BB rat diabetes susceptibility and body weight regulation genes colocalize on Chromosome 2

Abstract.

The genetic etiology of Type 1 (insulin-dependent) diabetes mellitus is complicated by the apparent presence of several diabetes susceptibility genetic regions. Type 1 diabetes in the inbred BioBreeding (BB) rat closely resembles 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 histocompatibility complex (MHC) on Chr 20. In addition, a segregation analysis of an F₂ intercross between the diabetes-prone congenic BB DR^lyp/lyp,u/u and F344^{+/+, lv/lv} rats indicated that at least one more genetic factor was responsible for Type 1 diabetes. In this study, we generated F₂N₂ progeny in a cross between non-diabetic F₂(DR^lyp/lyp,u/u× F344)^lyp/lyp,u/u and diabetic DR^lyp/lyp,u/u rats. In a subsequent total genome scan, a third factor 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 of the BB allele (b/b) for the Chr 2 region was significantly associated with a greater weight reduction after fasting than the homozygosity of the F344 allele (f/f, p < 0.008). In conclusion, the development of Type 1 diabetes in the congenic DR^lyp/lyp rat is controlled by at least three genes: lymphopenia, MHC, and a third factor that may play a role in metabolism and body weight regulation.