A NON-MHC LOCUS ESSENTIAL FOR AUTOIMMUNE TYPE-I DIABETES IN THE KOMEDA DIABETES-PRONE RAT

The Long-Evans Tokushima Lean (LETL) rat, characterized by rapid onset of insulin-dependent (type I) diabetes mellitus (IDDM), no sex differ ence in the incidence of IDDM, autoimmune destruction of pancreatic be ta cells, and no significant T cell lymphopenia, is a desirable animal model for human IDDM. We have established a diabetes-prone substrain of the LETL rat, named Komeda Diabetes-Prone (KDP) rat, showing a 100% development of moderate to severe insulitis within 220 d of age. The cumulative frequency of IDDM was 70% at 120 d of age, and reached 82% within 220 d of age. Here, we performed the first genome-wide scan for non-MHC IDDM susceptibility genes in this strain. The analysis of thr ee crosses has led to the revelation of a major IDDM susceptibility ge ne, termed Iddm/kdp1, on rat chromosome (Chr) 11. Homozygosity for the KDP allele at this locus is shown to be essential for the development of moderate to severe insulitis and the onset of IDDM. Comparative ma pping suggests that the homologues of Iddm/kdp1 are located on human C hr 3 and mouse Chr 16 and would therefore be different from previously reported IDDM susceptibility genes.