Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases

Abstract

Offspring exposed to gestational diabetes mellitus (GDM) have an increased risk for chronic diseases, and one promising mechanism for fetal metabolic programming is epigenetics. Therefore, we postulated that GDM exposure impacts the offspring's methylome and used an epigenomic approach to explore this hypothesis. Placenta and cord blood samples were obtained from 44 newborns, including 30 exposed to GDM. Women were recruited at first trimester of pregnancy and followed until delivery. GDM was assessed after a 75-g oral glucose tolerance test at 24-28 weeks of pregnancy. DNA methylation was measured at>485,000 CpG sites (Infinium HumanMethylation450 BeadChips). Ingenuity Pathway Analysis was conducted to identify metabolic pathways epigenetically affected by GDM. Our results showed that 3,271 and 3,758 genes in placenta and cord blood, respectively, were potentially differentially methylated between samples exposed or not to GDM (p-values down to 1 × 10(-06); none reached the genome-wide significance levels), with more than 25% (n = 1,029) being common to both tissues. Mean DNA methylation differences between groups were 5.7 ± 3.2% and 3.4 ± 1.9% for placenta and cord blood, respectively. These genes were likely involved in the metabolic diseases pathway (up to 115 genes (11%), p-values for pathways = 1.9 × 10(-13)<p<4.0 × 10(-03); including diabetes mellitus p = 4.3 × 10(-11)). Among the differentially methylated genes, 326 in placenta and 117 in cord blood were also associated with newborn weight. Our results therefore suggest that GDM has epigenetic effects on genes preferentially involved in the metabolic diseases pathway, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming.

Keywords: DNA methylation; epigenetics; epigenome-wide; fetal metabolic programming; in utero; maternal hyperglycemia.

Figure 1. Overview of the analytical strategy used to identify genes and metabolic pathways showing epigenetic dysregulation in response to GDM exposure.

Figure 2. Ingenuity pathway analysis: top-ranked common disease and disorder pathways that were epigenetically affected by gestational diabetes mellitus. Top-ranked common disease and disorder pathways to which belonged differentially methylated genes in placenta (p < 0.01, n = 781), cord blood (p < 0.01, n = 758) and both tissues (p < 0.05, n = 1029). #, number of genes involved in each pathway.

Figure 3. Ingenuity pathway analysis: top-ranked diseases and disorders associated to each of the common disease and disorder pathways epigenetically affected by gestational diabetes mellitus. Light gray bars, Ingenuity Pathway Analysis (IPA) results obtained with differentially methylated genes in placenta (p < 0.01, n = 781); black bars, IPA results obtained with differentially methylated genes in cord blood (p < 0.01, n = 758); gray bars, IPA results obtained with differentially methylated genes that were common to both tissues (p < 0.05, n = 1029). n, number of genes involved in each disease/disorder.