This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A significant inherited susceptibility locus for non-insulin dependent diabetes (NIDDM) is suggested by a high concordance in identical twins, strong familial aggregation, and evidence from segregation analysis for a major gene for both the disease and intermediate phenotypes. Despite extensive study, no predisposing biochemical defect has been identified conclusively. Known loci explain <1% of inherited diabetes. The positional search strategy offers a powerful alternative approach to identify diabetes susceptibility genes and to understand the early stages of NIDDM pathophysiology. Our data reject the hypothesis that NIDDM represents a single homogeneous disease with high penetrance. This proposal is the logical evolution of our quest for an important genetic basis to NIDDM pathogenesis, given the results of our genome screen, our greatly expanded pedigree resource, the tremendous advances in both the human linkage and physical maps, and the evolving ideas in complex disease analysis. We hypothesize that NIDDM susceptibility is determined by a locus with major clinical impact in an oligogenic disease model, and that this locus will result in an identifiable phenotypic subgroup of pedigrees with a strong family history of NIDDM onset before age 65.
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