Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease

Background & Aims: The clinical manifestations of Crohn's disease (CD) are diverse, ranging from fibrostenosing small-bowel disease to colon-predominant inflammation. These distinctions may represent genetic, immunologic, and microbial heterogeneity. NOD2 gene mutations in CID have been described recently and may alter innate immune responses. We hypothesized that NOD2 mutations may be associated with distinct phenotypic expressions of CID. Methods: Two cohorts of consecutively identified patients referred to an inflammatory bowel disease center (n = 142 collected between 1993 and 1996; n = 59 collected between :1999 and 200:1) were genotyped for 3 single nucleotide variants of NOD2-R675W, G881R, and 3020insC-and phenotyped for disease behavior, disease location, and serum immune markers. Results: Univariate analysis showed that CID-associated NOD2 variants were significantly associated with fibrostenosing disease in each cohort (P = 0.049 and P = 0.002, respectively). When both cohorts were analyzed together, the association between NOD2 variants and fibrostenosing disease was more significant (P = 0.001). These relationships were observed in both Jews and non-Jews. Forty-six percent of patients with fibrostenosing disease carried at least 1 of these alleles, compared with only 23.5% of patients without fibrostenosing disease (odds ratio, 2.8; 95% confidence interval, 16-5.2). Multivariate and conditioning analyses showed a primary association between NOD2 allelic variants and fibrostenosing disease, but not with small-bowel disease. Conclusions: In this description of a genotype/phenotype correlation in CID patients and NOD2 variants, data suggest that variation in this gene contributes to the occurrence of fibrostenotic CID of the small bowel.