Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis

Abstract

Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes with focus on pancreatic islet cell inflammation and β-cell apoptosis.

Keywords: GWAS; apoptosis; beta-cell; gene expression.

Figure 1

A number of type 1 diabetes (T1D) candidate genes are known to modulate β-cell apoptosis, viral infection, and islet inflammation. Genes marked in green and red designate protective and deleterious roles in the β-cell, respectively. Some of the T1D risk genes including HIP14, TNFAIP3, TYK2, and CTSH are regulators of cytokine effects at the level of pro-apoptotic signal transduction. Other genes such as IFIH1 and PTPN2 are involved in the cellular responses to viral double stranded RNA (dsRNA). Downstream signaling events include alterations in expression and secretion of inflammatory cytokines and chemokines that may exert detrimental autocrine effects and/or attract immune cells, thereby amplifying insulitis. Secreted micro RNAs (miRNAs) from β-cells may also increase islet inflammation and β-cell damage by modulating immune cell activity. Finally, genetic variants in HLA genes may cause β-cell hyperexpression of major histocompatibility complex (MHC) I presenting β-cell (neo)epitopes to cytotoxic T cells.