Abstract
BackgroundOffspring of pregnancy complicated with gestational diabetes (GDM) are at high risk for metabolic diseases. The mechanisms behind the association of intrauterine exposure to GDM and high risk of health problems in later life remain largely unknown. The aim of this study was to clarify the alteration in methylation levels at differentially methylated regions (DMRs) of GNAS and IGF2 in fetuses of GDM women and to explore the possible mechanisms linking maternal GDM with high risk of metabolic diseases in later life of GDM offspring.MethodsLymphocytes were isolated from umbilical cord blood of infants born to 87 women with GDM and 81 women with normal pregnancy. Genomic DNA was extracted and DNA methylation levels of GNAS and IGF2 DMRs were determined by Massarray quantitative methylation analysis.ResultsThe methylation levels were detected in 7 CpG sites of GNAS DMRs and 6 sites of IGF2 DMRs. Methylation levels were significantly higher at sites 4, 5 and 7 of GNAS DMR in GDM compared to normal pregnancy (P = 0.007, 0.008 and 0.008, respectively). The methylation level at site 4 of GNAS was significantly correlated with the presence of GDM (P = 0.003), the methylation levels at site 5 and 7 were significantly correlated with the presence of GDM (P = 0.002 for both) and gestational age (P = 0.027 for both). There was no significant difference in any sites of IGF2 DMR (P > 0.05 for all).ConclusionsWe concluded maternal GDM-induced hypermethylation at GNAS DMR and this condition may be among the mechanisms associating maternal GDM with increased risk of metabolic diseases in later life of offspring.
Highlights
Offspring of pregnancy complicated with gestational diabetes (GDM) are at high risk for metabolic diseases
The methylation levels were detected in 7 CpG sites of Guanine nucleotide binding protein alpha subunit (GNAS) differentially methylated region (DMR) and 6 sites of Insulin-like growth factor 2 (IGF2) DMRs (Figures 1 and 2)
Methylation levels at sites 4, 5 and 7 of GNAS DMR were significantly higher in Gestational diabetes mellitus (GDM) compared to normal pregnancy (P = 0.007, 0.008 and 0.008, respectively), but there were no significant differences in methylation levels at sites 2, 8, 9 and 12 (P = 0.254, 0.122, 0.254 and 0.077, respectively)
Summary
Offspring of pregnancy complicated with gestational diabetes (GDM) are at high risk for metabolic diseases. The mechanisms behind the association of intrauterine exposure to GDM and high risk of health problems in later life remain largely unknown. The aim of this study was to clarify the alteration in methylation levels at differentially methylated regions (DMRs) of GNAS and IGF2 in fetuses of GDM women and to explore the possible mechanisms linking maternal GDM with high risk of metabolic diseases in later life of GDM offspring. The persistent epigenetic change in imprinted genes induced by prenatal environment may be among the mechanisms contributing to the association between maternal GDM and health problems in later life of offspring. GDM induces differential methylation of genes in fetal DNA from offspring born to GDM mothers. Differential methylation of fetal MEST and ABCA1 was observed [17,18]
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