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

Caitlin Howe, Bianca Cox, Ruby Fore, James E Jungius, Tuomas Kvist, Harriet Miles, Lucas A. Salas, Sheryl L Rifas-Shiman, Anne Starling, Paul D Yousefi, Christine Ladd-Acosta, Andrea A. Baccarelli, Elisabeth Binder, Vaia Lida Chatzi, Darina Czamara, Dana Dabelea, Dawn L. DeMeo, Akram Ghantous, Zdenko Herceg, Ero KajantieJari Lahti, Augusto Litonjua, Tim S Nawrot, Ellen Nohr, Debbie A Lawlor, Emily Oken, Constanza Pizzi, Michelle Plusquin, Katri Raikkonen, Caroline L Relton, Gemma C Sharp, Thorkild I. A. Sørensen, Jordi Sunyer, Martine Vrijheid, Weiming Zhang, Marie-France Hivert, Carrie V Breton, The Pregnancy and Childhood Epigenetics (PACE) consortium

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Abstract

Background
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 Consortium.

Methods
Seven pregnancy cohorts (3,677 mother-newborn pairs, 317 with GDM) contributed results from epigenome wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 array. Associations between GDM and DNA methylation were examined using robust linear regression, adjusting 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 controls. One DMR (chr1:248100345-248100614) was located in the OR2L13 promoter and the other (chr10:135341870-135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a PFDR threshold of 0.05.

Conclusions
Maternal GDM was 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.
Original languageEnglish
Article numberdc190524
Number of pages8
JournalDiabetes Care
Early online date10 Oct 2019
DOIs
Publication statusE-pub ahead of print - 10 Oct 2019

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Howe, C., Cox, B., Fore, R., Jungius, J. E., Kvist, T., Miles, H., Salas, LA., Rifas-Shiman, S. L., Starling, A., Yousefi, P. D., Ladd-Acosta, C., Baccarelli, AA., Binder, E., Chatzi, V. L., Czamara, D., Dabelea, D., DeMeo, DL., Ghantous, A., Herceg, Z., ... The Pregnancy and Childhood Epigenetics (PACE) consortium (2019). Maternal Gestational Diabetes and Newborn DNA Methylation: Findings from the Pregnancy and Childhood Epigenetics Consortium. Diabetes Care, [dc190524]. https://doi.org/10.2337/dc19-0524