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Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N = 365) and control subjects (N = 668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as "expression quantitative trait loci," modulating HLA-DR and -DQ expression. From our analysis of available data, we conclude that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The biobreeding diabetes-prone (BBDP) rat spontaneously develops type 1 diabetes. Two of the genetic factors contributing to this syndrome are the major histocompatibility complex (Iddm1) and a Gimap5 mutation (Iddm2) responsible for a T-lymphopenia. Susceptibility to experimentally induced type 1 diabetes is widespread among nonlymphopenic (wild-type Iddm2) rat strains provided they share the BBDP Iddm1 allele. The question follows as to whether spontaneous and experimentally induced type 1 diabetes share susceptibility loci besides Iddm1. Our objectives were to map a novel, serendipitously discovered Iddm locus, confirm its effects by developing congenic sublines, and assess its differential contribution to spontaneous and experimentally induced type 1 diabetes. RESEARCH DESIGN AND METHODS--An unexpected reduction in spontaneous type I diabetes incidence (86 to 31%, P < 0.0001) was observed in a BBDP line congenic for a Wistar Furth--derived allotypic marker, RT7 (chromosome 13). Genome-wide analysis revealed that, besides the RT7 locus, a Wistar Furth chromosome 8 fragment had also been introduced. The contribution of these intervals to diabetes resistance was assessed through linkage analysis using 134 F2 (BBDP x double congenic line) animals and a panel of congenic sublines. One of these sublines, resistant to spontaneous type 1 diabetes, was tested for susceptibility to experimentally induced type 1 diabetes. RESULTS--Both linkage analysis and congenic sublines mapped a novel locus (Iddm24) to the telomeric 10.34 Mb of chromosome 8, influencing cumulative incidence and age of onset of spontaneous type 1 diabetes but not insulitis nor experimentally induced type 1 diabetes. CONCLUSIONS--This study has identified a type 1 diabetes susceptibility locus that appears to act after the development of insulitis and that regulates spontaneous type 1 diabetes exclusively. Diabetes 56:1731-1736, 2007 [ABSTRACT FROM AUTHOR]

Iddm4 is a dominant non-major histocompatibility complex (MHC) determinant of diabetes susceptibility in BBDR rats treated with poly I:C, plus depletion of regulatory T cells. In congenic MHC-identical normal WF rats, Iddm4d sensitively and specifically predicts induced diabetes. We report a new diabetes-susceptible subcongenic line that carries Iddm4 in a < 2.6 megabase interval. Candidate genes include the T cell receptor β chain variable ( TCRVβ) family. We found that TCRVβ 4 in WF rats contains a stop codon, whereas 5/5 diabetes-susceptible rat strains express TCRVβ 4. We conclude that Iddm4-mediated diabetes resistance in rats may be due to a recessive protective mutation in TCRVβ 4. [ABSTRACT FROM AUTHOR]

NOD mice develop type 1 autoimmune diabetes and exhibit genetically dominant resistance to transplantation tolerance induction. These two phenotypes are genetically separable. Costimulation blockade fails to prolong skin allograft survival in (NOD x C57BL/6)F1 mice and in NOD-related strains made diabetes-resistant by congenic introduction of protective major histocompatibility complex (MHC) or non-MHC Idd region genes. Here, we tested the hypothesis that the genetic basis for the resistance of NOD mice to skin allograft tolerance also applies to islet allografts. Surprisingly, costimulation blockade induced permanent islet allograft survival in (NOD x C57BL/6)F1 mice but not in NOD mice. After costimulation blockade, islet allograft survival was prolonged in diabetes-resistant NOD.B6 Idd3 mice and shortened in diabetes-free C57BL/6 mice congenic for the NOD Idd3 variant. Islet allograft tolerance could not be induced in diabetes-resistant NOD.B10 Idd5 and NOD.B10 Idd9 mice. The data demonstrate that 1) NOD mice resist islet allograft tolerance induction; 2) unlike skin allografts, resistance to islet allograft tolerance is a genetically recessive trait; 3) an Idd3 region gene(s) is an important determinant of islet allograft tolerance induction; and 4) there may be overlap in the mechanism by which the Idd3 resistance locus improves self-tolerance and the induction of allotolerance. [ABSTRACT FROM AUTHOR]

