Association of prenatal glycemic marker cumulative exposure with placental DNA methylation change

BACKGROUND: Maternal glycemic dysregulation during pregnancy increases risk of pregnancy complications and long-term offspring health outcomes, potentially through DNA methylation alterations. OBJECTIVES: To investigate the association between maternal glycemic marker concentration during pregnancy and placental DNA methylation, and to examine whether the methylation changes correlate with neonatal anthropometry. METHODS: Cumulative glycemic exposure was estimated using area under the curve for glucose (AUCgluc), insulin (AUCinsl), and glycated hemoglobin (AUCHbA1c), measured at 8-13, 16-22, 24-29, and 34-37 gestational weeks. Placental DNA methylation was measured using an Illumina array and tested for associations with AUCgluc, AUCHbA1c, and AUCinsl for all women and stratified by fetal sex. Correlations of the differentially methylated sites with neonatal anthropometry and placenta weight were also tested. RESULTS: Four sex-specific methylation associations were identified at FDR-adjusted P < .05. In women with male offspring, higher AUCgluc was associated with decreased methylation at cg23951198 (CBLN3 and KHNYN) and increased methylation at cg15608939 (NTN1), and higher AUCinsl was associated with decreased methylation at cg26529437 (ITGB8). In women with female offspring, higher AUCHbA1c associated with decreased methylation at cg05471842 (AMICA1). Higher methylation at the AUCgluc-associated cg15608939 in males and lower methylation at the AUCHbA1c-associated cg05471842 in females were correlated with increased birth weight, and lower methylation at the AUCgluc-associated cg23951198 in males was correlated with increased placental weight. Genes mapped to top CpGs were enriched for metabolic, immune, and inflammatory pathways and are linked to cardiometabolic diseases and traits. CONCLUSION: Increased glycemic marker exposure was associated with placental DNA methylation near genes enriched for inflammatory and cardiometabolic pathways. Placenta-mediated epigenetic mechanisms may link maternal glycemic dysregulation and offspring disease risk.