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

Epigenetics. 2017;12(10):825-832. doi: 10.1080/15592294.2017.1370172. Epub 2017 Nov 27.

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; intrauterine environment; siblings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • DNA-Binding Proteins / genetics*
  • Diabetes, Gestational / genetics*
  • Diabetes, Gestational / metabolism
  • Diabetes, Gestational / pathology
  • Epigenomics
  • Female
  • Fetal Blood / metabolism
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hepatocyte Nuclear Factor 4 / genetics*
  • Humans
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hyperglycemia / pathology
  • Male
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / pathology
  • Pregnancy
  • Siblings
  • Transcription Factors / genetics*

Substances

  • DNA-Binding Proteins
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • RREB1 protein, human
  • Transcription Factors

Grants and funding

This study was supported by grants from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant No. HI15C3131), Seoul National University Hospital (Grant No. 30–2015–0240) and Seoul National University Bundang Hospital (Grant No. 14–2014–030).