Type 1 Diabetes in the BB Rat: A Polygenic Disease

  1. Robert H. Wallis1,
  2. KeSheng Wang2,3,
  3. Leili Marandi1,
  4. Eugene Hsieh1,4,
  5. Terri Ning1,
  6. Gary Y.C. Chao1,
  7. Janice Sarmiento1,
  8. Andrew D. Paterson2,5 and
  9. Philippe Poussier1
  1. 1Sunnybrook Health Sciences Centre Research Institute, Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada; the
  2. 2Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada; the
  3. 3Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, Tennessee; the
  4. 4Department of Laboratory Medicine and Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; and the
  5. 5Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
  1. Corresponding author: Philippe Poussier, philippe.poussier{at}sri.utoronto.ca.

  1. 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.BB1u.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, are contained within the chromosomes 1, 2, 7, and 12 loci.

CONCLUSIONS This 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.

Footnotes

  • 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.

  • See accompanying original article, p. 796.

    • Received September 2, 2008.
    • Accepted December 18, 2008.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Published online before print January 23, 2009, doi: 10.2337/db08-1215 Diabetes April 2009 vol. 58 no. 4 1007-1017
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