Epigenetic Landscape of Pain in Diabetic Neuropathy

The available treatments for neuropathic pain are still unsatisfactory – they cope with low efficiency and serious side effects. To our knowledge, this is a pioneering study evaluating whole-genome DNA methylation in unique populations of type 2 diabetes mellitus patients that were histopalogically diagnosed with diabetic neuropathy, with or without neuropathic pain. We provided an evidence on the significant differences in methylation patterns between painful and painless phenotypes. Epigenomes of patients from two independent cohorts were assessed in whole blood samples with Infinium Methylation EPIC BeadChip. We performed differential analysis and identified epigenetic signals that highlight the dissimilarities between painful and painless subjects. We estimated epigenetic age of the patients and evaluated eventual acceleration of biological age in painful and painless phenotypes using set of epigenetic predictors. With the differential analysis we identified 27 CpG sites that reached the level of statistical significance in both studied cohorts, presented the methylation change between painful and painless diabetic neuropathy > 1% in one of the populations and had the direction of methylation change concordant between the two cohorts. 19 of selected probes were genic and resulted in a list of 19 unique genes. Multidimensional scaling analysis confirmed the potential of generated set of CpG sites to separate painful and painless subjects and to highlight the dissimilarities between two phenotypes. Evaluation of biological age showed that there was no association between painful phenotype and acceleration of biological age expressed by any of the assessed epigenetic clocks. DNA methylation based prediction of telomere length was found to vary between painful and painless groups in both studied cohorts. Obtained results confirmed the presence of epigenetic differences between painful and painless diabetic neuropathy patients. Promising genes were identified that may be linked to neuropathic pain through DNA methylation mechanisms.