Introduction and Objective: DNA methylation (DNAm) changes have been associated with diabetic retinopathy (DR), but primarily in circulating white blood cells (WBCs). It is critical to determine whether DNAm patterns in WBCs are reflective of those in the retina. We compared DNAm patterns in the retina and WBCs of same individuals of the Joslin Medalist Study with ≥50 years of type 1 diabetes (T1D), 35% with no-mild DR and 50% with severe DR.Methods: DNAm was assessed by whole genome bisulfite sequencing (WGBS, 32.8×coverage, Illumina NovaSeq) of retina and WBCs within the same individuals with no-mild or severe DR (n=5 per group). Retinal proteomics (mass spectrometry) was done in those with or without severe DR (n=10). Principal component analysis (PCA) and linear regression models adjusted by age and sex tested the differential DNAm patterns in severe DR vs. no-mild DR.Results: WGBS output a total of 105M CpG sites. There was dramatic differentiation of DNAm patterns between retina and WBCs on PCA. Within the retina or WBCs, there were clear differential DNAm patterns in people with DR vs. those without, with 487 and 1960 differentially methylated regions (DMR) in the retina and WBCs, respectively (Bonferroni p<1E-8), and 14 and 32 changed KEGG pathways (p<0.05). However, only 23-upregulated and 3-downregulated DMR-related genes and 6 pathways overlapped between retina and WBCs, suggesting DNAm patterns are significantly different between these tissues. In proteomics, 543 proteins were changed (p<0.05) in the retina comparing DR vs. no DR. Three upregulated and 15 downregulated protein targets overlapped with those detected by DMR analysis, some with essential functions in neurovascular retina.Conclusion: DNAm changes induced by T1D and associated with DR severity are very different between retina and leukocytes. Future epigenetic studies on DR need to use retina, rather than surrogate tissues.
M. Ma: None. S. Jangolla: None. H. Shah: None. K. Park: None. W. Fickweiler: None. J. Dreyfuss: None. H. Pan: None. I. Wu: None. J.K. Sun: Research Support; Optovue, Boehringer-Ingelheim. Other Relationship; Boehringer-Ingelheim. Research Support; Novo Nordisk, Roche Pharmaceuticals. Other Relationship; Roche Pharmaceuticals. Research Support; Physical Sciences, Inc, Boston Micromachines, Adaptive Sensory Technologies. L.P. Aiello: Consultant; Boehringer-Ingelheim, Ceramedix, Inc. Advisory Panel; Novo Nordisk. Stock/Shareholder; KalVista. G.L. King: None.
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