1114-OR: Nephropathy- and Retinopathy-Associated DNA Methylation Changes Are Tissue-Specific in Type 1 Diabetes

Introduction and Objective: DNA methylation (DNAm) changes have been reported to affect diabetes complications. However, most studies have used DNA from white blood cells (WBCs) to infer renal pathologies. We tested DNAm patterns of tissue specificity, aging, and severity of diabetic nephropathy (DN) and retinopathy (DR) in three tissues (renal cortex, retina, and WBCs) from the same donors in Joslin Medalist Study of people with type 1 diabetes (T1D) for ≥50 years. Methods: Cytosine methylation was measured at CpG islands (~930K probes) in 90 samples (of the three tissues from 30 donors) using the Infinium Methylation EPIC v2.0 microarray assay. Age and sex adjusted principal component analysis (PCA) and differential methylation loci (DML) tests with linear regression models were used for analyses. Results: PCA of DNAm depicted dramatic separation between tissues irrespective of complication status. DML analysis of DN vs. No DN and DR vs. No DR for significant (FDR ≤0.05) probes showed major differences across tissues with minimal to none overlapping (Figure 1). Majority of significant probes were hyper-methylated in renal cortex for DN while hypo-methylated in retina for DR. Horvath’s epigenetic clock did not show accelerated aging with DN in renal cortex or WBCs. Conclusion: DN/DR related DNAm changes in renal cortex/retina are distinct from WBCs, indicating the necessity for studying renal and retinal tissues. Further, epigenetic aging in renal cortex was not accelerated by DN. Disclosure S. Jangolla: None. J. Dreyfuss: None. A. Suarez: None. I. Wu: None. H. Shah: None. G.L. King: None.