DCCT/EDIC Epigenetics (DNA Methylation) Study

Metabolic memory (persistent benefits of early glycemic control on preventing/delaying diabetic complications development) was observed in the Diabetes Control and Complications Trial (DCCT) and follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, dbGaP phs000086.v3.p1, but mechanisms are unclear. We investigated the involvement of epigenetic DNA methylation (DNAme) by examining its associations with preceding glycemic history, and subsequent complications development over 18 years in blood DNAs of 499 randomly-selected DCCT/EDIC participants with type 1 diabetes. We found associations between DNAme near DCCT-closeout and mean-DCCT-HbA1c at 186 CpGs (FDR<15%, including 43 at FDR<5%), many located in complications-related genes. These CpGs are enriched in C/EBP motifs, enhancer/transcription regions in blood cells/progenitors, and open chromatin-states in myeloid cells. Remarkably, several CpGs in combination explain 68-97% of the mean-DCCT-HbA1c risk of complications development during EDIC. DNAme at key CpGs appears to mediate the association between hyperglycemia and complications in metabolic memory, through modifying myeloid cell enhancer activity.]]>
Participants in the DCCT/EDIC study had type 1 diabetes (T1D) and were randomly assigned to receive either conventional (CONV) therapy maintaining clinical well-being with no specific glucose targets, or intensive (INT) therapy maintaining near-normal blood glucose levels. At DCCT entry, participants were enrolled into two cohorts based on microvascular disease severity, primary prevention (PRIM) and secondary intervention (SCND). This resulted in 4 design groups: PRIM cohort on CONV treatment (PRIM CONV), PRIM INT, SCND CONV, and SCND INT. Whole blood genomic samples of 1419 participants were collected at DCCT closeout and archived in the EDIC Central Biochemistry lab for the 1991-1993 DCCT Family study. Totally 372 samples were filtered out for any of the following reasons: adolescent participants, participants without informed consent or insufficient DNA. From the remaining 1042 samples, 500 were randomly-selected from each of four DCCT/EDIC groups/strata (125 per group), namely PRIM INT, PRIM CONV, SCND INT and SCND CONV. After obtaining DNA methylation profiles for each sample, all the samples passed the quality control process, but one sample was identified as outlier by clustering analysis and thus excluded from the study.]]>
The landmark Diabetes Control and Complications Trial (DCCT, 1983-1993) and Epidemiology of Diabetes Interventions and Complications (EDIC, 1994-present) observational follow-up study evaluated the effects of glycemic control on complications progression. During DCCT, relative to conventional (CONV) diabetes therapy for glucose control, intensive (INT) therapy significantly reduced the risk of vascular complications in type 1 diabetes (T1D). Following the DCCT, all participants were encouraged to practice INT therapy, and after the first 4 years of follow-up, the mean HbA1c levels were equivalent. After 18 years of follow-up during EDIC, participants practicing INT therapy during DCCT continued to experience significantly lower rates of retinopathy, neuropathy, and DKD despite no significant differences in HbA1c. Notably, a strong association between HbA1c and complications development was observed, with HbA1c mediating >95% of the effect of treatment group on the risk of complications. This phenomenon termed "metabolic memory" has been shown to be associated with epigenetic mechanisms. However, it is unknown whether DNAme plays a mediatory role in the association between HbA1c and complications, which is addressed in this study.]]>