Type 1 diabetes in the BB rat: a polygenic disease.
OBJECTIVE
Two type 1 diabetes susceptibility genes have been identified in the spontaneously diabetic biobreeding diabetes-prone (BBDP) rat, the major histocompatibility complex (MHC) (RT1) class II u haplotype (Iddm1) and Gimap5 (Iddm2). The strong effects of these have impeded previous efforts to map additional loci. We tested the hypothesis that type 1 diabetes is a polygenic disease in the BBDP rat.


METHODS
We performed the most comprehensive genome-wide linkage analysis for type 1 diabetes, age of disease onset (AOO), and insulitis subphenotypes in 574 F2 animals from a cross-intercross between BBDP and type 1 diabetes-resistant, double congenic ACI.BBDP-RT1u,Gimap5 (ACI.BB(1u.lyp)) rats, where both Iddm1 and Iddm2 were fixed as BBDP.


RESULTS
A total of 19% of these F2 animals developed type 1 diabetes, and eight type 1 diabetes susceptibility loci were mapped, six showing significant linkage (chromosomes 1, 3, 6 [two loci], 12, and 14) and two (chromosomes 2 and 17) suggestive linkage. The chromosomes 6, 12, and 14 intervals were also linked to the severity of islet infiltration by immunocytes, while those on chromosomes 1, 6 (two loci), 14, 17, and a type 1 diabetes-unlinked chromosome 8 interval showed significant linkage to the degree of islet atrophy. Four loci exhibited suggestive linkage to AOO on chromosomes 2 (two loci), 7, and 18 but were unlinked to type 1 diabetes. INS, PTPN22, IL2/IL21, C1QTNF6, and C12orf30, associated with human type 1 diabetes, are contained within the chromosomes 1, 2, 7, and 12 loci.


CONCLUSIONS
This study demonstrates that the BBDP diabetic syndrome is a complex, polygenic disease that may share additional susceptibility genes besides MHC class II with human type 1 diabetes.
Wallis
Robert H
RH
Sunnybrook Health Sciences Centre Research Institute, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Wang
KeSheng
K
Marandi
Leili
L
Hsieh
Eugene
E
Ning
Terri
T
Chao
Gary Y C
GY
Sarmiento
Janice
J
Paterson
Andrew D
AD
Poussier
Philippe
P
D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D016678:Genome; D006029:Glycosuria; D006801:Humans; D008957:Models, Genetic; D051381:Rats; D011913:Rats, Inbred BB / Q000235:genetics*