| Research Abstract |
Unlike monogenic diseases, classical linkage analysis is not feasible and therefore a novel strategy is required for genetic dissection of multifactorial diseases such as diabetes mellitus. In this study we constructed a novel strategy for genetic dissection for multifactorial diseases in general and diabetes mellitus in particular.
For genetic dissection of type 2 diabetes with low Xs values, methods with enough power are required. To increase the power of genetic analysis, we newly eatablished meta-analysis for association studies between genotypes and phenotypes, including quantitative traits. By using this method, we showes significant association between insertion/deletion polymorphism of the ACE gene and susuceptibility to diabetic nephropathy in more than 5000 subjects, and between a quantiative phenotype, body mass index, and mutation in beta 3 adrenergic receptor gene in more than 9000 subjects.
To make genetic analysis simpler, we used inbred animal models for diabetes mellitus (NOD mice for type 1 diabetes and NSY mice for type 2 diabetes). Quantiatative trait locus (QTL) mapping in F2 mice in crosses of NSY with contsol C3H/He mice mapped at least 3 QTL (Nidd1, NIdd2, NIdd3) on mouse chromosomes 11, 14 and 6. Nidd1 appears to affect glucose tolerance through imapired insulin secretion, whereas Nidd2 through insulin resistance. Nidd3 singnificantly affects insulin resistance and abdominal fat accumulation as well as glucose tolerance. Consomic and congenic strains for each of these loci are now in progress to further localization and functional analysis of these QTL.
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