Non-insulin dependent diabetes mellitus (NIDDM) has a strong familial component, but neither physiologic nor candidate gene studies have identified the events that lead from normal glucose homeostasis to the diabetic state in predisposed individuals. The applicants propose a genetic approach to localize genes that predispose to NIDDM with the goal of defining NIDDM pathogenesis. In ongoing studies of 19 multiplex families ascertained under uniform criteria, they identified several regions of possible interest including different potential loci for NIDDM and fasting glucose which approach statistical significance on multipoint analysis. However, no region achieves significance in families on two-point analysis, suggesting that a single locus is unlikely to explain over 70% of families in this uniform population. The applicants propose a continuation of studies aimed at identifying major genetic loci in subsets of NIDDM families by increasing the power of studies in a greatly expanded but similarly ascertained family set, excluding known causes of the NIDDM phenotype, testing putative susceptibility loci by linkage in an independent pedigree cohort and by association, and by applying the most recent data analysis methods to this expanded date set. Specifically, they propose to complete a 10 cM genome screen with highly informative markers in key members of 62 families (43 new families with 464 family members). Markers showing possible linkage will be further evaluated by (1) typing remaining family members, (2) typing closely spaced adjacent markers, and (3) by testing linkage in an independent set of families with 230 sib pairs. Data will be analyzed using both 2-point and multipoint parametric and sib pair methods. Evidence for genetic subgroups will be sought for linked markers by admixture and by stratifying families based on age of onset and obesity. Early onset (MODY-3) mutations will be detected by molecular screening. The applicants will search for loci controlling intermediate phenotypes of fasting insulin, insulin secretion, and fasting and post-challenge glucose using multipoint quantitative trait analysis in nondiabetic family members.
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