The impact of gestational diabetes mellitus (GDM) upon the epigenetics of mother and newborn infant and long-term risk of type 2 diabetes – Epi-GDM

Gestational diabetes mellitus (GDM) is a form of diabetes that is first diagnosed during pregnancy and poses an important risk factor to the subsequent health of the mother and her developing child. After delivery, a history of GDM is associated with increased risk of subsequent early onset type 2 diabetes (T2D) in the mother and metabolic abnormalities in the offspring, such as obesity and impaired glucose tolerance. GDM and other forms of diabetes share similar risk factors (advanced age, obesity, first-degree relatives with T2D and ethnic background) and appear to share at least some of the same genetic risk factors that are inherited at birth.

In addition, however, there is evidence that exposure to GDM may also confer health risks to the offspring via a process unrelated to genetic variations in the genetic code, known as epigenetics. For example, it is known that chemical marks on the DNA occur that do not alter the DNA code itself, but can subtly change gene expression patterns, especially during development. There is now evidence that such changes during foetal development may have a lasting impact upon metabolism. As such, GDM can be viewed as a useful model for the study of the role of genetics and epigenetics in the development of diabetes, with GDM studies potentially contributing to identify early molecular mechanisms that confer increased risk of T2D.

We hypothesise that exposure to hyperglycemia during pregnancy causes epigenetic alterations in specific genomic regions of both mother and offspring that perturbs the function of genes in key tissues controlling glucose homeostasis and increases the risk of metabolic disorders in mother and child in later life, in particular T2D. In order to address this hypothesis we will undertake the following three tasks:

1/ Identify a comprehensive bona-fide list of site locations across the genome that have a particular important chemical mark, known as a DNA methyl-group, either attached at that site or not, depending upon whether the mother has GDM. This catalogue of locations is important since these marks, referred to as Differently Methylated Regions (DMRs), can then be assessed for functional consequences in terms of altered gene expression and increased incidental risk of disease. We will identify the list of altered genomic sites or DMRs that are shared by both the mother and offspring associated with GDM exposure, by measuring the methylation status using the Infinium MethylationEPIC BeadChip array at 850,000 gene and key regulatory sites in 800 mother and offspring case-control samples, followed by replication using the same genomic arrays measured for an additional 1200 samples.

2/ Assess whether identified GDM-associated DMRs measured at baseline are associated with incident T2D and related diabetogenic traits in prospective cohorts of offspring, who have been exposed to GDM during pregnancy; mothers with a history of GDM, and population-based middle-aged adults followed for up to 10 years to see if they develop T2D.

3/ Undertake appropriate functional analyses in T2D relevant tissues and use cellular models to provide first evidence of plausible molecular mechanisms for the risk of metabolic abnormalities associated with the identified epigenetic DNA marks.

The Epigenetics of GDM (Epx-GDM) consortium brings together highly experienced leaders in genomics of T2D, GDM studies, statistical genetics, genetic epidemiology of common diseases and pancreatic beta-cell and insulin sensitive cellular biology of T2D, in order to be able to successfully address this multidisciplinary endeavour.