Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and their use to explore epigenetic mediation and improve prediction

Abstract

Epigenetics encapsulates a group of molecular mechanisms including DNA methylation, histone modification and microRNAs (miRNAs). Gestational diabetes (GDM) increases the risk of adverse perinatal outcomes and is associated with future offspring risk of obesity and type 2 diabetes. It has been hypothesised that epigenetic mechanisms mediate an effect of GDM on offspring adiposity and type 2 diabetes and this could provide a modifiable mechanism to reduce type 2 diabetes in the next generation. Evidence for this hypothesis is lacking. Epigenetic epidemiology could also contribute to reducing type 2 diabetes by identifying biomarkers that accurately predict risk of GDM and its associated future adverse outcomes. We reviewed published human studies that explored associations between any of maternal GDM, type 2 diabetes, gestational fasting or post-load glucose and any epigenetic marker (DNA methylation, histone modification or miRNA). Of the 81 relevant studies we identified, most focused on the potential role of epigenetic mechanisms in mediating intrauterine effects of GDM on offspring outcomes. Studies were small (median total number of participants 58; median number of GDM cases 27) and most did not attempt replication. The most common epigenetic measure analysed was DNA methylation. Most studies that aimed to explore epigenetic mediation examined associations of in utero exposure to GDM with offspring cord or infant blood/placenta DNA methylation. Exploration of any causal effect, or effect on downstream offspring outcomes, was lacking. There is a need for more robust methods to explore the role of epigenetic mechanisms as possible mediators of effects of exposure to GDM on future risk of obesity and type 2 diabetes. Research to identify epigenetic biomarkers to improve identification of women at risk of GDM and its associated adverse (maternal and offspring) outcomes is currently rare but could contribute to future tools for accurate risk stratification.

Keywords: Epidemiology; Epigenetics; Gestational diabetes; Mediation prediction; Pregnancy; Review.

Fig. 1

Summary of pathways that produce an intergenerational association between GDM and offspring type 2 diabetes (T2D). This figure is available as part of a downloadable slideset

Fig. 2

An overview of the PubMed search strategy to identify studies of interest. This figure is available as part of a downloadable slideset

Fig. 3

Summary of human epigenetic studies related to GDM or hyperglycaemia in pregnancy. In (c) the size of the circles reflects the number of studies in each tissue. The numbers of studies (given within the circles) total 84 (rather than 81) because three studies contributed to both of the broad areas and are depicted twice in this figure. In (d), for case–control studies, the length of the vertical bar below the white horizontal line shows the proportion of GDM cases, relative to the total length of the bar. T1D, type 1 diabetes. This figure is available as part of a downloadable slideset