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

Jean Pierre Hugot, Mathias Chamaillard, Habib Zouali, Suzanne Lesage, Jean Pierre Cézard, Jacques Belaiche, Sven Almer, Curt Tysk, Colm A. O'morain, Miquel Gassull, Vibeke Binder, Yigael Finkel, Antoine Cortot, Robert Modigliani, Pierre Laurent-Puig, Corine Gower-Rousseau, Jeanne Macry, Jean Frédéric Colombel, Mourad Sahbatou, Gilles Thomas

Research output: Contribution to journalArticlepeer-review

4790 Scopus citations


Crohn's disease 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 mapped 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-κB; 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-κB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Original languageEnglish
Pages (from-to)599-603
Number of pages5
Issue number6837
StatePublished - 31 May 2001
Externally publishedYes


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