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Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease

Abstract

Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease1. We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10−4). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease (P<2×10−7) and contains the cytokine gene cluster. This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence—each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.

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Figure 1: Linkage and LD mapping.
Figure 2: Multilocus haplotype results.
Figure 3: Multipoint T/U plot for the IBD5 risk haplotype.

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Acknowledgements

The authors would like to thank the following individuals for their invaluable participation in the patient sample collection: G. Wild, A. Watier, P. Pare, L. Dion, M.-L. Bernier, J. Rivard, J. Letourneau, J. Delisle, L. Lapierre and D. Lafrance. The authors would also like to thank L. Gaffney for her help in the preparation of this manuscript. This work was supported by the Crohn's and Colitis Foundation of Canada, the McGill Inflammatory Bowel Disease Network, and the Canadian Genetic Diseases Network, and by research grants from Bristol-Myers Squibb, Millennium Pharmaceutical, Affymetrix and Ellipsis Biotherapeutics Corporation. K.A.S. is a Senior Scientist of the Canadian Institutes for Health Research, M.S.S. is a fellow of the Canadian Association of Gastroenterology and the Canadian Institutes of Health Research, S.B.B. is a Scholar of the National Health Research Development Programme , A.B. is a Research Scholar of the Fonds de la Recherche en Santé du Quebec and T.J.H. is recipient of a Clinician Scientist Award from the Canadian Institutes for Health Research.

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Correspondence to John D. Rioux, Eric S. Lander, Katherine A. Siminovitch or Thomas J. Hudson.

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Rioux, J., Daly, M., Silverberg, M. et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 29, 223–228 (2001). https://doi.org/10.1038/ng1001-223

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