NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans

A genome scan for B10-derived loci that reduce the frequency of diabetes an d insulitis in NOD mice demonstrated a large region (34 cM) of Linkage on t he proximal end of chromosome 1. This locus was designated Idd5 and encompa ssed candidate genes including Il1r1, Il1r2, Stat1, Stat4, Nramp1, and Bcl2 . In the current study, we have confirmed the existence of Idd5 by developi ng a series of congenic mouse strains that are resistant to diabetes and de termined that Idd5 is actually two genes located within a 9.4-cM interval. Idd5.1 is in the proximad 1.5-cM portion of the interval and contains the c andidates Casp8, Cflar (FLIP), Cd28, and Cd152 (CTLA4). Idd5.1 overlaps the orthologous CTLA4/IDDM12 locus in humans. Idd5.2 is in the distal 5.1-cM p ortion of the 9.4-cM interval and contains the candidates Nramp1, which has a functional polymorphism between NOD and B10, and Cmkar2 (CXCR2, interleu kin [IL]-8 receptor alpha). Candidate genes eliminated by this analysis inc lude Ilr1, Ilr2, Zap70, Orch5, Stat1, Stat4, Bcl2, Cmkar4 (CXCR4), and Il10 . On its own, the Idd5 locus provides a significant amount of protection f rom diabetes (50% reduction from parental frequency) and when combined with another resistance locus (Idd3 on chromosome 3), provides nearly complete protection from diabetes and insulitis.