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Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease


Crohn's disease1,2 and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped3 to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

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Figure 1: Strategy used to identify the IBD1 locus.
Figure 2: Representation of the IBD1/NOD2 protein variants.

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  1. Calkins, B. M. & Mendelhoff, A. I. in Inflammatory Bowel Disease (eds Kirsner, J. B. & Shorter, R. G.) 31–68 (Williams & Wilkins, Baltimore, 1995).

    Google Scholar 

  2. Hugot, J. P., Zouali, H., Lesage, S. & Thomas, G. Etiology of the inflammatory bowel diseases. Int. J. Colorectal Dis. 14, 2–9 (1999).

    Article  CAS  Google Scholar 

  3. Hugot, J. P. et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 379, 821–823 (1996).

    Article  ADS  CAS  Google Scholar 

  4. Olavesen, M. G. et al. Analysis of single-nucleotide polymorphisms in the interleukin-4 receptor gene for association with inflammatory bowel disease. Immunogenetics 51, 1–7 (2000).

    Article  CAS  Google Scholar 

  5. Hugot, J. P. et al. Mutation screening in the CD19 and CD43 (sialophorin) genes in Crohn Disease patients. Gastroenterology 116, A740 (1999).

    Google Scholar 

  6. Zouali, H. et al. Refined mapping of the inflammatory bowel disease 1 gene. Eur. J. Hum. Genet. (submitted).

  7. Spielman, R. S., McGinnis, R. E. & Ewens, W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Martin, E. R., Monks, S. A., Warren, L. L. & Kaplan, N. A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am. J. Hum. Genet. 67, 146–154 (2000).

    Article  CAS  Google Scholar 

  9. Kuster, W., Pascoe, L., Purrmann, J., Funk, S. & Majewski, F. The genetics of Crohn's disease: complex segregation analysis of a family study with 265 patients with Crohn's disease and 5387 relatives. Am. J. Med. Genet. 32, 105–108 (1989).

    Article  CAS  Google Scholar 

  10. Monsen, U., Iselius, L. & Hellers, G. Evidence for a recessive gene in Crohn's disease. Acta Chir. Scand. 559 (suppl.), 7–42 (1990).

    Google Scholar 

  11. Orholm, M. et al. Investigation of inheritance of chronic inflammatory bowel disease by complex segregation analysis. Br. Med. J. 306, 20–24 (1993).

    Article  CAS  Google Scholar 

  12. Colombel, J. F. et al. Clinical characteristics of Crohn's disease in 72 families. Gastroenterology 111, 604–607 (1996).

    Article  CAS  Google Scholar 

  13. The IBD International Genetics Consortium. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am. J., Hum. Genet. 68, 1165–1171 (2001).

    Article  Google Scholar 

  14. Ogura, Y. et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kB. J. Biol. Chem. 276, 4812–4818 (2001).

    Article  CAS  Google Scholar 

  15. Inohara, N., Ogura, Y., Chen, F. F., Muto, A. & Nuñez, G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J. Biol. Chem. 276, 2551–2554 (2001).

    Article  CAS  Google Scholar 

  16. Inohara, N. et al. Nod 1, an Apaf-1-like activator of caspase-9 and nuclear factor kB. J. Biol. Chem. 274, 14560–14567 (1999).

    Article  CAS  Google Scholar 

  17. Bertin, J. et al. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kB. J. Biol. Chem. 274, 12955–12958 (1999).

    Article  CAS  Google Scholar 

  18. Inohara, N. et al. An induced proximity model for NF-kB activation in the Nod1/RICK and RIP signaling pathways. J. Biol. Chem. 275, 27823–27831 (2000).

    CAS  PubMed  Google Scholar 

  19. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  ADS  CAS  Google Scholar 

  20. Sundberg, J. P., Elson, C. O., Bedigian, H. & Birkenmeier, E. H. Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice. Gastroenterology 107, 1726–1735 (1994).

    Article  CAS  Google Scholar 

  21. McKay, D. M. Intestinal inflammation and the gut microflora. Can. J. Gastroenterol. 13, 509–516 (1999).

    Article  CAS  Google Scholar 

  22. Schreiber, S., Nikolaus, S. & Hampe, J. Activation of nuclear factor kB in inflammatory bowel disease. Gut 42, 477–484 (1998).

    Article  CAS  Google Scholar 

  23. Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. & Karin, M. Immunosuppression by glucocorticoids: inhibition of NF-kB activity through induction of IκB synthesis. Science 270, 286–290 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Wahl, C., Liptay, S., Adler, G. & Schmid, R. M. Sulfasalazine: a potent and specific inhibitor of nuclear factor κB. J. Clin. Invest. 101, 1163–1174 (1998).

    Article  CAS  Google Scholar 

  25. Satsangi, J. et al. Two stage genome wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosome 3, 7 and 12. Nature Genet. 14, 199–202 (1996).

    Article  CAS  Google Scholar 

  26. Hampe, J. et al. Linkage of inflammatory bowel disease to Human chromosome 6p. Am. J. Hum. Genet. 65, 1647–1655 (1999).

    Article  CAS  Google Scholar 

  27. Cho, J. H. et al. Linkage and linkage disequilibrium in chromosome band 1p36 in American Chaldeans with inflammatory bowel disease. Hum. Mol. Genet. 9, 1425–1432 (2000).

    Article  CAS  Google Scholar 

  28. Duerr, R. H., Barmada, M. M., Zhang, L., Pfutzer, R. & Weeks, D. E. High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12. Am. J. Hum. Genet. 66, 1857–1862 (2000).

    Article  CAS  Google Scholar 

  29. Rioux, J. D. et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am. J. Hum. Genet. 66, 1863–1870 (2000).

    Article  CAS  Google Scholar 

  30. Lennard-Jones, J. E. Classification of inflammatory bowel disease. Scand. J. Gastroenterol. 170 (suppl.), 2–6 (1989).

    Article  CAS  Google Scholar 

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We acknowledge patients and their families, and thank family recruitment doctors: J. Balanzo, B. Bonaz, Y. Bouhnik, G. Cadiot, S. Cucchiara, B. Crusius, J. J. Delchier, B. Duclos, J. L. Dupas, J. P. Galmiche, J. P. Gendre, D. Golfain, C. Grännö, D. Heresbach, A. Lachaux, H. Lautraite, C. Lenaerts, E. Lerebours, V. Levy, R. Löfberg, H. Malchow, P. Marteau, A. Morali, F. Pallone, S. Pena, A. Rotenberg, I. Rousseau, J. Schmitz, F. Shanahan, I. Sobhani, H. Svensson, A. Van Gossum, M. Van Winckel and M. Veyrac. For assistance we are grateful to J. C. Beaudoin, F. Chareyre, C. Giudicelli, T. Hung Bui, M. Legrand, A. Marcadet, A. Martins. C. de Toma, E. Tubacher. We thank H. Cann for critically reading the manuscript. This project received support from European Community, MENRT, INSERM, Direction Générale de la Santé, Association François Aupetit, IRMAD and the Swedish Society of Medicine.

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Correspondence to Gilles Thomas.

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Hugot, JP., Chamaillard, M., Zouali, H. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

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