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NOD2/CARD15 Mutations and Presence of Granulomas in Pediatric and Adult Crohn’s Disease

Shaoul, Ron MD*; Karban, Amir MD; Weiss, Batia MD; Reif, Shimon MD; Wasserman, Dror MD; Pacht, Avi MD§; Eliakim, Rami MD; Wardi, Joram MD||; Shirin, Haim MD**; Wine, Eitan MD; Leshinsky-Silver, Esther PhD**; Levine, Arie MD

Original Article

Objectives: The etiology and mechanism leading to granuloma formation in patients with Crohn’s disease (CD) are presently unknown. The first susceptibility gene to be identified as a risk factor for CD is the NOD2/CARD15 gene on Chromosome 16. Mutations in NOD2 could affect the intracellular response to bacterial products and may eventually lead to granuloma formation. The association between NOD2 and granulomas has not been previously explored. We evaluated a possible association between NOD2 mutations and granuloma formation, and compared the prevalence of granulomas in both pediatric and adult cohorts.

Methods: Patients were consecutively recruited through pediatric gastroenterology and adult gastroenterology programs. Patients were eligible if CD was confirmed, and they had undergone full colonoscopy with biopsy and/or surgical resection. Patients underwent genotyping for NOD2 disease-associated mutations.

Results: A total of 230 patients were enrolled into the study, of whom 169 patients met all inclusion/exclusion criteria (Group 1, 77 patients [age range 1–16 years]; Group 2, 92 patients [age range 17–68 years]). Surgical resection was performed more often in adults (P < 0.005), and gastroscopy was performed more frequently in children (P < 0.001). Granulomas were found in 34% of the patients studied. The prevalence of granulomas did not differ by age, age group, or gender. A disease-associated NOD2 mutation was found in 37.8% of patients. Granulomas were found in 39% of patients with NOD2 mutations compared with 31% of those without NOD 2 mutations (difference was not significant). In addition, no difference was noted for the specific mutations.

Conclusions: We did not find any correlation between NOD2 mutations and granuloma formation. The cause of granulomas in CD remains elusive.

From the *Bnei Zion Medical Center, Haifa, Israel; the †Pediatric and Adult Gastroenterology Divisions of the Rambam Medical Center, Haifa, Israel; the ‡Dana Medical Center, Tel Aviv, Israel; the §Carmel Medical Center, Haifa, Israel; and the ||Molecular Genetics Laboratory and ¶Pediatric Gastroenterology Units, **E. Wolfson Medical Center, Holon, Israel.

Received for publication February 10, 2004; accepted June 10, 2004.

Reprints: Arie Levine, MD, Director, Pediatric Gastroenterology Unit, E. Wolfson Medical Center, POB 5, Holon, Israel 58100 (e-mail: or

© Crohn's & Colitis Foundation of America, Inc.
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