Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome.

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research design and methods This study included 830 mother-offspring dyads from the GUSTO cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (FPG) and 2h plasma glucose (2hPG) post-75g oral glucose challenge (OGTT) with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, pre-pregnancy BMI and blood pressure measures were associated with both FPG and 2hPG; while Chinese ethnicity (p=1.9×10 -4), maternal height (p=1.1×10 -4), pregnancy weight gain (p=2.2×10 -3), pre-pregnancy alcohol consumption (p=4.6×10 -4), and tobacco exposure (p=1.9×10 -3) showed significantly opposite associations between the two glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the two glucose measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that two traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.