Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients

Abstract

Ulcerative colitis (UC) and Crohn's disease (CD) are heterogeneous disorders characterized by chronic intestinal inflammation. Genetic predisposition is a major risk factor in both diseases. The CARD15 (NOD2) gene has been implied as a candidate gene in the pathogenesis CD. Our aim was to delineate the frequency of three missense and one frameshift variant of CARD15 in Israeli Jewish CD and UC patients. DNA was extracted from blood samples from 238 unrelated inflammatory bowel disease (IBD) patients, 68 with UC and 170 with CD. The DNA was genotyped for two missense mutations, R675W and G881R, and one frameshift mutation, 980FS981X. Mutations in CARD15 were observed with significantly greater frequency in CD patients (46/170, 27%) than in UC patients (7/68, 10%) (P = 0.005). Homozygous and compound heterozygous carriers were restricted to seven (4%) patients with CD as compared to none of the UC patients (P = 0.01). Similar rates in Ashkenazi and non-Ashkenazi Jewish patients were observed. Age-of-onset of disease was lower in Ashkenazi mutation carriers as compared to non-carriers of Ashkenazi origin (18.7 +/- 8.6 years vs. 25.8 +/- 13.4 years, respectively, P = 0.03). No other phenotypic characteristics could distinguish mutation carriers from non-carriers. We conclude that germline mutations in the CARD15 gene are more frequently found in CD than UC patients and appear to predict an earlier age-of-onset in Ashkenazi Jewish patients. No association could be demonstrated between CARD15 mutations and specific disease course or behavior.

Is Age of Onset of Crohn's Disease Governed by Mutations in NOD2/Caspase Recruitment Domains 15 and Toll-Like Receptor 4? Evaluation of a Pediatric Cohort

“…Carriage of fs1007 in our population was uncommon, and homozygotes for fs1007 or R702W were exceedingly rare in our population. This has also been noted in previous studies from Israel from our group and others (31,34,35), so in any case, these mutations or double-dose NOD2/CARD15 mutations do not explain early AOO in the vast majority of cases in our population.…”

Response to Medical Treatment in Patients with Crohn’s Disease: The Role of NOD2/CRAD15, Disease Phenotype, and Age of Diagnosis

“…All patients underwent colonoscopy and either upper gastrointestinal series with small bowel follow-through or abdominal CT-enterography. All patients had been part of previous studies testing for the three NOD2/CARD15 mutations associated with CD: G908R, R702W, and 1007fs [12][13][14]. The previous genetic analysis and this study were approved by the ethical committee of the participating centers.…”

Familial Mediterranean fever—A review

“…Mutations in the gene NOD2/CARD15 are also associated with CD. 109 However, some studies have found an increased frequency of MEFV mutations in persons with UC, especially those with episodic arthritis, and this may suggest a possible modifying effect of MEFV in the disease process. 21,110,111 Other studies have found that CD seems to be more prevalent in FMF and presents later than in patients without FMF.…”