Genome-wide DNA methylation analysis of extreme phenotypes in the identification of novel epigenetic modifications in diabetic retinopathy

BACKGROUND: Aberrant epigenetic modifications such as DNA methylation may contribute to the pathogenesis of DR. We aimed at elucidating the role of novel DNA methylation modifications in diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM) using an extreme phenotypic design. METHODS/RESULTS: Two consecutive studies were conducted. A cross-sectional study using an extreme phenotypic design was conducted to identify rare methylation modifications that might contribute to DR pathogenesis. A 2-year longitudinal nested case–control study was conducted to validate the results and assess whether these novel methylation modifications could be used as biomarkers for predicting DR onset. A large number of differentially methylated CpG sites were identified in the cross-sectional study, and two (cg12869254 and cg04026387) corresponding to known genes were replicated in the longitudinal study. Higher methylation of cg12869254 significantly correlated with macular RNFL thinning in the superior and nasal subregions, and that of cg04026387 correlated with reduced deep capillary plexus VD in the superior and inferior subregions after adjusting for covariates. CONCLUSIONS: Cg12869254 and cg04026387 hypermethylation may complement the known risk factors that contribute to the pathogenesis of DR and as novel biomarkers for disease prediction. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-022-01354-z.