A Susceptibility Allele From a Non-Diabetes-Prone Mouse Strain Accelerates Diabetes in NOD Congenic Mice

Abstract

The nonobese diabetic (NOD) mouse is genetically predisposed for the spontaneous development of type 1 diabetes. Linkage analyses have identified at least 19 susceptibility loci (Idd1–Idd19) that contribute to disease pathogenesis in which lymphocytes mediate the specific destruction of insulin-producing β-cells. Interestingly, nondiabetic mouse strains have been shown to confer susceptibility alleles to affected progeny in NOD outcrosses for some of the Idd loci. In particular, we noted that diabetic backcross progeny, derived from NOD and C57BL/6 (B6) mouse strains, demonstrated increased heterozygousity for an interval encompassing Idd14 on chromosome 13. This result suggested that B6 mice harbor a more diabetogenic allele(s) than NOD mice for this locus. To confirm this observation, a NOD congenic mouse strain, containing a B6-derived interval covering the majority of chromosome 13, was generated. Adding to the combination of already potent susceptibility alleles elsewhere in the NOD genome, the chromosome 13 B6-derived interval was able to increase the overall risk of developing type 1 diabetes, which resulted in an earlier onset and increased incidence of type 1 diabetes in congenic mice as compared with NOD mice. Furthermore, this B6-derived interval, in combination with the NOD genetic background, was able to overcome environmental conditions that typically suppressed type 1 diabetes in the NOD mouse strain.