Gastroenterology

Gastroenterology

Volume 123, Issue 3, September 2002, Pages 679-688
Gastroenterology

Clinical–Alimentary Tract
Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease☆,☆☆,★

https://doi.org/10.1053/gast.2002.35393Get rights and content

Abstract

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 CD have been described recently and may alter innate immune responses. We hypothesized that NOD2 mutations may be associated with distinct phenotypic expressions of CD. 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 2001) 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 CD-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, 1.6–5.2). 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 CD patients and NOD2 variants, data suggest that variation in this gene contributes to the occurrence of fibrostenotic CD of the small bowel.

GASTROENTEROLOGY 2002;123:679-688

Section snippets

Human subjects

Two cohorts of patients were examined in this study. Both cohorts were consecutively identified as CD patients from an IBD referral center (Cedars–Sinai Medical Center Inflammatory Bowel Disease Center). The first cohort (n = 142) was ascertained between 1993 and 1996 and has been previously described.2 The second cohort (n = 59) was collected between 1999 and 2001. Thus, the study population consisted of 201 consecutively ascertained patients evaluated by the Cedars–Sinai Medical Center

Patients with Crohn's disease have an increased frequency of rare allelic variants of NOD2

An association between CD and allelic variants of NOD2 has been previously described.21, 22, 23 All 3 studies identified an association between CD and an insertion polymorphism in NOD2, 3020insC or 980fs (SNP 13), but only the Hugot et al. study21 further identified 2 missense mutations, R675W (SNP 8) and G881R (SNP 12). We first wished to determine whether our North American CD referral patient population exhibited similar allelic variants of NOD2 and could serve as a relevant population in

Discussion

CD is a multigenic disorder with diverse clinical manifestations. Several population-based studies have described an association of NOD2 gene mutations in CD.21, 22, 23 This study describes a genotype/phenotype association for NOD2 allelic variants in CD. Specifically, we describe an association between the presence of NOD2 mutations and small-bowel stricturing CD. Both the genetic association and its phenotypic association with fibrostenosis was observed in Jews and non-Jews with similar

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    ☆

    Address requests for reprints to: Maria T. Abreu, M.D., Inflammatory Bowel Disease Center, Cedars–Sinai Medical Center, 8631 West 3rd Street, Suite 245E, Los Angeles, California 90048. e-mail: [email protected]; fax: (310) 423-0147.

    ☆☆

    Supported by grants DK 46763 and DK 54967, the Cedars–Sinai Board of Governors' Chair in Medical Genetics, and the Feintech Family Chair in Inflammatory Bowel Disease.

    ★

    Drs. Targan, Landers, and Vasiliauskas are Prometheus stockholders.

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    Copyright © 2002 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.