Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium

• Type of Material: Article
• Authors: Caitlin G. Howe, University of Southern California; Bianca Cox, Hasselt University; Ruby Fore, Harvard Medical School; James Jungius, University of Bristol; Tuomas Kvist, University of Helsinki; Samantha Lent, Harvard Medical School; Harriet E. Miles, University of Bristol; Lucas A. Salas, Geisel School of Medicine at Dartmouth; Sheryl Rifas-Shiman, University of Helsinki; Anne P. Starling, University of Colorado Anschutz Medical Campus; Paul Yousefi, Harvard Medical School; Christine Ladd-Acosta, Johns Hopkins University; Andrea Baccarelli, Columbia University; Elisabeth Binder, Emory University; Vaia Lida Chatzi, University of Southern California; Darina Czamara, Max Planck Institute of Psychiatry; Dana Dabelea, University of Colorado Anschutz Medical Campus; Dawn L. DeMeo, Harvard Medical School; Akram Ghantous, International Agency for Research on Cancer; Zdenko Herceg, International Agency for Research on Cancer; Eero Kajantie, National Institute for Health and Welfare; Jari M. T. Lahti, University of Bristol; Debbie A. Lawlor, University of Bristol; Augusto Litonjua, Harvard Medical School; Tim S. Nawrot, Hasselt University; Ellen A. Nohr, University of Southern Denmark; Emily Oken, University of Helsinki; Costanza Pizzi, University of Turin; Michelle Plusquin, Hasselt University; Katri Raeikkoenen, University of Bristol; Caroline L. Relton, University of Bristol; Gemma C. Sharp, Harvard Medical School; Thorkild I.A. Sorensen, University of Bristol; Jordi Sunyer, ISGlobal; Martine Vrijheid, ISGlobal; Weiming Zhang, University of Colorado Anschutz Medical Campus; Marie-France Hivert, Harvard Medical School; Carrie V. Breton, University of Southern California
• Language: English
• Date: 2020-01-01
• Publisher: AMER DIABETES ASSOC
• Publication Version: Final Published Version
• Copyright Statement: © 2019 by the American Diabetes Association.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.2337/dc19-0524
• Title of Journal or Parent Work: DIABETES CARE
• Volume: 43
• Issue: 1
• Start Page: 98
• End Page: 105
• Grant/Funding Information: Funding for authors and cohorts can be found in the Supplementary Data.
• Keywords: CORD BLOOD; CLASSIFICATION; Science & Technology; Endocrinology & Metabolism; DIAGNOSIS; HYPERGLYCEMIA; CRITERIA; GENES; Life Sciences & Biomedicine; ASSOCIATION
• Research Categories: Health Sciences, Epidemiology; Biology, Genetics

Abstract

OBJECTIVE Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-Analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, usingDNAmethylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations betweenGDMandDNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-Analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870-135342620) was located in the gene bodyof CYP2E1. IndividualCpGanalyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted P value threshold of 0.05. CONCLUSIONS MaternalGDMwas associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.