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Genetic dissection of Iddm26 in the spontaneously diabetic BBDP rat

Genes & Immunity volume 15, pages 378–391 (2014)Cite this article

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Abstract

The 40 Mb T1D susceptibility locus Iddm26 was mapped to chromosome 2 through linkage analysis of a conditioned cross-intercross between the diabetes-prone BBDP and the diabetes-resistant ACI.BBDP-Iddm1,Iddm2 (ACI.1u.Lyp). It is flanked by Iddm32 and Iddm33, which control the kinetics of disease progression. To fine-map Iddm26 and characterize immune phenotypes controlled by this locus, several congenic sublines were generated carrying smaller, overlapping intervals spanning Iddm26 and fragments of Iddm32 and 33. Analysis of disease susceptibility, age of disease onset, and immune phenotypes in these sublines identified subloci regulating these different parameters. Two ACI.1u.Lyp-derived subloci, Iddm26.1 and Iddm26.2, imparted significant protection from diabetes, decreasing the cumulative incidence by as much as 57% and 28%, respectively. Iddm26.2, which overlaps with the human PTPN22 locus, only affected disease susceptibility, whereas Iddm26.1 also significantly affected disease kinetics, delaying T1D onset by more than 10 days compared with the parental BBDP strain. These Iddm26 subloci also regulated various immune phenotypes, including the proportion of splenic macrophages by Iddm26.1, and the proportion of activated T-cells in secondary lymphoid organs by Iddm26.2. The analysis of Iddm26 congenic animals in two different SPF facilities demonstrated that the influence of this locus on T1D is environment-dependent.

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Acknowledgements

We thank K Kathirkamathamby for providing us with mAbs used in the immune phenotyping analysis, and the Sunnybrook Comparative Research Facility and the OCI Animal Resource Centre for the care and maintenance of our animal colonies. This work was supported by grants from the Canadian Institutes of Health Research (64216 and MOP77713), Genome Canada (administered by Ontario Genomics Institute) and the Juvenile Diabetes Research Foundation (17-2011-520). JS was supported by studentships from the Canadian Institutes of Health Research and the Banting and Best Diabetes Centre.

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Authors and Affiliations

  1. Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    J Sarmiento, G Y C Chao & P Poussier

  2. Sunnybrook Research Institute, Biological Sciences Platform, Toronto, Ontario, Canada

    J Sarmiento, R H Wallis, T Ning, L Marandi, G Y C Chao & P Poussier

  3. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    A D Paterson

  4. Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada

    A D Paterson

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  1. J Sarmiento
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Correspondence to P Poussier.

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Sarmiento, J., Wallis, R., Ning, T. et al. Genetic dissection of Iddm26 in the spontaneously diabetic BBDP rat. Genes Immun 15, 378–391 (2014). https://doi.org/10.1038/gene.2014.29

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