Epigenetic biomarkers of type 1 diabetes progression

We have assembled a team combining expertise in immunology, molecular genetics and epigenetics to determine the underlying epigenetic alterations occurring during diabetes progression using existing TrialNet Natural History RNA and PBMCs.Background/RationaleGenome wide studies have identified multiple genes that contribute to autoimmune risk and yet their functional pathological contributions have remained obscure. Defining regulatory epigenetic variations may provide evidence of the “missing hereditability" and address this gap in our knowledge of type I diabetes (T1D).Description of ProjectA family history of Type I diabetes is a major risk factor for development of diabetes and identical twins both develop diabetes (concordant) 40% of the time. Major efforts over the last decade have identified dozens of genetic loci that contribute to this genetic risk. Many of these loci harbor well-known immunologically relevant genes. Yet, although these genetic loci represent exciting hints at pathogenesis, surprisingly little is known about how these genetic lesions contribute to disease. Indeed the proteins encoded by these risk alleles appear to be functionally normal. Recent discoveries in epigenetics have defined additional mechanisms that regulate gene function and may account for why 60% of identical twins are discordant (including methylation of genes and the expression of micro RNAs that both block gene function). Much of this work has been done in the fields of developmental biology and in cancer and only recently has attention been turned to autoimmunity. We propose here to address whether epigenetic changes accounts for some of the “missing heritability” and contribute to type I diabetes susceptibility and progression. Using biological samples (cells, DNA and RNA) from type 1 diabetes subjects obtained and banked by the TrialNet Repository before and after the development of diabetes, we will define the epigenetic changes that occur during disease progression and which may account for immune activation. These studies may reveal new biomarkers for monitoring T1D susceptibility and progression and provide new mechanistic insight and targets fo T1D treatment.