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Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V locus

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Abstract

Iddm14 (formerly Iddm4) is a non-MHC-linked genetic locus associated with autoimmune diabetes. Its effects have been well-documented in BB-derived rats in which diabetes is either induced by immunologic perturbation or occurs spontaneously. The role of Iddm14 in non-BB rat strains is unknown. Our goal was to extend the analysis of Iddm14 in new diabetes-susceptible strains and to identify candidate genes in the rat Iddm14 diabetes susceptibility locus that are common to these multiple diabetic strains. To determine if Iddm14 is important in strains other than BB, we first genotyped a (LEW.1WR1 × WF)F2 cohort in which diabetes was induced by perturbation with polyinosinic:polycytidylic acid. We found that Iddm14 is a major determinant of diabetes susceptibility in LEW.1WR1 rats. We then used nucleotide sequencing to establish a strain distribution pattern of polymorphisms (insertions, deletions, and single nucleotide polymorphisms [SNPs]) that predicts susceptibility to diabetes in a panel of inbred and congenic rats. Using the positional information from the congenic strains and the new linkage data, we identified a susceptibility haplotype in the T-cell receptor Vβ chain (Tcrb-V) locus. This haplotype includes Tcrb-V13, which is identical in five susceptible strains but different in resistant WF and F344 rats. We conclude that Iddm14 is a powerful determinant of both spontaneous and induced autoimmune diabetes in multiple rat strains, and that Tcrb-V13 SNPs constitute a haplotype of gene elements that may be critical for autoimmune diabetes in rats.

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References

  • Awata T, Guberski DL, Like AA (1995) Genetics of the BB rat: association of autoimmune disorders (diabetes, insulitis, and thyroiditis) with lymphopenia and major histocompatibility complex class II. Endocrinology 136:5731–5735

    Article  PubMed  CAS  Google Scholar 

  • Blankenhorn EP, Rodemich L, Martin-Fernandez C, Leif J, Greiner DL et al (2005) The rat diabetes susceptibility locus Iddm4 and at least one additional gene are required for autoimmune diabetes induced by viral infection. Diabetes 54:1233–1237

    Article  PubMed  CAS  Google Scholar 

  • Blankenhorn EP, DeScipio C, Rodemich L, Cort L, Leif JH et al (2007) Refinement of the Iddm4 diabetes susceptibility locus reveals TCRVbeta4 as a candidate gene. Ann NY Acad Sci 1103:128–131

    Article  PubMed  CAS  Google Scholar 

  • Cuppen E (2005) Haplotype-based genetics in mice and rats. Trends Genet 21:318–322

    Article  PubMed  CAS  Google Scholar 

  • Dudek NL, Thomas HE, Mariana L, Sutherland RM, Allison J et al (2006) Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways. Diabetes 55:2412–2418

    Article  PubMed  CAS  Google Scholar 

  • Ellerman KE, Like AA (2000) Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia 43:890–898

    Article  PubMed  CAS  Google Scholar 

  • Fuller JM, Kwitek AE, Hawkins TJ, Moralejo DH, Lu W et al (2006) Introgression of F344 rat genomic DNA on BB rat chromosome 4 generates diabetes-resistant lymphopenic BB rats. Diabetes 55:3351–3357

    Article  PubMed  CAS  Google Scholar 

  • Galley KA, Danska JS (1995) Peri-islet infiltrates of young non-obese diabetic mice display restricted TCR β-chain diversity. J Immunol 154:2969–2982

    PubMed  CAS  Google Scholar 

  • Haskins K (2005) Pathogenic T-cell clones in autoimmune diabetes: more lessons from the NOD mouse. Adv Immunol 87:123–162

    Article  PubMed  CAS  Google Scholar 

  • Hornum L, Rømer J, Markholst H (2002) The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of iddm1. Diabetes 51:1972–1979

    Article  PubMed  CAS  Google Scholar 

  • Hornum L, Lundsgaard D, Markholst H (2007) PolyI:C induction of diabetes is controlled by Iddm4 in rats with a full regulatory T cell pool. Ann NY Acad Sci 1110:65–72

    Article  PubMed  CAS  Google Scholar 

  • Institute of Laboratory Animal Resources, Commission on Life Sciences and National Research Council (1996) Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC, 119 pp

  • Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M et al (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

    Article  PubMed  CAS  Google Scholar 

  • Klaff LS, Koike G, Jiang JJ, Wang YL, Bieg S et al (1999) BB rat diabetes susceptibility and body weight regulation genes colocalize on Chromosome 2. Mamm Genome 10:883–887

    Article  PubMed  CAS  Google Scholar 

  • Klöting I, van den Brandt J, Klöting N, Radovic B (2003) Alleles of diabetes-resistant BN rats contribute to insulin-dependent type 1 diabetes mellitus. J Autoimmun 20:119–123

    Article  PubMed  Google Scholar 

  • Lenzen S, Tiedge M, Elsner M, Lortz S, Weiss H et al (2001) The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia 44:1189–1196

    Article  PubMed  CAS  Google Scholar 

  • MacMurray AJ, Moralejo DH, Kwitek AE, Rutledge EA, Van Yserloo B et al (2002) Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (lan)-related gene. Genome Res 12:1029–1039

    Article  PubMed  CAS  Google Scholar 

  • Martin AM, Blankenhorn EP, Maxson MN, Zhao M, Leif J et al (1999a) Non-major histocompatibility complex-linked diabetes susceptibility loci on chromosomes 4 and 13 in a backcross of the DP BB/Wor rat to the WF rat. Diabetes 48:50–58

    Article  PubMed  CAS  Google Scholar 

  • Martin AM, Maxson MN, Leif J, Mordes JP, Greiner DL et al (1999b) Diabetes-prone and diabetes-resistant BB rats share a common major diabetes susceptibility locus, iddm4: Additional evidence for a “universal autoimmunity locus” on rat chromosome 4. Diabetes 48:2138–2144

    Article  PubMed  CAS  Google Scholar 

  • Mordes JP, Leif J, Novak S, DeScipio C, Greiner DL et al (2002) The iddm4 locus segregates with diabetes susceptibility in congenic WF.iddm4 rats. Diabetes 51:3254–3262

    Article  PubMed  CAS  Google Scholar 

  • Mordes JP, Guberski DL, Leif JH, Woda BA, Flanagan JF et al (2005) LEW.1WR1 rats develop autoimmune diabetes spontaneously and in response to environmental perturbation. Diabetes 54:2727–2733

    Article  PubMed  CAS  Google Scholar 

  • Mordes JP, Poussier P, Rossini AA, Blankenhorn EP, Greiner DL (2007) Rat models of type 1 diabetes: Genetics, environment, and autoimmunity. In: Shafrir E (ed) Animal models of diabetes: frontiers in research. CRC Press, Boca Raton, FL, pp 1–39

    Google Scholar 

  • Penhale WJ, Stumbles PA, Huxtable CR, Sutherland RJ, Pethick DW (1990) Induction of diabetes in PVG/c strain rats by manipulation of the immune system. Autoimmunity 7:169–179

    Article  PubMed  CAS  Google Scholar 

  • Quinn A, McInerney M, Huffman D, McInerney B, Mayo S et al (2006) T cells to a dominant epitope of GAD65 express a public CDR3 motif. Int Immunol 18:967–979

    Article  PubMed  CAS  Google Scholar 

  • Sherman DH, Hochman PS, Dick R, Tizard R, Ramachandran KL et al (1987) Molecular analysis of antigen recognition by insulin-specific T-cell hybridomas from B6 wild-type and bm12 mutant mice. Mol Cell Biol 7:1865–1872

    PubMed  CAS  Google Scholar 

  • Shizuru JA, Taylor-Edwards C, Livingstone A, Fathman CG (1991) Genetic dissection of T cell receptor Vβ gene requirements for spontaneous murine diabetes. J Exp Med 174:633–638

    Article  PubMed  CAS  Google Scholar 

  • Smith LR, Kono DH, Theofilopoulos AN (1991) Complexity and sequence identification of 24 rat V beta genes. J Immunol 147:375–379

    PubMed  CAS  Google Scholar 

  • Stienekemeier M, Hofmann K, Gold R, Herrmann T (2000) A polymorphism of the rat T-cell receptor beta-chain variable gene 13 (BV13S1) correlates with the frequency of BV13S1-positive CD4 cells. Immunogenetics 51:296–305

    Article  PubMed  CAS  Google Scholar 

  • Verdaguer J, Yoon JW, Anderson B, Averill N, Utsugi T et al (1996) Acceleration of spontaneous diabetes in TCR-β-transgenic nonobese diabetic mice by β-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-α chains. J Immunol 157:4726–4735

    PubMed  CAS  Google Scholar 

  • Wallis RH, Wang K, Dabrowski D, Marandi L, Ning T et al (2007) A novel susceptibility locus on rat chromosome 8 affects spontaneous but not experimentally induced type 1 diabetes. Diabetes 56:1731–1736

    Article  PubMed  CAS  Google Scholar 

  • Wedekind D, Weiss H, Jorns A, Lenzen S, Tiedge M et al (2005) Effects of polyinosinic-polycytidylic acid and adoptive transfer of immune cells in the Lew.1AR1-iddm rat and in its coisogenic LEW.1AR1 background strain. Autoimmunity 38:265–275

    Article  PubMed  CAS  Google Scholar 

  • Williams CB, Gutman GA (1989) T cell receptor beta-chain genes in the rat. Availability and pattern of utilization of V gene segments differs from that in the mouse. J Immunol 142:1027–1035

    PubMed  CAS  Google Scholar 

  • Yokoi N, Komeda K, Wang HY, Yano H, Kitada K et al (2002) Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 31:391–394

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Vikranth Mulkanoor for assistance with the nucleic acid sequencing. This work was supported in part by grants DK36024 (DLG), DK49106 (DLG, JPM, EPB), and DK25306 (JPM), ADA grants 7-08-RA-106 (JPM) and 7-06-RA-14 (EPB), AI42386 (JMF, AL), and Center Grant DK32520 from the National Institutes of Health. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA

    John P. Mordes, Elaine Norowski, Jean Leif & Dale L. Greiner

  2. Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, PA, 19129, USA

    Laura Cort & Elizabeth P. Blankenhorn

  3. Department of Medicine, University of Washington, Seattle, WA, 98195, USA

    Jessica M. Fuller & Åke Lernmark

  4. Department of Clinical Sciences (Malmö), Clinical Research Center, Lund University, Malmö, Sweden

    Jessica M. Fuller & Åke Lernmark

Authors
  1. John P. Mordes
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  2. Laura Cort
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  3. Elaine Norowski
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  4. Jean Leif
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  5. Jessica M. Fuller
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  6. Åke Lernmark
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  7. Dale L. Greiner
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  8. Elizabeth P. Blankenhorn
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Correspondence to Elizabeth P. Blankenhorn.

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Mordes, J.P., Cort, L., Norowski, E. et al. Analysis of the rat Iddm14 diabetes susceptibility locus in multiple rat strains: identification of a susceptibility haplotype in the Tcrb-V locus. Mamm Genome 20, 162–169 (2009). https://doi.org/10.1007/s00335-009-9172-y

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  • DOI: https://doi.org/10.1007/s00335-009-9172-y

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