Nature Genetics
4, 404 - 409 (1993)
doi:10.1038/ng0893-404
Polygenic control of autoimmune diabetes in nonobese diabetic miceS. Ghosh1, 5, S.M. Palmer1, N.R. Rodrigues1, H.J. Cordell1, C.M. Hearne1, R.J. Cornall1, J.-B. Prins1, P. McShane1, G.M. Lathrop2, L.B. Peterson3, L.S. Wicker4
& J.A. Todd1
1Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
2INSERM U 358, 27 Rue Juliette Dodu, 75010 Paris, France
3Department of Cellular and Molecular Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
4Autoimmune Diseases Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA
5Present address: Department of Internal Medicine, Division of Medicine and Genetics, University of Michigan, Ann Arbor, Michigan 48109-0652, USA Partial exclusion mapping of the nonobese (NOD) diabetic mouse genome has shown linkage of diabetes to at least five different chromosomes. We have now excluded almost all of the genome for the presence of susceptibility genes with fully recessive effects and have obtained evidence of linkage of ten distinct loci to diabetes or the pre−diabetic lesion, insulitis, indicative of a polygenic mode of inheritance. The relative importance of these loci and their interactions have been assessed using a new application of multiple polychotomous regression methods. A candidate disease gene, interleukin−2 (Il−2), which is closely linked to insulitis and diabetes, is shown to have a different sequence in NOD, including an insertion and a deletion of tandem repeat sequences which encode amino acid repeats in the mature protein.
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