title: Exposure to Maternal Diabetes in Utero and DNA Methylation Patterns in the Offspring.
abstract: Perturbations in early life environments, including intrauterine exposure to maternal gestational diabetes (GDM), are hypothesized to lead to metabolic imprinting resulting in increased risk of cardiometabolic outcomes later in life. We aimed to 1) identify candidate genes and biological pathways associated with differentially methylated regions (DMRs) in relation to exposure to GDMin uteroand, 2) using mediation analysis, more definitively investigate the potential for mediation of the effect of exposure to maternal diabetesin uteroon cardiometabolic traits in childhood risk through our identified DMRs. Genome-wide methylation analysis of peripheral blood mononuclear cell's DNA was conducted in 21 healthy children, ages 8-12 years. P-values from multiple linear regression analyses for >27,000 CpG sites were ranked to identify DMRs between the exposure groups. Among the top 10 ranked DMRs, we identified several genes, including NPR1, PANK1, SCAND1, and GJA4, which are known to be associated with cardiometabolic traits. Gene enrichment analysis of the top 84 genes, each with p<=0.005, identified the ubiquitin proteasome system (UPS) as the most enriched biological pathway (p = 0.07). The UPS pathway reflects biological processes known to be associated with endothelial function, inflammation, lipid metabolism, insulin resistance and β-cell apoptosis, whose derangements are central to the pathogenesis of cardiometabolic diseases. Increased methylation ofPYGO1andCLN8had the greatest relative mediation effect (RME = 87%, p=0.005 and RME=50%, p=0.01) on the impact of exposure to maternal diabetesin uteroon VCAM-1 levels in the offspring. Multiple candidate genes and the UPS were identified for future study as possible links between exposure to maternal gestational diabetesin uteroand adverse cardiometabolic traits in the offspring. In particular, increased methylation ofPYGO1andCLN8may be biological links between intrauterine exposure to maternal diabetes and significantly increased VCAM-1 levels in the offspring.
authors.affiliation: Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: West
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
authors.forename: Dana
authors.initials: D
authors.lastname: Dabelea
keywords: Cardiometabolic; DNA methylation; Epigenetics; Gestational diabetes; Intrauterine