Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder which results from cellular infiltration and destruction of the pancreatic islet cells. The events that initiate this pathogenic process are poorly understood. The tendency of IDDM to cluster in families and the 35-40 percent concordance rate in identical twins suggest that both genetic and environmental factors contribute to IDDM susceptibility. It has been recognized for more than 20 years that a gene or genes in the HLA region plays a significant role in the development of IDDM. However, the segregation of IDDM within families fits no simple pattern and the contribution of other genes to IDDM susceptibility has long been suspected. In an attempt to understand the underlying causes of IDDM, there has been a search for regions of the human genome that demonstrate genetic linkage to IDDM. Besides HLA, one additional region has been identified where there is strongly suggestive evidence of linkage and six other regions with at least modest evidence warranting further study. However, linkage approaches such as these, which assay allele sharing in affected sib pairs, have only limited power to detect genes with the range of effects expected for IDDM susceptibility genes other than HLA. Association studies, in contrast, do have such power, but in the past have often been hindered by small sample sizes, inadequate study designs, and limited scope. The availability of newer resources and technologies now make this approach applicable on a much larger scale. This application proposes to evaluate the role of 100 or more candidate genes whose products are specifically involved in immune system function as possible IDDM susceptibility genes. By targeting molecules for investigation because of their functional role in the immune system it may be possible to identify IDDM susceptibility genes that are associated with IDDM but would have gone undetected in a screen for genetic linkage. Investigators will take advantage of the substantial collection of 616 IDDM multiplex families, dense genetic maps that place highly polymorphic markers near most candidate genes, more robust family-based methods for detecting associations, and high-throughput genotyping techniques to analyze this large selection of candidate immune system genes in a single study. Identification of IDDM susceptibility genes by such an approach should provide important insights into immune pathways that are disrupted in IDDM and may suggest novel preventative or therapeutic approaches.
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