DNA methylation mediates HbA1c-associated complications development in Type 1 diabetes

Metabolic memory, the persistent benefits of early glycemic control on preventing/delaying diabetic complications development, is observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycemic history, and with subsequent development of complications over an 18-year period in blood DNAs of 499 randomly-selected DCCT/EDIC participants with type 1 diabetes. We demonstrate the associations between DNAme near DCCT-closeout and mean HbA1c during DCCT (mean-DCCT-HbA1c) at 186 CpGs (FDR<15%, including 43 at FDR<5%), many of which are located in complications-related genes. Biological function exploration studies reveal these CpGs are enriched in C/EBP transcription factor binding sites, as well as enhancer/transcription regions in blood cells and hematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68–97% of the association of mean-DCCT-HbA1c with the risk of complications development during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.