Genetic mapping of a susceptibility locus for autoimmune type 1 diabetes in the LETL rat

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The LETL rat, characterizing as rapid onset of insulin-dependent (type 1) diabetes mellitus (IDDM), no sex difference in the incidence of onset, autoimmune destruction of pancreatic B-cells and no significant T-cell lymphopenia, is a desirable animal model for human IDDM (Kawano et al., 1991).1. We established two substrains, one a diabetes-prone (KDP) and the other a non-diabetic (KND) substrains from the original inbred LETL rats with a low incidence (-20%) of diabetes. The features of KDP rats are highincidence (>70%) of diabetes without lymphopenia and 100% development of mild to severe insulitis at 120-220days of age.2. We have now demonstrated a first genome-wide scan of non-MHC IDDM susceptibility genes in this animal. By analysis of three crosses, we have mapped a major recessively-acting IDDM susceptibility gene, termed Iddm4, to rat chromosome (Chr) 11. Homozygosity for the KDP allele was strongly associated with development of severe insulitis and onset of IDDM.With comparative mapping study among the rat, mouse and human, the homolog of this gene may be located on human Chr 3 and mouse Chr 16, which suggests that this gene is a novel type of IDDM susceptibility genes.