Cell free DNA as a biomarker of type 2 diabetes and diabetic complications

Abstract

cfDNA analysis in liquid biopsies such as blood has become a powerful tool for diagnostics in cancer patients and screening for trisomies in pregnancies. Previous studies show that obese mice, have higher levels of cfDNA in their plasma compared to control mice and patients with type 2 diabetes (T2D) experiencing vascular complications have elevated levels of mitochondrial cfDNA in their blood. Hence, we hypothesize that like cancer patients, T2D patients also have characteristic profiles of circulating cfDNA with a potential to be employed as a prognostic or diagnostic tool in T2D as well. Use of cfDNA in cancer patients benefits from the fact that the cfDNA originating from the tumor contains somatic mutations that differentiate it from the patients' original genomic DNA. The diagnosis takes place based on these mutations which help oncologists decide the best treatment options. Unlike most cancers, however, type 2 diabetes, does not involve any defined point mutations to distinguish between the cfDNA fragments isolated from the blood. Hence, instead, we will employ tissue specific DNA methylation signatures to identify the tissue of origin of the cfDNA species identified in T2D patients with or without late complications. We also propose that during progression of T2D damages will arise from tissues before diagnosis takes place, thus releasing cfDNA from damaged tissues that can be utilized as early markers. We propose to elucidate cfDNA profiles and their tissue-of-origin in NGT vs. T2D patients to identify cfDNA-based novel biomarkers which will help prognosis and diagnosis of T2D and related complications long before hyperglycemia develops. By utilizing these biomarkers, medical doctors can take therapeutic action before T2D progresses to an advanced stage at which point the disease burden is already high and hard to treat.