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

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

Correspondence: philippe.poussier{at}sri.utoronto.ca

Objective.: The Biobreeding diabetes prone (BBDP) rat spontaneously develops type 1 diabetes (T1D). 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 T1D (exT1D) is widespread among non-lymphopenic (wild type Iddm2) rat strains provided they share the BBDP Iddm1 allele. The question follows as to whether spontaneous T1D (spT1D) and exT1D share susceptibility loci besides Iddm1. Our objectives were to map a novel, serendipitously discovered Iddm locus, confirm its effects by developing congenic sub-lines, and assess its differential contribution to spT1D and exT1D.

Research Design and Methods.: An unexpected reduction in spT1D incidence (86% to 31%, p<0.0001) was observed in an BBDP line congenic for a Wistar Furth (WF)-derived allotypic marker, RT7 (chromosome 13). Genome wide analysis revealed that, besides the RT7 locus, a WF 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 sub-lines. One of these sub-lines, resistant to spT1D, was tested for susceptibility to exT1D.

Results.: Both linkage analysis and congenic sub-lines mapped a novel locus (Iddm24) to the telomeric 10.34Mb of chromosome 8 influencing cumulative incidence and age of onset of spT1D but not insulitis nor exT1D.

Conclusion.: This study has identified a T1D susceptibility locus that appears to act after the development of insulitis, and regulates spT1D, exclusively.

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