Journal article
A Novel Susceptibility Locus on Rat Chromosome 8 Affects Spontaneous but Not Experimentally Induced Type 1 Diabetes
Diabetes (New York, N.Y.), v 56(6), pp 1731-1736
01 Jun 2007
PMID: 17389329
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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.
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Details
- Title
- A Novel Susceptibility Locus on Rat Chromosome 8 Affects Spontaneous but Not Experimentally Induced Type 1 Diabetes
- Creators
- Robert H. Wallis - Women's College, KolkataKeSheng Wang - Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, CanadaDominika Dabrowski - Departments of Medicine and Immunology, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, CanadaLeili Marandi - Departments of Medicine and Immunology, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, CanadaTerri Ning - Departments of Medicine and Immunology, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, CanadaEugene Hsieh - Departments of Medicine and Immunology, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, Canada, Department of Laboratory Medicine and Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaAndrew D. Paterson - Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada, Department of Public Health Sciences, University of Toronto, Toronto, Ontario, CanadaJohn P. Mordes - Diabetes Division, University of Massachusetts Medical School, Worcester, MassachusettsElisabeth P. Blankenhorn - Drexel UniversityPhilippe Poussier - Departments of Medicine and Immunology, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, Canada
- Publication Details
- Diabetes (New York, N.Y.), v 56(6), pp 1731-1736
- Publisher
- American Diabetes Association
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000246930000031
- Scopus ID
- 2-s2.0-34249739206
- Other Identifier
- 991019231754504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Endocrinology & Metabolism