A novel susceptibility locus on rat chromosome 8 affects spontaneous but not experimentally induced type 1 diabetes.
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.


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.
Wallis
Robert H
RH
Department of Medicine, Sunnybrook and Women's College Health Sciences Centre Research Institute, University of Toronto, Toronto, Ontario, Canada.
Wang
KeSheng
K
Dabrowski
Dominika
D
Marandi
Leili
L
Ning
Terri
T
Hsieh
Eugene
E
Paterson
Andrew D
AD
Mordes
John P
JP
Blankenhorn
Elisabeth P
EP
Poussier
Philippe
P
D000818:Animals; D002874:Chromosome Mapping; D003921:Diabetes Mellitus, Experimental / Q000453:epidemiology* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051381:Rats; D011913:Rats, Inbred BB; D016615:Telomere / Q000235:genetics