Altered DNA Methylation in Patients With Youth Onset Type 2 Diabetes in the iCARE Cohort

Type 2 diabetes (T2D) incidence in children is on the rise. Early environmental exposures are suspected risk factors for youth-onset T2D. However, the underlying mechanism by which these exposures confer risk have not been explained. We hypothesize that early exposures alter DNA methylation (DNAm) patterns that play a key role in youth-onset T2D. This study examined DNAm patterns and potential biological pathways implicated in youth-onset T2D. We examined whole blood DNAm from 306 youths (ages 9-26; diagnosed before 18) from the iCARE cohort using the Illumina EPIC methylation array. DNAm changes associated with T2D were identified by comparing the DNAm profiles of children with (n=224) and without (n=82) T2D, matched for BMI and ethnicity, using linear regression. We identified 2,982 differentially methylated CpGs (adjusted p-value <0.05, effect size ≥1%), a subset of which were previously associated with T2D in adults (TXNIP: effect size –11%; ABCG1: 3%; SREBF1: 3%). In addition, we identified CpGs with roles in mitochondrial metabolic regulation (VWA8: –7%) and insulin-induced vasodilation (MPRIP: 7%). Our findings build the basis for future studies to identify pathways involved in youth-onset T2D, assess the utility of these signatures as biomarkers for screening and early detection, and identify protective environmental exposures. We would like to acknowledge the important contributions and guidance of the iCARE Participant Advisory Group and Data Access Committee in this work’s interpretation.