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

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

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

  2. 2

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

  3. 3

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

  4. 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).

  5. 5

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

  6. 6

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

  7. 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).

  8. 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).

  9. 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).

  10. 10

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

  11. 11

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

  12. 12

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

  13. 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).

  14. 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).

  15. 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).

  16. 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).

  17. 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).

  18. 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).

  19. 19

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

  20. 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).

  21. 21

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

  22. 22

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

  23. 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).

  24. 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).

  25. 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).

  26. 26

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

  27. 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).

  28. 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).

  29. 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).

  30. 30

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

Download references

Acknowledgements

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.

Author information

Correspondence to Gilles Thomas.

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.