UPPER GASTROINTESTINAL INVOLVEMENT IN PATIENTS WITH CROHNʼS DISEASE IS STRONGLY ASSOCIATED WITH DOUBLE DOSE OF THE NOD2/CARD15 ALLELIC VARIANTS

Abstract

Purpose: To assess the frequency and association between upper gastrointestinal (UGI) Crohn's disease (CD) and the 3 major NOD2/CARD15 allelic variants G908R, L1007fs, R702W. Methods: Using our IBD database we identified CD pts with confirmed UGI tract involvement who had genetic testing. Associations and differences were assessed with the Chi-square or Fisher's exact test and Mann-Whitney test. Logistic regression models were conducted to estimate the odd ratios (OR) and 95% confidence intervals (CI) of the associations. Results: Between April 2003 and May 2004 178 pts (79 M & 99 F) had genetic testing. 9 (5%) pts had UGI involvement (3 jejunal and 6 duodenogastric). 4 pts (44%) had fistulizing, 2 (22%) stricturing and 3 (34%) inflammatory phenotypes. Other characteristics include: all Caucasians, 2 females (22%), median age at diagnosis 17 yrs (range 11–31), median disease duration 7 yrs, family history of IBD in 4 (44%) and smoking history in 4 (44%). 3 (33%) pts had wild type NOD2/CARD15 while the other 6 (67%) had 2 allelic variants (3 homozygous for L1007fs, 1 homozygous for R702W, 1 with G908/L1007fs & 1 with R702W/L1007fs). Among pts without UGI involvement the frequency of allelic variation was as follows: 116 (68%) had the wild type, 47 (28%) had one allelic variant, 7 (4%) were compound heterozygous (i.e. 2 different variants) and none were homozygous for the same variant. Compared to pts without UGI involvement, pts with UGI involvement were more likely to have 2 NOD2/CARD15 allelic variants (66% vs 4%; OR 38; 95% CI: 7.7- 92.3), to be homozygous for L1007fs (33% vs 0%; OR 8.4; CI 3.5- 36.9), to have a family history of IBD (44% vs 19%; OR 3.8; 95% CI: 1.2-8.1), to be males (78% vs 41%; OR 5.2; CI: 1.1-14.2) and to be younger at diagnosis (17 vs 25; p = 0.023). There was no significant difference between pts with and without UGI disease with regard to disease phenotype, the frequency of extraintestinal manifestations, smoking history, and median disease duration (7 vs 5 yrs). Pts with UGI involvement were more likely to develop metabolic bone disease (osteopenia or osteoporosis) (33%vs9%;p = 0.016) Conclusions: CD pts with upper GI involvement are more likely to have 2 allelic variants of the NOD2/Card15 gene particularly L1007fs homozygosity. Our data suggest that pts with 2 NOD2/CARD15 allelic variants should be carefully evaluated for upper GI involvement.