Insulin-dependent diabetes mellitus (IDDM) is a serious chronic disease which results from autoimmune 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 low (35-40 percent) concordance in identical twins suggest that both genetic and environmental factors contribute to IDDM susceptibility. Although intense attention has been centered on genetic susceptibility associated with the HLA system on chromosome 6p, other genes also contribute. We and others have searched for regions of the human genome that demonstrate genetic linkage to IDDM. Beside HLA, we have identified 1 additional region where there is significant evidence of linkage and 4 other regions with suggestive evidence. In this current application, we propose to extend these promising results by accomplishing the following aims. 1. Merge our consortium genotype data with those from the groups of John Todd and Mark Lathrop and carry our analyses of the combined material. 2. Expand our genome scan beyond its present state, by typing additional genetic markers (simple tandem repeat polymorphism, STRPs). 3. Genotype additional markers in five candidate regions where linkage with IDDM is suggestive, to maximize the evidence for linkage and to search for linkage disequilibrium. 4. Identify susceptibility genes for IDDM in candidate regions we have defined, using genomic mismatch scanning (GMS), as well as more standard techniques of positional cloning. 5. Apply the technology of GMS to test for shared genetic ancestry (identity by descent) at the loci for 100-200 immunologically defined candidate genes, regardless of map location (see linked grant by Concannon). Identification of genes for IDDM susceptibility should provide important insights into immune pathways that are disrupted in IDDM and may suggest novel preventative or therapeutic approaches.
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