Non-insulin-dependent diabetes mellitus (NIDDM) is a complex and heterogeneous disease characterized by hyperglycemia, hyperinsulinemia and peripheral insulin resistance. It is a major public health problem affecting approximately 5 percent of the world population. While substantial evidence has been presented that there is a major genetic component to NIDDM susceptibility, the identification of the major susceptibility genes for the common form of NIDDM is yet to be accomplished. Recently published studies suggest that several susceptibility loci exist, and that the occurrence and/or frequency of predisposing alleles at these loci varies among populations. In this study, we propose to conduct a genome-wide search for NIDDM susceptibility loci among the Samoans of the Western Pacific. The prevalence of NIDDM in this population is comparatively high with an incidence of approximately 20 percent. Because of their unique population history that has led to a reduction in genetic diversity and their recent exposure to modernization, it is suspected that the contribution of alleles at specific loci to NIDDM susceptibility is likely to be different in Samoans than in other populations. This objective will be achieved through three specific aims. First, 300 sib- pairs affected with NIDDM will be ascertained. Second, a genome-wide scan will be conducted using a panel of high density microsattelite polymorphisms spaced throughout the genome at a resolution of approximately 10 cM. Third, the location of NIDDM susceptibility loci will be determined by using affected-sib-pair identify-by-descent methods. The genome-wide search will overcome the shortcomings of past candidate gene approaches where positive findings have not been replicated across populations. The affected sib-pair method is the most appropriate approach for searching for NIDDM susceptibility loci, because it makes and requires no assumption about the mode of inheritance of the disease. The ultimate goal of this project is to identify specific genes that contribute to individual susceptibility to NIDDM. Areas of significant linkage identified by the 10 cM scan will be subjected to high density mapping (approximately 1.0 cM) to confirm evidence of linkage. This will be followed by a positional candidate gene analysis to identify the specific genes responsible for increased susceptibility to NIDDM.
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