Letters to Nature

Nature 411, 599-603 (31 May 2001) | doi:10.1038/35079107; Received 5 February 2001; Accepted 30 March 2001

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

Jean-Pierre Hugot1,2,3, Mathias Chamaillard1,2, Habib Zouali1, Suzanne Lesage1, Jean-Pierre Cézard3, Jacques Belaiche4, Sven Almer5, Curt Tysk6, Colm A. O'Morain7, Miquel Gassull8, Vibeke Binder9, Yigael Finkel10, Antoine Cortot11, Robert Modigliani12, Pierre Laurent-Puig2, Corine Gower-Rousseau11, Jeanne Macry13, Jean-Frédéric Colombel11, Mourad Sahbatou1 & Gilles Thomas1,2,14

  1. Fondation Jean Dausset CEPH, 27 rue J. Dodu 75010 Paris, France
  2. INSERM U434, 27 rue J. Dodu 75010 Paris, France
  3. PEWG-IBD, Department of Paediatric Gastroenterology, Hôpital Robert Debré, 75019 Paris, France
  4. GETAID and Department of Gastroenterology, CHU de Liège, 4000 Belgium
  5. Division of Gastroenterology and Hepatology, IHM, Linköpings Universitet, SE-581 85 Linköping, Sweden
  6. Department of Gastroenterology, Örebro Medical Center Hospital, SE-701 85 Örebro, Sweden
  7. Department of Gastroenterology, Adelaide & Meath Hospital, Dublin 24, Ireland
  8. Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, 08916 Spain
  9. Department of Gastroenterology Herlev Hospital, 2730 Herlev, Denmark
  10. Astrid Lindgren Children's Hospital, SE-161 76 Stockholm, Sweden
  11. Registre EPIMAD, Hôpital Calmette, 59037 Lille, France
  12. Department of Gastroenterology, Hopital Saint Louis, 75475 Paris, France
  13. INSERM U458, Hôpital Robert Debré, 75019 Paris, France
  14. Department of Surgery, Hôpital Saint Antoine, 75012 Paris, France

Correspondence to: Gilles Thomas1,2,14 Correspondence and requests for materials should be addressed to G.T. (e-mail: Email: thomas@cephb.fr).

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.