., Mustaniemi, S., Vääräsmäki, M., Jarvelin, M.-R., Sebert, S., Kajantie, E., Froguel, P., & Andrew, T. (2021). Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome. Diabetes Care Sep 2021, 44 (9) 1992-1999; DOI: 10.2337/dc20-2960

Epigenome-wide association study reveals methylation loci associated with offspring gestational diabetes mellitus exposure and maternal methylome

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Author: Canouil, Mickaël1,2; Khamis, Amna1,2,3; Keikkala, Elina4,5;
Organizations: 1Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, F-59000, France
2University of Lille, Lille University Hospital, Lille, F-59000, France
3Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K
4PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, FI-90014 Oulu, Finland
5Finnish Institute for Health and Welfare, Public Health Promotion Unit, 00271 Helsinki and 90100 Oulu, Finland
6Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany, and Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, and Forschergruppe Diabetes e.V., Munich-Neuherberg, Germany
7Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, United Kingdom
8Center for lifecourse Health research, Faculty of Medicine, University of Oulu, Oulu, Finland
9Unit of Primary Health Care, Oulu University Hospital, OYS, Kajaanintie 50, 90220 Oulu, Finland
10Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex UB8 3PH, United Kingdom
11Norwegian University of Science and Technology, Department of Clinical and Molecular Medicine, NO-7491 Trondheim, Norway
12Children’s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
13Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 0.7 MB)
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Language: English
Published: American Diabetes Association, 2021
Publish Date: 2021-08-25


Objective: Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure.

Research Design and Methods: We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring.

Results: We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10⁻²) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy.

Conclusions: Our study reveals the potential complexity of the epigenetic transmission between GDM mothers and their offspring, likely determined by not only GDM exposure, but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.

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Series: Diabetes care
ISSN: 0149-5992
ISSN-E: 1935-5548
ISSN-L: 0149-5992
Volume: 44
Issue: 9
Pages: 1992 - 1999
DOI: 10.2337/dc20-2960
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: This study was funded by the French National Research Agency (Agence Nationale de la Recherche; ANR). This study has been granted from the FFRD, sponsored by Fédération Française des Diabétiques (FFD), Abbott, AstraZeneca, Eli Lilly, Merck Sharp & Dohme (MSD) and Novo Nordisk. The co-authors were supported by PRECISE, LONGITOOLS and The Medical Research Council, UK (grants no. MR/M013138/1, MRC/BBSRC MR/S03658X/1 (JPI HDHL)). FinnGeDi study was supported by: Academy of Finland, Signe and Ane Gyllenberg Foundation, Sigrid Jusélius Foundation, Foundation for Pediatric Research, Finnish Diabetes Research Foundation, Novo Nordisk Foundation.
EU Grant Number: (874739) LONGITOOLS - Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases
Copyright information: © 2021 by the American Diabetes Association. The final authenticated version is available online at