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OBJECTIVES: Three variants of the CARD15/NOD2 gene (SNP8, SNP12, and SNP13) have been associated with Crohn's disease (CD). We assessed the impact of NOD2 variants on the CD risk across diverse populations and examined possible associations with disease phenotype.METHODS: We performed a metaanalysis searching MEDLINE and EMBASE (last search 05/2004) and contacting field experts.RESULTS: Forty-two eligible studies contributed data on 206 comparisons. No variants were detected in Asians. In non-Jewish descent Caucasians carriage of SNP8, SNP12, or SNP13 had an odds ratio (OR) for CD of 2.20 (95% CI: 1.84–2.62), 2.99 (95% CI: 2.38–3.74), and 4.09 (95% CI: 3.23–5.18), respectively. For Jewish descent patients the corresponding ORs were 1.74, 1.93, and 2.45, respectively. The OR in carriers of at least two alleles was 17.1 (95% CI: 10.7–27.2). Large studies tended to yield more conservative estimates than smaller studies, so publication or other bias cannot be excluded. Among CD patients, carrying at least one high-risk variant increased slightly the risk for familial disease (OR = 1.49, (95% CI: 1.18–1.87)), modestly the risk of stenosing CD (OR = 1.94, (95% CI: 1.61–2.34)), and more prominently the risk of small bowel involvement (OR = 2.53, (95% CI: 2.01–3.16)).CONCLUSIONS: SNP8, SNP12, and SNP13 have differential effects on CD risk, with SNP13 having the strongest genetic effect. These NOD2 variants are also significant risk factors for CD phenotype, in particular ileal location.