Epigenome-wide and transcriptome-wide analyses reveal gestational diabetes is associated with alterations in the human leukocyte antigen complex

Alexandra M. Binder, Jessica LaRocca, Corina Lesseur, Carmen J. Marsit, Karin B. Michels

Gestational diabetes mellitus (GDM) affects approximately 10 % of pregnancies in the United States and increases the risk of adverse health outcomes in the offspring. These adult disease propensities may be set by anatomical and molecular alterations in the placenta associated with GDM. To assess the mechanistic aspects of fetal programming, we measured genome-wide methylation (Infinium HumanMethylation450 BeadChips) and expression (Affymetrix transcriptome microarrays) in placental tissue of 41 GDM cases and 41 matched pregnancies without maternal complications from the Harvard Epigenetic Birth Cohort. Specific transcriptional and epigenetic perturbations associated with GDM status included alterations in the major histocompatibility complex (MHC) region, which were validated in an independent cohort, the Rhode Island Child Health Study. Gene ontology enrichment among gene regulation influenced by GDM revealed an over-representation of immune response pathways among differential expression, reflecting these coordinated changes in the MHC region. This differential methylation and expression may be capturing shifts in cellular composition, reflecting physiological changes in the placenta associated with GDM. Our study represents the largest investigation of transcriptomic and methylomic differences associated with GDM, providing comprehensive insight into how GDM shapes the intrauterine environment, which may have implications for fetal (re)programming.