Genetic analysis of the LEW.1AR1-iddm rat: an animal model for spontaneous diabetes mellitus.

The LEW.1AR1-iddm/Ztm rat is a new animal model of type 1 diabetes mellitus, which shows an autosomal recessive mode of inheritance for the diabetes-inducing gene. The aim of this study was to define predisposing loci of the diabetic syndrome by linkage analysis using microsatellite markers. A backcross population of 218 rats (BN x LEW.1AR1-iddm) x LEW.1AR1-iddm was analyzed using 157 polymorphic microsatellite markers covering the entire genome. Three genomic regions showed a significant linkage to the diabetic syndrome. The first susceptibility locus on rat Chromosome (RNO) 1 (LOD score 4.13) mapped to the region 1q51-55, which codes for potential candidate genes like Ins1 and Nkx2-3. The second susceptibility locus was also localized on RNO1 in the centromeric region 1p11 (LOD score 2.7) encompassing the Sod2 gene. The third quantitative trait loci (LOD score 2.97) was located on RNO20 within the major histocompatibility complex region. Comparative mapping revealed that the homologous regions in the human genome contain the IDDM loci 1, 5, 8, and 17. The identification of diabetes susceptibility regions of the genetically uniform LEW.1AR1-iddm rat strain will pave the way toward a detailed characterization of the loci conferring diabetes development as well as their functional relevance for the pathogenesis of type 1 diabetes mellitus.