DNA Methylation and 28-Year Incidence of Kidney Disease in Type 1 Diabetes.

Background: Prior epigenome-wide association studies (EWAS) of DNA methylation (DNAm) and diabetic kidney disease (DKD) in type 1 diabetes (T1D) focused on advanced disease. We hypothesized DNAm is a biomarker of earlier manifestations of DKD, microalbuminuria (MA) and overt nephropathy (ON), independent of traditional risk factors in T1D. We thus performed separate EWAS of 28-year MA and ON in the Pittsburgh Epidemiology of Diabetes Complications (EDC) T1D cohort.

Methods: We analyzed baseline whole blood DNAm (total n=405 participants; 683,597 CpGs) and time-to-event in EDC participants free of each respective complication at baseline (n=224 eligible for MA analysis, n=306 eligible for ON analysis). We also identified differentially methylated regions (DMRs), assessed associations between DKD-associated CpGs and established clinical risk factors, and performed in silico functional analyses. In secondary analyses, we performed EWAS of ESKD in participants with existing DKD at baseline (ON or estimated glomerular filtration rate (eGFR) 15-59 ml/min/1.73m2, n=99) for comparison to prior studies.

Results: DNAm at cg06568490 (HDAC11) and cg13618568 (CRELD2) was associated with MA incidence (False Discovery Rate [FDR]<0.05). Associations between both CpGs and MA remained similar after risk factor adjustment. We also identified 48 significant DMRs (Šidák value<0.05) for MA. For ON, no individual CpGs had FDR<0.05, but there were 35 significant DMRs. Pathways in Signal Transduction were the most significantly enriched for both endpoints. In EWAS of ESKD, no CpGs were significant in minimally adjusted models, while cg09867934 (ETFDH) was significantly associated with ESKD after adjusting for clinical risk factors (FDR=0.002), but there was little overlap with previously published studies of DNAm and ESKD in T1D.

Conclusions: Epigenetic modification of loci including HDAC11, which has been associated with kidney fibrosis, and CRELD2, which is involved in angiogenesis, may contribute to early kidney damage in T1D, thus warranting further study as potential biomarkers of future risk.