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

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          Abstract

          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-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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          Author and article information

          Journal
          Nature
          Nature
          Springer Science and Business Media LLC
          0028-0836
          0028-0836
          May 31 2001
          : 411
          : 6837
          Affiliations
          [1 ] Fondation Jean Dausset CEPH, 27 rue J. Dodu 75010 Paris, France.
          Article
          35079107
          10.1038/35079107
          11385576
          713a78ad-e2d7-4da2-8857-b705ed4ecc0f

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