Iddm4 is one of several susceptibility genes that have been identified in the BB rat model of type 1 diabetes. The BB rat allele of this gene confers dominant predisposition to diabetes induction by immune perturbation in both the diabetes-prone and the diabetes-resistant substrains, whereas the Wistar Furth (WF) allele confers resistance. We have positioned the gene in a 2.8-cM region on rat Chromosome (Chr) 4, proximal to Lyp/Ian4l1. We have produced a radiation hybrid map of the Iddm4-region that includes a number of rat genes with their mouse and human orthologs. We present a comparative map of the rat Iddm4 region in rat, human, and mouse, assigning the gene to a 6.3-Mb segment between PTN and ZYX at 7q32 in the human genome, and to a 5.7-Mb segment between Ptn and Zyx in the mouse genome. [ABSTRACT FROM AUTHOR]

Diabetes-prone (DP) BB rats develop autoimmune type 1 diabetes spontaneously. At least five loci are linked to disease expression: the major histocompatibility complex (iddm2), two susceptibility loci (iddm4, iddm5), and, possibly, a resistance locus (iddm3). Spontaneous disease also requires homozygosity for lyp/iddm1, which causes lymphopenia. It has not been determined whether lyp/iddm1 is required for predisposition to diabetes autoimmunity in addition to being required for its spontaneous expression. We analyzed backcross rats segregating for diabetes but not lymphopenia using Wistar-Furth (WF) and diabetes-resistant (DR) BB animals. The latter are nonlymphopenic (lyp+/+) and develop diabetes only in response to immunological perturbants. Treatment of (DR-BB x WF)F1 x WF animals (all lyp+/+) using a standard induction protocol caused type 1 diabetes in 58% of progeny. Expression of type 1 diabetes was strongly linked to iddm4. The results suggest that lyp/iddm1 does not determine the predisposition to autoimmunity in BB rats and that iddm4 is a major diabetogenic locus in both DP- and DR-BB animals. The iddm4 gene maps to a region containing several major autoimmunity loci, including aia2, aia3, and cia3. We propose that BB rat diabetes requires 1) class II RT1u (iddm2) for susceptibility, 2) additional loci for disease initiation and progression in response to perturbants, and 3) lyp for spontaneous disease. [ABSTRACT FROM AUTHOR]

BB rats are used as models of autoimmune human IDDM. Genetic control of IDDM in both species is complex, including both major histocompatibility complex (MHC)-linked and non-MHC-linked genes. DP-BB rats develop IDDM spontaneously. Expression of disease in these animals requires homozygosity at the lyp locus, which causes lymphopenia. All genetic analyses of BB rat diabetes to date have backcrossed to the DP-BB strain or used (DP-BB x non-BB)F2 animals to ensure that a fraction of progeny are homozygous for lyp. Here we report the analysis of a backcross of the DP-BB rat to the histocompatible WF rat. Neither WF nor (WF x DP-BB)F1 animals develop spontaneous IDDM. However, 95% of (WF x DP-BB)F1 rats and a fraction of (WF x DP-BB) x WF backcross animals readily develop IDDM after treatment with polyinosinic:polycytidylic acid and a cytotoxic anti-RT6.1 monoclonal antibody. Using simple sequence length polymorphism analysis, we have mapped loci on chromosomes 4 and 13 that show significant linkage to IDDM expression and insulitis. The susceptibility locus on chromosome 4 is linked to, but not identical to, lyp. We propose a disease model for the BB rat that requires 1) the RT1u MHC haplotype for disease susceptibility, 2) a new locus on chromosome 4 for disease initiation (as measured by insulitis), 3) a new locus on chromosome 13 for disease progression in response to environmental perturbation, and 4) lyp for spontaneous expression of disease. [ABSTRACT FROM AUTHOR]

Genetic analyses of human type 1 diabetes (T1D) have yet to reveal a complete pathophysiologic mechanism. Inbred rats with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1B/Du) can illuminate such mechanisms. Using T1D-susceptible LEW.1WR1 rats that express RT1B/Du and a susceptible allele of the Ubd promoter, we demonstrate that germline knockout of Tcrb-V13S1A1, which encodes the Vβ13a T cell receptor β chain, completely prevents diabetes. Using the RT1B/Du-identical LEW.1W rat, which does not develop T1D despite also having the same Tcrb-V13S1A1 β chain gene but a different allele at the Ubd locus, we show that knockout of the Ubash3a regulatory gene renders these resistant rats relatively susceptible to diabetes. In silico structural modeling of the susceptible allele of the Vβ13a TCR and its class II RT1u ligand suggests a mechanism by which a germline TCR β chain gene could promote susceptibility to T1D in the absence of downstream immunoregulation like that provided by UBASH3A. Together these data demonstrate the critical contribution of the Vβ13a TCR to the autoimmune synapse in T1D and the regulation of the response by UBASH3A. These experiments dissect the mechanisms by which MHC class II heterodimers, TCR and regulatory element interact to induce autoimmunity. [ABSTRACT FROM AUTHOR]