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

Abstract

Intrauterine exposure to hyperglycemia 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. In this study, we compared pairwise DNA methylation differences between siblings whose intrauterine exposure to maternal gestational diabetes (GDM) were discordant. Methylation of peripheral blood DNA of 18 sibling pairs was measured using Infinium HumanMethylation450 BeadChip assays. 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 HNF4A showed inverse correlations with mRNA expression levels, though non significant. In a gene set enrichment analysis, metabolism and signal transduction pathways were enriched. In conclusion, we found DNA methylation markers associated with intrauterine exposure to maternal GDM, including those within genes previously implicated in diabetes or obesity.

Keywords

• dna methylation
• epigenome-wide association study
• gestational diabetes mellitus
• siblings
• intrauterine environment