| Co-Investigator(Kenkyū-buntansha) |
MAKINO Susumu Shionogi AC Center, Head, ACセンター, センター長
KAWAGUCHI Yoshihiko Osaka University Medical School, Assisstant Professor, 医学部, 助手 (20303943)
MIYAZAKI Jun-ichi Osaka University Medical School, Professor, 医学部, 教授 (10200156)
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| Research Abstract |
Diabetes mellitus is a multifactorial disease, caused by a complex interaction of genetic and environmental factors. 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.
To make genetic analysis simpler, we used inbred animal models for diabetes mellitus (NOD mice for type I diabetes and NSY mice for type 2 diabetes). Quantiatative trait locus (0TL) 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. Consomic and congenic strains for each of these loci are now in progress to further localization and functional analysis of these QTL.By using congenic strains with historical recombinant chromosomes within the MHC, we mapped a
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second component (Iddl 6) of MHC-linked diabetogenic gene (Iddl) in the NOD mouse. A new recombinant within the Iddl 6 interval was obtained and the incidence of diabetes in being monitored for fine mapping and positional cloning of Iddl 6.
In humans, a marker in linkage disequilibrium with IDDM13 on chromosome 2q was identified, which will greatly facilitate the identification of responsible gene for IDDM 13. For genetic dissection of type 2 diabetes, whose Is is much lower than type 1 diabetes, 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. Less
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