Identification of epigenetic biomarkers associated with the development of diabetic kidney disease in individuals with type 2 diabetes: a nested cohort study

Abstract: Introduction. Type 2 diabetes (T2D) is the most common type of diabetes, and it can cause complications such as diabetic kidney disease (DKD), the main cause of end-stage renal disease worldwide. There is an urgent need to develop new biomarkers that would improve DKD’s risk prediction in patients with T2D. This research aimed at identifying novel epigenetic biomarkers associated with future DKD in patients with T2D. Methods. Nested cohort study of 487 newly diagnosed individuals with T2D within the ANDIS and ANDIU cohorts, followed-up over a period of 11.5 years. Genome-wide DNA methylation analysis was performed in blood samples taken at registration in the cohorts, and its association with future DKD was assessed through weighted-cox regression models. Results. DNA methylation of 37 CpG sites was found to be significantly associated with future DKD in the sample, with an effect size of 5% (q<0.05). The HR ranged from 0.0005 (95% CI 0 - 0.07) to 37.05 (95% CI 4.88 - 281.28) per 1% of methylation increase. 20 CpG sites (54%) were hypermethylated in patients with diabetes who developed DKD, in relation to those who did not develop DKD. Some of these 37 CpG sites are annotated to genes with important reported biological processes, such as ADAMTS16, involved in regulation of arterial blood pressure; RPH3AL in positive regulation of insulin secretion, and EHMT1 in methylation of histones. Discussion. Our study found that DNA methylation in blood taken at baseline is associated with future DKD in the study’s population, indicating that DNA methylation markers can be potential valuable biomarkers for predicting DKD in T2D. Conclusions. To the author’s knowledge, no study has investigated the association between DNA methylation and future DKD. There is a need, however, to refine the study design and to validate the results in different populations.