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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 (Iddml) and Gimap5 (Iddni2). 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.
RESEARCH DESIGN AND 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 congenie ACI.BBDPRT1u,Gimap5 (ACI.BB^sup lulyp^) rats, where both Iddml 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 012orf30, 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. Diabetes 58:1007-1017, 2009
The biobreeding diabetes-prone (BBDP) rat spontaneously develops type 1 diabetes with high incidence around puberty through a T-cell-mediated autoimmune destruction of pancreatic β-cells (1). Two genes that contribute to disease pathogenesis in this animal have been identified, the RT1u allele (Iddml) and the GTPase immunity-associated protein family member 5 (Gimap5, Iddm2) (2-4). Genetic variation in Gimap5 has been recently associated with humoral antipancreatic autoimmunity in human type 1 diabetes as well as with human systemic lupus erythematosus (5,6). Crosses between BBDP rats and type 1 diabetes-resistant strains have shown that homozygosity for the BBDP Gimap5 allele and at...