DNA methylation profiles in sibling pairs discordant for intrauterine exposure to maternal gestational diabetes

Intrauterine exposure to hyperglycemic environment is reported to confer increased metabolic risk in later life, supporting the “developmental origins of health and disease” hypothesis. Epigenetic alterations are suggested as one of the possible underlying mechanisms. We measured DNA methylation using Infinium HumanMethylation450 BeadChip in siblings discordant for maternal gestational diabetes mellitus (GDM), which may allow possible genetic and environmental confounding effects to be reduced. Of the 465,447 CpG sites analyzed, 12 showed differential methylation (false discovery rate < 0.15), including markers within genes associated with monogenic diabetes (HNF4A) or obesity (RREB1). The overall methylation at the HNF4A gene region showed inverse correlations with mRNA expression levels though non-significant. In a gene set enrichment analysis, differentially methylated CpGs-associated genes were involved in metabolism and signal transduction pathways. Our findings implicate epigenetic mechanisms in relation to prenatal exposure to maternal hyperglycemia. A discordant sibship design with whole blood samples of 18 maternal GDM-exposed siblings and 18 GDM-unexposed sibling controls assayed