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.

CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

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SUMMARY The aim of this study was to develop and validate an endoscopic index for assessing the severity of Crohn's disease. Endoscopic findings were prospectively collected by a multicentre group in 75 patients with Crohn's colitis according to a previously validated procedure. The presence of nine preselected lesions was recorded in the following segments (1) rectum, (2) sigmoid and left colon, (3) transverse colon, (4) right colon, and (5) ileum. In addition the extent of the diseased and ulcerated areas were estimated in each segment. These segmental data were recorded on a standard form, together with the endoscopist's global estimate of lesion severity. A stepwise multiple regression was used to derive an index which was correlated with the endoscopist's global evaluation of lesion severity. Four mucosal lesions: deep and superficial ulcerations, ulcerated and non-ulcerated stenosis, and both estimates of extent involved were selected and weighted to obtain a Crohn's Disease Endoscopic Index of Severity which correlated with the endoscopist's global appraisal of lesion severity (r=0.83). This index was then prospectively shown to be valid in a further series of 113 colonoscopies (r=0-81). The index was calculated in 54 patients with active Crohn's disease, before and at the end of a course of corticosteroids: index variations correctly reflected changes in colitis severity as evaluated by the endoscopists (r=0-72). For endoscopists familiar with the data collection procedure, this Crohn's Disease Endoscopic Index of Severity should be of value in the follow up of patients, especially in clinical trials.Several indices'-3 have been proposed to measure the activity (andlor severity) of Crohn's disease (CD) and used to evaluate drug efficacy in therapeutic trials.45 All these indices are based only on clinical Endoscopists participating the study: