A Novel Susceptibility Locus on Rat Chromosome 8 Affects Spontaneous but Not Experimentally Induced Type 1 Diabetes

  1. Robert H. Wallis1,
  2. KeSheng Wang2,
  3. Dominika Dabrowski1,
  4. Leili Marandi1,
  5. Terri Ning1,
  6. Eugene Hsieh13,
  7. Andrew D. Paterson24,
  8. John P. Mordes5,
  9. Elisabeth P. Blankenhorn6 and
  10. Philippe Poussier1
  1. 1Departments of Medicine and Immunology, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, Canada
  2. 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
  3. 3Department of Laboratory Medicine and Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  4. 4Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
  5. 5Diabetes Division, University of Massachusetts Medical School, Worcester, Massachusetts
  6. 6Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania
  1. Address correspondence and reprint requests to Philippe Poussier, Sunnybrook and Women's Health Sciences Centre, 2075 Bayview Ave., Room A3 38, Toronto, Ontario, Canada, M4N 3M5. E-mail: philippe.poussier{at}sri.utoronto.ca

Abstract

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 1 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 × 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 27 March 2007. DOI: 10.2337/db06-1790.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 2, 2007.
    • Received December 22, 2006.
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  1. Published online before print March 27, 2007, doi: 10.2337/db06-1790 Diabetes June 2007 vol. 56 no. 6 1731-1736
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