Type 1 Diabetes in the BB Rat: A Polygenic Disease

Type 1 Diabetes in the BB Rat: A Polygenic Disease Robert H. Wallis 1 , KeSheng Wang 2 , 3 , Leili Marandi 1 , Eugene Hsieh 1 , 4 , Terri Ning 1 , Gary Y.C. Chao 1 , Janice Sarmiento 1 , Andrew D. Paterson 2 , 5 and Philippe Poussier 1 1 Sunnybrook Health Sciences Centre Research Institute, Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada; the 2 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada; the 3 Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, Tennessee; the 4 Department of Laboratory Medicine and Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; and the 5 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. Corresponding author: Philippe Poussier, philippe.poussier{at}sri.utoronto.ca . R.H.W., K.W., L.M., and E.H. contributed equally to this article. Abstract 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. 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 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,