Epigenetic analyses suggest different pathways during pregnancy for development of type 1 diabetes in children with high versus low-neutral human leukocyte antigen-risk.

Abstract

The development of Type 1 diabetes (T1D) is shaped by genetic predisposition and epigenetic regulation. Human leukocyte antigen (HLA) risk alleles are major genetic determinants, but the epigenetic landscape in relation to disease onset remains unclear. Early-life epigenetic modifications may reveal how environmental and epigenetic factors interact in T1D pathogenesis. We investigated epigenetic differences in cord blood DNA from individuals with different HLA risk alleles who later developed T1D using epigenome-wide association studies. High-risk HLA carriers showed differentially methylated genes (DMGs) mainly involved in immune and autoimmune processes, resembling patterns in other autoimmune diseases. In contrast, low-to-neutral risk carriers exhibited DMGs linked to signaling cascades, metabolic pathways, and Type 2 diabetes-related mechanisms such as beta cell function and insulin signaling. These findings indicate that heterogeneity in T1D pathogenetic mechanisms based on HLA background may influence disease development.