Early Pregnancy Peripheral Blood DNA Methylation and Risk of Gestational Diabetes Mellitus: A Nested Case-Control Study

Abstract Introduction: Genome-wide DNA methylation profiling has been used to identify CpG sites relevant to gestational diabetes mellitus (GDM). However, these sites have not been verified in larger samples. Here, our aim was to evaluate the changes in target CpG sites in the peripheral blood of pregnant women with GDM in their first trimester. Research Design and Methods: This nested case-control study examined a large cohort of women with GDM in early pregnancy (10–15 weeks; n = 80). Target CpG sites were extracted from related published literature and bioinformatics analysis. The DNA methylation levels at 337 CpG sites located in 27 target genes were determined using MethylTarget™ sequencing. The best cut-off levels for methylation of CpG sites were determined using the generated ROC curve. The independent effect of CpG site methylation status on GDM was analyzed using conditional logistic regression. Results Methylation levels at 6 CpG sites were significantly higher in the GDM group than in controls, whereas those at 7 CpG sites were significantly lower (P < 0.05). The area under the ROC curve at each methylation level of the significant CpG sites ranged between 0.593 and 0.650 for GDM prediction. After adjusting for possible confounders, the hypermethylation status of candidate sites cg68167324 (OR = 3.168, 1.038–9.666) and cg24837915 (OR = 5.232, 1.659–16.506) was identified as more strongly associated with GDM; conversely, the hypermethylation of sites cg157130156 (OR = 0.361, 0.135–0.966) and cg89438648 (OR = 0.206, 0.065–0.655) might indicate lower risk of GDM. Conclusions The methylation status of target CpG sites in the peripheral blood of pregnant women during the first trimester is associated with GDM pathogenesis, and has potential as a predictor of GDM.