Type 1 Diabetes in the BB Rat: A Polygenic Disease

Abstract

OBJECTIVETwo 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 METHODSWe 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.BB1u.lyp) rats, where both Iddm1 and Iddm2 were fixed as BBDP.RESULTSA 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.CONCLUSIONSThis 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.

A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat

“…To develop the F2 cohort, we crossed BBDP male and ACI.1u.lyp female rats to generate F1 progeny that were then intercrossed to produce F2(BBDP 3 ACI.1u.lyp) rats for linkage analysis. The results of this analysis have been previously reported (4). Nonlymphopenic, ACI.1u, and BB Non-Lyp inbred strains that are homozygous for wild type Gimap5 have been previously described (28,29).…”

“…To assess diabetes onset, we tested rats three times a week for the presence of glycosuria and ketonuria starting at 2 mo of age as previously described (4). Once animals became glycosuric, the diagnosis of diabetes was established on the basis of hyperglycemia (blood glucose .16.7 mM) for 2 consecutive days.…”

“…Because of the strong influence of these loci on disease development, the identification of additional loci conferring T1D risk has been difficult to accomplish. A study by Wallis et al (4) has used a comprehensive, genomewide linkage analysis for T1D and related phenotypes in F2 animals derived from a conditioned cross-intercross between the BBDP and the T1D-resistant, double-congenic ACI.BBDP-RT1 u , Gimap5 (ACI.1u.lyp) strain, in which both Iddm1 and Iddm2 had been fixed as BBDP. This method has allowed the identification of several Iddm loci, including Iddm26 on the telomeric end of chromosome 2.…”

Iddm30 Controls Pancreatic Expression of Ccl11 (Eotaxin) and the Th1/Th2 Balance within the Insulitic Lesions

“…lyp females to generate F 1 progenies that were then intercrossed for linkage analysis. The results of this linkage analysis for type 1 diabetes, severity of insulitis, and age of disease onset have been reported previously (2).…”

“…This impaired development of regulatory T cells appears to be the main diabetogenic mechanism contributed by this mutation (12,14,15). Although multiple additional Iddm loci linked to either T1D, severity of insulitis, or age of disease onset were subsequently mapped in the BBDP rat, the chromosomal intervals of these loci were large, thus making the search for the causal genes within and the characterization of the underlying pathogenic mechanisms controlled by these genes difficult (2,16,17). A successful approach to obtain insight into the genetic basis of autoimmunity has been to identify and map disease-related subphenotypes that are highly penetrant, quantifiable, and under simpler genetic control than the multistep, full-blown autoimmune disease (3,14,(18)(19)(20)(21).…”