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

Crohn's disease(1,2) and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiol ogy. A susceptibility locus for Crohn's disease has been mapped(3) to chrom osome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three ind ependent associations for Crohn's disease: a frameshift variant and two mis sense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily o f 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 activati ng function is regulated by the carboxy-terminal leucine-rich repeat domain , which has an inhibitory role and also acts as an intracellular receptor f or components of microbial pathogens. These observations suggest that the N OD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocyte s, thus documenting a molecular model for the pathogenic mechanism of Crohn 's disease that can now be further investigated.