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

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, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA 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 body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate–adjusted P value 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.

Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

“…Results from a recent meta-analysis from seven pregnancy cohorts among 3677 mother-newborn pairs showed that gestational diabetes was not associated with differential methylation at a single CpG level, but it was associated with lower cord blood methylation levels within two specific regions [1]. In the current population-based EWASs, we did not find any associations in the full group, but maternal early-pregnancy glucose concentrations were associated with DNA methylation at cg03617420 (XKR6) among normal weight women, and at cg12081946 (IL17D) among overweight or obese women.…”

“…Previous studies using candidate-gene approaches suggested that maternal gestational diabetes is associated with epigenetic modifications in placenta and cord blood at loci relevant to growth, energy homeostasis, and diabetes mellitus [14,[16][17][18]. Epigenome-wide association studies (EWAS) of gestational diabetes or maternal glucose concentrations showed varying results, with no clear pattern of associations [1,15,[19][20][21][22][23][24][25]. The inconsistent results of candidate-gene studies and EWAS may be due to differences in study design.…”

Gestational Diabetes Mellitus Affects Offspring’s Epigenome. Is There a Way to Reduce the Negative Consequences?

“…Previous DNA methylation studies on cord blood found an association between GDM-induced changes in methylation and early childhood weight [50] and adiposity [51] or brain-related conditions including impairments in neurodevelopment [52] and child depression [53]. A large epigenome-wide DNA methylation study from the Pregnancy and Childhood Epigenetics (PACE) consortium was analyzed for an association between maternal GDM and cord blood methylation and showed that GDM is associated with lower methylation within two genes: the promoter of OR2L13, a gene associated with autism, and the gene body of CYP2E1, which encodes WHAT and is upregulated in type 1 and type 2 diabetes [54]. Similar findings were published by Weng et al, who showed that exposure to GDM results in changes in the methylation of cord blood cell genes which are strongly linked to type 1 diabetes mellitus, as well as neuronal development-related pathways associated with depression, attention deficit hyperactivity disorder, autism and intellectual impairment [55].…”

Maternal dysglycaemia, changes in the infant’s epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial

“…Maternal undernutrition [17] and micronutrient status [18], maternal obesity [19,20], and socioeconomic status [21] have all been associated with changes in the methylation status of the offspring epigenome. Both candidate gene [22][23][24] and genome-wide studies [25][26][27][28][29][30][31] have reported that GDM exposure is associated with significant changes in the infant's or child's methylome, and a recent meta-analysis of 7 pregnancy cohorts identified differentially methylated regions (DMRs) associated with GDM within OR2L13 and CYP2E1 [32]. However, the majority of these studies have focussed on GDM versus no GDM, rather than the continuous relationship between maternal glucose levels and DNA methylation [33,34], and none has studied the GDM-associated signal within a high-risk population of women with obesity; thus, the relationship between the degree of maternal dysglycaemia and the contribution of maternal post-challenge/postprandial glucose excursions to the infant's methylation signature in this high-risk group remains unknown.…”