| Budget Amount *help |
¥10,300,000 (Direct Cost: ¥10,300,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Research Abstract |
Unlike monogenic diseases, classical linkage analysis is not feasible for genetic dissection of multifactorial diseases such as diabetes mellitus. We therefore applied a novel strategy for genetic dissection of type 1 diabetes as a model case for multifactorial diseases in general.
To make complex interaction of genetic and environmental factors in humans simpler, we used inbred animal models for type 1 diabetes mellitus (NOD mice). To dissect multigenic inheritance into monogenic inheritance, congenic strains with single different chromosome from parental strain were established and analyzed. By using NOD strain congenic for recombinant MHC with the same class II MHC as the NOD, but different flanking markers from the NOD, a second component (Idd16) of MHC-linked susceptibility for type 1 diabetes has been identified and localized adjacent to, but distinct from candidate genes for Idd1, A and E, in the class II region. Analysis of homologous region in humans revealed that a second component of MHC-linked susceptibility for type 1 diabetes, which affects age-at-onset of the disease, is also located adjacent to, but distinct from class II DQ and DR loci. These data suggest the power of congenic strategy for genetic dissection of complex traits, such as type 1 diabetes. When the same approach was applied for Idd3 on chromosome 3, a congenic NOD strain which possess the same sequence in the Il2 gene, a candidate for Idd3 on chromosome 3, as the NOD, but different flanking markers from the NOD, was found to have the phenotypes indistinguishable from the NOD parental strain, strongly suggesting that the NOD allele of Il2 is responsible for Idd3 effect.
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