BB rat diabetes susceptibility and body weight regulation genes colocalize on chromosome 2.
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 F(2) 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 F(2)N(2) progeny in a cross between non-diabetic F(2)(DR(lyp/lyp,u/u) x 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.
Klaff
L S
LS
R.H. Williams Laboratory, Department of Medicine, University of Washington, 1959 N.E. Pacific Street, Box 357710, Seattle, Washington 98195, USA.
Koike
G
G
Jiang
J
J
Wang
Y
Y
Bieg
S
S
Pettersson
A
A
Lander
E
E
Jacob
H
H
Lernmark
A
A
D000818:Animals; D020296:Animals, Congenic; D001835:Body Weight / Q000235:genetics*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D010641:Phenotype; D051381:Rats; D011913:Rats, Inbred BB / Q000033:anatomy & histology / Q000235:genetics*; D011916:Rats, Inbred F344