Epigenetic signatures of gestational diabetes mellitus on ATP5A1, PRKCH, SLC17A4 and HIF3A cord blood methylation

Background: Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these increased disease risks. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies. Methods and Results: Using Illumina's 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 of which are associated with genes) displayed significant methylation differences between GDM and control samples. Three of four candidate genes, ATP5A1, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The GDM effect on FCB methylation was more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM. However, the effect remained significant after adjustment for the maternal BMI and gestational week in a multivariate regression model. Conclusions: Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis and prognosis of adverse prenatal exposures and assessing the success of interventions during pregnancy. Bisulphite converted DNA from the 38 samples were hybridised to the Illumina Infinium 450K Human Methylation Beadchip Please note that the experiments were carried out as two batches (GSM2355316-GSM2355353 and GSM2355354-GSM2355447), and they were normalized and filtered independently.