NOD2/CARD15 GENE ALLELIC VARIATION IN CROHNʼS DISEASE

Abstract

Purpose: Limited information exists on the specific associations between each of the three major NOD2/CARD15 gene allelic variants (G908R, L1007fs, and R702W) and different Crohn's disease (CD) characteristics. We sought to assess the specific associations between each of the 3 variants and Crohn's disease clinical features. Methods: Using our IBD database we identified CD pts who had genetic testing. 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), median age 36 (15–81) had genetic testing. Other characteristics included: 95% Caucasians; 36% with history of current or past smoking; 21% with a family history of IBD. 114 pts (64%) had ileal involvement, 9 (5%) had upper GI tract involvement & 55 (31%) had only colonic disease. Disease phenotype was fistulizing in 67 pts (38%), stricturing in 25 (14%) and inflammatory in 86 (48%). 60 pts (34%) had at least a single mutation: 47 with one allelic variant (7 G908R, 15 L1007fs, 25 R702W), 3 homozygous for L1007fs & 1 for R702W and 9 were compound heterozygous. G908R heterozygosity was associated with ileal involvement (OR 1.9; 95% CI: 1.2-5.6) while L1007fs homozygosity was associated with upper GI involvement (OR 44; 95% CI: 16–112). There was no association between R702W mutation and any of the characteristics assessed. Compound heterozygosity was associated with ileal and upper GI involvement (OR 4.8 & 9.7; CI: 1.2-10.4 & 1.8-42.2 respectively), fistulizing and stricturing disease (OR 1.8 & 4.1; CI: 1.1-4.7 & 1.6-9.6 respectively). Among the 14 pts with G908R variant 10 (71%) were current or past smokers compared to 31% among pts without this variant. (OR 3.8; 95% CI: 1.2-7.6). There was no significant difference in the rates of current/past smoking among pts with either L1007fs or R702W variants and pts without these variants (44%, 38% and 33% respectively; p = ns). Conclusions: G908R heterozygosity is associated with ileal involvement while L1007fs homozygosity or the presence of any two allelic variants is strongly associated with upper GI involvement. CD pts with the G908R allelic variant are more likely to be current or past smokers. This strong association suggests a possible gene-environment interaction where smoking may play a role in the development of CD in subjects with G908R variant.