#1 Methylation of genes in adolescents with type 2 diabetes that is associated with exposure to maternal diabetes during pregnancy
Prasoon Agarwal, University of Manitoba; Brandy A Wicklow, College of Medicine, University of Manitoba; Allison B Dart, University of Manitoba; Elizabeth Sellers, University of Manitoba; Wayne Xu, University of Manitoba; James R Davie, University of Manitoba; Vernon W Dolinsky, University of Manitoba
Obesity affects about 500 million people worldwide and over 30% of the population is obese in North America. In the recent years, the mounting evidence describes a strong association between environmental exposures during early life (pre- and postnatal) and the conditioning of biological responses over the life course of the offspring that define disease risk. Obesity and type 2 diabetes(T2D) are also increasing in children at alarming rates, predisposing youth to an earlier onset of associated complications and increasing the burden of health care provision. Hypothesis: Maternal diabetes during gestation alters the methylome of the offspring in infancy and persistence of differentially methylated regions in older children is associated with obesity and obesity-related complications in the offspring.
Methods: Peripheral blood mononuclear cells were obtained from a retrospective cohort of children diagnosed with obesity and T2D with clinical documentation of maternal diabetes status during pregnancy. We have sequenced for iCARE cohort (n=23 T2D, n=10 controls) samples. Saturation analysis indicates that samples with more than 10 million reads are reproducible (estimate correlation > 0.97). Data was analyzed using diffReps software with a criterion of 500bp window size and Negative Binomial(NB) test was applied to obtain the differentially methylated regions(DMRs).
147443 DMRs were obtained in T2D samples compared to normal. Obese adolescents with T2D tended to be more hypomethylated. We identified several novel DMRs, out of which 816 were in proximal promoter region of genes. DMRs in several metabolic pathways were highly represented. These genes included APOC2, GPIHBP1, CPT1B, P2RX4, AKT1, GRB10, among others.
Our results indicate that diabetes during pregnancy affects the methylation of genes involved in various metabolic pathways in the cells of the exposed offspring that had developed T2D as adolescents. This suggests that DNA methylation could play a crucial role in defining the risk for youth-onset T2D.