Placenta DNA Methylation Adaptation to Maternal Glucose Tolerance in Pregnancy

ABSTRACT Maternal hyperglycemia during pregnancy is associated with fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study of term placentas and prenatal maternal glucose response 2-hour post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal glucose levels post-load were strongly associated with lower DNA methylation of 4 CpGs (FDR q<0.05) within the Phosphodiesterase 4B gene ( PDE4B ). Additionally, three other CpGs were differentially methylated relative to maternal glucose response within the TNFRSF1B; LDLR ; and BLM genes (FDR q<0.05). Methylation levels correlated with expression in placental tissue for all 4 CpG sites in PDE4B ( r s : 0.26–0.35, P<0.01), LDLR ( r s : 0.22, P=0.03) and at TNFRSF1B ( r s : -0.25, P=0.01). Our study provides evidence that maternal glucose response during pregnancy is associated with DNA methylation of genes within the placenta that are partially under epigenetic control.