BB rat diabetes susceptibility and body weight regulation genes colocalizeon Chromosome 2

The genetic etiology of Type 1 (insulin-dependent) diabetes mellitus is com plicated by the apparent presence of several diabetes susceptibility geneti c regions. Type 1 diabetes in the inbred BioBreeding (BB) rat closely resem bles the human disorder and was previously shown to involve two genes: the lymphopenia (lyp) region on Chromosome (Chr) 4 and RT1(u) in the major hist ocompatibility complex (MHC) on Chr 20, In addition, a segregation analysis of an F-2 intercross between the diabetes-prone congenic BE DRlyp/lyp,u/u and F344(+/+,lv/lv) rats indicated that at least one more genetic factor wa s responsible for Type 1 diabetes. In this study, we generated F2N2 progeny in a cross between non-diabetic F-2(DRlyp/lyp,u/u x F344)(lyp/lyp,u/u) and diabetic DRlyp/lyp,u/u rats. In a subsequent total genome scan, a third fa ctor was mapped to the 21.3-cM region on Chr 2 between D2Mit14 and D2Mit15 (peak LOD score 4.7 with 67% penetrance). Interestingly, the homozygosity o f the BB allele (b/b) for the Chr 2 region was significantly associated wit h a greater weight reduction after fasting than the homozygosity of the F34 4 allele (f/f, p < 0.008). In conclusion, the development of Type 1 diabete s in the congenic DRlyp/lyp rat is controlled by at least three genes: lymp hopenia, MHC, and a third factor that may play a role in metabolism and bod y weight regulation.