Genetic dissection of type 1 diabetes susceptibility gene, Idd3, by ancestral haplotype congenic mapping.

One of the strongest non-MHC susceptibility genes for type 1 diabetes, Idd3, has been mapped to a 0.15-cM segment of chromosome 3, where a strong candidate gene, Il2, encoding cytokine IL2, is located. To prove that the NOD allele of Il2 is responsible for the Idd3 effect, it is necessary to find a recombinant chromosome with the NOD allele of Il2, but with different flanking markers from NOD mice, and to demonstrate that NOD mouse strains that are congenic for the recombinant Il2 region develop type 1 diabetes with similar incidence and age at onset of the disease. As a first step in this approach, we searched for recombinant Il2 region in NOD-related strains derived from the same outbred colony, Jcl:ICR. The same Il2 allele as is found in the NOD mouse was found in four out of seven NOD-related strains, indicating that the NOD allele of Il2 is common in NOD-related strains. One of these strains, IIS, was found to have a recombinant Il2 region with the same Il2 allele as the NOD, but different alleles at flanking markers from the NOD mouse. A preliminary study on a NOD strain congenic for the Il2 region of IIS has shown that the Il2 region of IIS confers susceptibility to type 1 diabetes, suggesting that Il2 may be responsible for the Idd3 effect.