Non-Insulin-Dependent Diabetes Mellitus (NIDDM) has a predominant genetic component, however, diabetogenic genes have not been identified in the majority of patients. Several metabolic abnormalities contribute to the NIDDM phenotype, including insulin resistance, insulin secretory failure, and also obesity which is an inherited risk factor independent of insulin resistance. These pathogenic metabolic traits may be determined by subsets of genes which contribute to the polygenic basis of NIDDM, and constitute more proximal or refined phenotypes for susceptibility genes. Our overall goal in the proposed studies is to identify genetic markers for NIDDM and prediabetic phenotypic characteristics such as Insulin resistance and obesity. Previous efforts have employed candidate gene RFLPs in population disease-association studies or linkage analysis in small numbers of families, and have failed to identify susceptibility genes for the common NIDDM phenotype. In the proposal, we have adapted methods currently used at our center to study alcoholism, and have developed an alternative approach which involves: 1] the use of highly polymorphic microsatellite (dC-dA)n (dG-dT)n repeats as marker loci; ii] systematic exclusion mapping of the genome, or the study of targeted candidate chromosomal regions, as opposed to candidate gene RFLPs; iii] lod score and affected sib-pair analyses in larger numbers of NIDDM pedigrees; iv] extensive family studies in a relatively genetically homogeneous population with a high prevalence of NIDDM; and v] linkage analyses which incorporate a more pathophysiological understanding of NIDDM and IGT phenotypes, and which examine quantitative metabolic traits (insulin resistance, obesity) as prediabetic phenotypes. We will study 3 subsets of families: 1) Pima Indians (years 1-3). These studies will be performed in collaboration with C. Bogardus and colleagues in Phoenix who will provide us with metabolic data and genomic DNA from 800 Pimas in 100 families. The IU and Phoenix groups will each study half the genome, and employ microsatellite repeat polymorphisms (PIC>.7) selected at ~10 cM intervals to systematically screen assigned chromosomes. Our ability to detect linkage in Pimas is enhanced since genetic heterogeneity of NIDDM is likely to be reduced in this population. Genetic markers can then be tested for linkage in more genetically heterogeneous racial or ethnic groups. 2) Families recruited through American Diabetes Association Initiative """"""""Studies on the Genetics of NIDDM"""""""" (years 3-5). Targeted candidate chromosomal regions will be genotyped using informative (dC-DA)n (dG-dT)n polymorphisms. These regions will contain i] marker loci we find linked to NIDDM or pre-diabetic phenotypes in the Pima Indians (for example, FABP2 on chromosome 4q), or ii] selected candidate genes. 3) African-American NIDDM pedigrees (years 1-5). Highly informative families with NIDDM will be identified from our large African-American patient base using an advanced computerized medical record system. In vivo insulin action, insulin secretion, body composition, and energy expenditure will be assessed using state-of-the-art methods. (dC-dA)n (dG-dT)n polymorphisms will be used as marker loci to study targeted candidate chromosal regions as described for ADA families. The study design unlike the ADA initiative, will differentiate between insulin- sensitive and insulin-resistant NIDDM phenotypes in Blacks. Taken together, our protocols optimize the search for genetic markers of NIDDM, and will direct attention to specific diabetogenic genes in linkage disequilibrium with marker loci.
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