Understanding Type 2 Diabetes: Epigenetic profiling in populations at high risk for the disease

Abstract

The epigenetic hypothesis argues that, in addition to genetic variation, epigenetics provides an additional set of mechanisms mediating the relationship between genotype and the environment that may contribute to the individual susceptibility to different disorders such as T2D. The aim of this study was to investigate the epigenetic profiling in two population at high risk of T2D, i) obese and ii) first degree relatives of type 2 diabetic patients (T2D-FRDs), using a candidate gene study and an EWAS approach, respectively. i) In human Peripheral Blood Leucocytes (PBLs), the ANKRD26 gene expression inversely correlates with BMI (r=-0.436; p<0.01), and was lowered by about 25% in obese subjects compared with lean individuals (p<0.01). Additionally, in the same individuals a site specific CpG hyper-methylation of the ANKRD26 promoter occurred in obese compared with lean subjects (p<0.001) and inversely correlates with the ANKRD26 gene expression (r=-0.850, p<0.05). ii) In Subcutaneous Adipose Tissue Stromal-Vascular Fraction cells (SVFs) from lean euglycaemic T2D-FDRs, 34 miRNAs and 84 genes were identified to be differentially expressed compared with the lean counterpart with no family history of T2D (control group) by Next Generation Sequencing. In addition, in the T2D-FDRs, the expression of the miRNAs, hsa-miR-23a-5p, -193a-5p and -193b-5p, was down-regulated compared with the control subjects (p<0.01), and inversely correlates with adipocyte cell size (p<0.01). Interestingly, bio-informatic analysis of these data highlighted that the expression changes of the miRNAs, hsa-miR-23a-5p, -193a-5p and -193b-5p, enriched pathways associated to adipocyte commitment/differentiation and function. Furthermore, the expression of the miRNAs target gene IGF2 and MXRA5 was up-regulated in the T2D-FDRs compared with controls (p<0.01), and inversely correlates with miRNA expression (p<0.01) and positively with adipocytes cell size (p<0.01). In conclusion, in the first study I evidenced that the down-regulation of the ANKRD26 gene and the site specific CpG hyper-methylation of its promoter represent a common abnormality in obese patients. In the second study, I instead concluded that specific changes in the expression of the miRNAs, hsa-miR-23a-5p, -193a-5p and -193b-5p, occurred in the individuals with familiarity for T2D and may cause adipose dysfunction and impaired adipose cell recruitment, which are typical in T2D-FDRs, by interfering with functions of adipocyte specific pathways.