HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db06-1790v1 56/6/1731    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wallis, R. H. Articles by Poussier, P. Search for Related Content PubMed PubMed Citation Articles by Wallis, R. H. Articles by Poussier, P. Social Bookmarking                What's this?

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

¹ Departments of Medicine and Immunology, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, Canada
² Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
³ Department of Laboratory Medicine and Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
⁴ Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
⁵ Diabetes Division, University of Massachusetts Medical School, Worcester, Massachusetts
⁶ Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania

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

Abbreviations: BBDP, biobreeding diabetes prone; BBDR, biobreeding diabetes resistant; LOD, logarithm of odds; mAb, monoclonal antibody; RGSC, Rat Genome Sequencing Consortium

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 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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?