Abstract
Type 1 diabetes (T1D; or insulin-dependent diabetes mellitus, IDDM) is an autoimmune disease with both genetic and environmental components. In addition to the human leukocyte antigen (HLA) complex, the single major genetic contributor of susceptibility1, an unknown number of other unidentified genes are required to mediate disease. Although many loci conferring susceptibility to T1D have been mapped2, their identification has proven problematic3 due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci implicated in diabetes-prone NOD (non-obese diabetic) mice, together with application of biologically relevant stratification methods4. We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B. Significant bias in transmission of IL12B alleles was observed in affected sibpairs and was confirmed in an independent cohort of simplex families. A single base change in the 3′ UTR showed strong linkage disequilibrium with the T1D susceptibility locus. The IL12B 3′ UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases.
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Acknowledgements
We thank E. Dawe, K. Davies and S. Lopaticki for purification and some genotyping of DNA samples; M. Craig, M. Silink and J. Couper for recruiting T1D families from their clinics; and E. Martin for providing the Tsp program. This work was supported by the National Health and Medical Research Council of Australia and by a Special Program Grant from the Juvenile Diabetes Foundation International and the NHMRC. S.Y. and S.L. were supported by the Collaborative Research Centre for Discovery of Genes for Common Human Diseases.
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Morahan, G., Huang, D., Ymer, S. et al. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet 27, 218–221 (2001). https://doi.org/10.1038/84872
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DOI: https://doi.org/10.1038/84872
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