[NOD2/CARD15 mutations and genotype-phenotype correlations in patients with Crohn's disease. Hungarian multicenter...

Recently mutations of the NOD2/CARD15 gene were identified as genetic markers for Crohn's disease (CD). It has also been suggested that the presence of mutation may influence the phenotype of the disease. The aim of this study was to determine the frequency of common NOD2/CARD15 mutations in Hungarian Crohn's patients.

DNA was obtained from 142 pts with Crohn's disease (70 male and 72 female, mean age: 36.2 yrs) and of 115 healthy subjects. Clinical data were obtained by filling in a questionnaire by the physician. DNA was screened for possible mutations by denaturing HPLC (WAVE Nucleic acid fragment analysis systems, Cheshire, UK) using published primers (Lesage et al, Am J Hum Gen 2002) for SNP's 8, 12, and 13. Mutations were then confirmed by direct sequencing on a ABI Prism 310 Genetic Analyzer (Perkin Elmer; Norwalk, USA).

Mutations of NOD2/CARD15 were significantly more frequent in patients (n = 42, 29.6%) than in controls (11.3%, p = 0.0007, OR = 3.3, 95% CI = 1.7-6.5). R702W and 3020insC mutations were significantly more common in IBD compared to controls (4.3% and 2.6%); 18 patients had the R702W mutation (12.7%, p = 0.001, 13 homozygous, one homozygous for R703C) and 22 the 3020insC (15.9%, p = 0.001, 4 homozygous). 7 patients (4.9%) were heterozygous for the G908R, which was not different from the controls (4.3%). 5 patients were compound heterozygous. The allele frequency of R702W (11.6% vs. 4.3%, p = 0.0026, OR = 5.9, 95% CI: 2.3-14.9) and 3020insC (9.1% vs. 2.6% p = 0.004, OR = 7.6, 95% CI = 2.4-24.0) was significantly higher in Crohn's disease compared to the controls. Age at presentation was not different between carriers and non-carriers (26.7 +/- [SD] 10.3 yrs vs. 27.7 +/- 11.8 yrs). There was a tendency of ileal location to be more common in carriers of the mutation (40.5% vs. 29.0%), while colonic location was less frequent (16.7% vs. 44%). The presence of the mutation did not affect disease behaviour (carrier: inflammatory: 30.9%, stenosing: 26.2%, penetrating: 42.9%, non-carrier: inflammatory: 36%, stenosing: 27%, penetrating: 37%). Among the extraintestinal manifestations arthritis (30.1% vs. 47%, p = 0.05) and primary sclerosing cholangitis (0% vs. 9%, p = 0.047%) was significantly less frequent in carriers of the mutation.

In concordance with European data we found a high number of NOD2/CARD15 R702W and 3020insC mutations in Hungarian patients with Crohn's disease. The G908R mutation was uncommon in Hungarian Crohn's patients. The presence of the mutation was associated with ileal but not with fibrostenosing disease and extraintestinal manifestations were less common in carriers of the mutation.