Gastroenterology

Gastroenterology

Volume 122, Issue 4, April 2002, Pages 867-874
Gastroenterology

Rapid Communications
The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease,☆☆,

https://doi.org/10.1053/gast.2002.32415Get rights and content

Abstract

Background & Aims: Mutations in the NOD2 gene are strongly associated with susceptibility to Crohn's disease (CD). We analyzed a large cohort of European patients with inflammatory bowel disease to determine which mutations confer susceptibility, the degree of risk conferred, their prevalence in familial and sporadic forms of the disease, and whether they are associated with site of disease. Methods: Individuals were genotyped for 4 NOD2 mutations: P268S, R702W, G908R, and 3020insC. Allelic transmission distortion to 531 CD– and 337 ulcerative colitis–affected offspring was assessed by the transmission disequilibrium test. Association was also tested in an independent cohort of 995 patients with inflammatory bowel disease and 290 controls. Cases were stratified by disease site and compared across NOD2 genotypes. Results: R702W, G908R, and 3020insC were strongly associated with CD but not with ulcerative colitis. Linkage disequilibrium was observed between P268S and the other mutations, forming 3 independent disease haplotypes. Genotype relative risks were 3.0 for mutation heterozygotes and 23.4 for homozygotes or compound heterozygotes. The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004). Conclusions: The R702W, G908R, and 3020insC mutations are strong independent risk factors for CD and are associated particularly with ileal disease.

GASTROENTEROLOGY 2002;122:867-874

Section snippets

Patient cohorts

Family collections consisted of trios of parents with a single affected offspring or families with at least 2 affected offspring. At least 1 parent was available for genotyping in 82% of families. Patients were recruited from King's College School of Medicine, Guy's Hospital, and St Mark's Hospital (London, England), Charite University Hospital (Berlin, Germany), the Department of General Internal Medicine at the Christian-Albrechts-Universitat (Kiel, Germany), and the Academic Medical Centre

Association of mutations with CD

Sibling pairs from the British/German family cohort have previously shown evidence of linkage to the IBD1 locus on chromosome 16.22 Allelic transmission distortion for 4 SNPs (P268S, R702W, G908R, and 3020insC; see Figure 1) was assessed in this family collection using the TDT.

. Diagram of the genomic structure of the NOD2 gene, the location of the mutations studied, and the predicted structural domains of the encoded protein. CARD, caspase recruitment domain; NBD, nucleotide binding domain; LRR,

Discussion

In this study, a cohort of more than 1200 unrelated cases of IBD has been genotyped for 4 mutations in the coding region of the NOD2 gene to address several questions relating to its contribution to IBD susceptibility. First, we used both TDT analyses and case-control studies to assess which of the mutations are independent risk factors for CD. The P268S, R702W, and 3020insC mutations were strongly associated with CD in the TDT, whereas all 4 mutations were present at a significantly higher

Acknowledgements

The authors thank Drs. J. Lennard-Jones, A. Macpherson, J. Lee, S. Bridger, S. Hodgson, M. Hudson, and S. van Deventer for patient ascertainment and Gillian Scott, Jo Hirst, and Alison Craggs for help in obtaining samples from IBD patients and families.

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    Address requests for reprints to: Christopher G. Mathew, Ph.D., Division of Medical and Molecular Genetics, GKT School of Medicine, King's College London, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, England. e-mail: [email protected]; fax: (44) 207-955-4644.

    ☆☆

    Supported in the United Kingdom by the Wellcome Trust, the Generation Trust, the TR-Golden Charitable Trust, the Kati Jacobs Appeal, Axys Pharmaceuticals Inc., and the Special Trustees of the Royal Victoria Infirmary and by an equipment grant from the Guy's and St. Thomas' Hospitals Charitable Trust. Supported in Germany by the Deutsche Forschungsgemeinschaft (For 423), a Training and Mobility of Research Network grant of the European Union (ERB-4061-PL-97-0389), a competence network “Chronisch-entzündliche Darmerkrankungen,” the German Human Genome Project, and the National Genome Research Network (all funded by the German Federal Department for Research and Education).

    A.P.C. and S.A.F. contributed equally to this work.

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