1326-P: Maternal HbA1c in Pregnancy Is Associated with Higher Placental DNA Methylation at CTNNA3

Adverse perinatal outcomes have been associated with exposure to maternal hyperglycemia during pregnancy, which can be assessed by glycated hemoglobin A1c (HbA1c) levels. Prior analyses in the Gen3G cohort revealed that maternal HbA1c measured at the 2^nd rather than at the 1^st trimester, was strongly associated with differences in DNA methylation in fetal tissues. Thus, in this study, we seek to identify novel epigenetic mechanisms of placental response to prolonged exposure to maternal hyperglycemia by conducting an Epigenome-Wide Association Study (EWAS) of maternal HbA1c measured at 2^nd trimester and DNAm of full-term placentas in 448 mother-child pairs of the Gen3G cohort. We tested associations at 791,131 CpG sites, adjusting for age, gestational age, week at HbA1c measurement, gravidity, smoking, pre-pregnancy BMI, sex, and the first ten principal components from ReFACTor to account for cell-type admixture. We also examined consistency in the direction of associations between maternal 2^nd trimester HbA1c, and 1^st trimester HbA1c for top CpGs detected in EWAS at p<10^-7. We further investigated causality of CpGs with the smallest p-value in the EWAS using Mendelian Randomization (MR). In EWAS, we observed with Bonferroni significance (p<6.3x10^-8) the association between maternal HbA1c (per %-unit) and higher placenta DNAm at cg23886783 mapping to the SLC20A1 gene (effect=0.9%, 95% CI= 0.5% to 1.2%, p=6.1x10^-8). No other CpG was observed with Bonferroni or FDR significance in the EWAS. In addition, we found consistency in the direction of associations between HbA1c measured at 1^st trimester and placental DNAm for the top six CpGs with the smallest p-value discovered in the EWAS of 2^nd trimester HbA1c. Among these top six CpGs, we found nominal evidence that maternal HbA1c was causally associated with higher DNAm at cg11963170 in CTNNA3 (MR effect=25.1% per 1 %-unit, 95% CI= 3.1% to 47%, p=0.04). Our findings help to reveal placental adaptations to long-term maternal hyperglycemia.