Genetic factors for human type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disorder characterized by specific destruction of the insulin-secreting beta cells of the pancreatic islets. It is believed that susceptibility to T1D is determined by the interactions of multiple genes with unknown environmental factors. Because the onset of the autoimmune process occurs many years before the onset of clinical diabetes, it is difficult to ascertain the nature of possible environmental triggers. Therefore, for the past two decades, a great deal of research has been focused on identifying T1D susceptibility genes. To date, only two susceptibility loci, the HLA region on chromosome 6p21 (IDDM1) and the insulin gene (INS) on chromosome 11p15 (IDDM2), have been well characterized. These two loci only contribute a portion of the familial clustering (~40% for IDDM1 and ~10% for INS), suggesting that other susceptibility loci must exist. The next confirmed locus for T1D was the PTPN22 gene, which contributes to multiple autoimmune disorders with a relative risk (RR) of 1.67-2.3. Recent studies have also provided evidence for the existence of two additional susceptibility genes, the SUMO4 gene on chromosome 6q25 (IDDM5) and the CTLA4 gene on chromosome 2q33 (IDDM12). In addition, extensive association studies and linkage analyses using various analytical methods have suggested a large number of putative genomic intervals that may contribute genetic susceptibility to T1D. This chapter summarizes the current state of genetic linkage and association studies in T1D, and discusses challenges and strategies for future studies.