Iddm14 (formerly
Iddm4) is a non-MHC-linked genetic locus associated with autoimmune diabetes. Its effects have been well-documented in BB-derived
rats in which diabetes is either induced by immunologic perturbation or occurs spontaneously. The role of
Iddm14 in non-BB rat strains is unknown. Our goal was to extend the analysis of
Iddm14 in new diabetes-susceptible strains and to identify candidate genes in the rat
Iddm14 diabetes susceptibility locus that are common to these multiple diabetic strains. To determine if
Iddm14 is important in strains other than BB, we first genotyped a (LEW.1WR1 × WF)F2 cohort in which diabetes was induced by perturbation
with polyinosinic:polycytidylic acid. We found that
Iddm14 is a major determinant of diabetes susceptibility in LEW.1WR1 rats. We then used nucleotide sequencing to establish a strain
distribution pattern of polymorphisms (insertions, deletions, and single nucleotide polymorphisms [SNPs]) that predicts susceptibility
to diabetes in a panel of inbred and congenic rats. Using the positional information from the congenic strains and the new
linkage data, we identified a susceptibility haplotype in the T-cell receptor Vβ chain (
Tcrb-V) locus. This haplotype includes
Tcrb-V13, which is identical in five susceptible strains but different in resistant WF and F344 rats. We conclude that
Iddm14 is a powerful determinant of both spontaneous and induced autoimmune diabetes in multiple rat strains, and that
Tcrb-V13 SNPs constitute a haplotype of gene elements that may be critical for autoimmune diabetes in rats.