Cannabinoid Receptor 2 Functional Variant Contributes to the Risk for Pediatric Inflammatory Bowel Disease

GOALS: We conducted a case-control association analysis to establish the role of a common CB2 functional variant, Q63R, in the susceptibility to inflammatory bowel disease (IBD). BACKGROUND: Endocannabinoids may limit intestinal inflammation through cannabinoid receptor 1 and/or 2 (CB1, CB2). STUDY: We genotyped 217 pediatric IBD patients [112 Crohn's disease (CD), 105 ulcerative colitis (UC)] and 600 controls for the CB2-Q63R variant by Taqman assay. Data were collected from clinical records on age at diagnosis, disease activity, duration and location, extraintestinal manifestations, therapy, clinical relapses, and need for surgery. RESULTS: We found a significant association of the CB2-R63 variant with IBD (allele frequencies, P=0.04; genotype distributions, P=0.0006), in particular with CD (allele frequencies, P=0.002; genotype distributions, P=0.00005) and with UC only for genotype distributions (P=0.03). RR carriers showed an increased risk for developing IBD [odds ratio (OR)=1.82; P=0.0002 for IBD; OR=2.02; P=10 for CD; OR=1.63; P=0.02 for UC at 95% confidence interval]. Upon genotype-phenotype evaluation, RR patients showed an increased frequency of moderate-to-severe disease activity at diagnosis in the case of both CD and UC (P=0.01 and P=0.02, respectively) and also an earlier clinical relapse in UC (P=0.04). In UC, all the clinical features related to the CB2 risk allele were still significantly associated with the variant when analyzed using a multivariate logistic regression model (P=0.001). CONCLUSIONS: The CB2-Q63R variant contributes to the risk for pediatric IBD, in particular CD. The R63 variant is associated with a more severe phenotype in both UC and CD. Taken together, our data point toward the involvement of the CB2 receptor in the pathogenesis and clinical features of pediatric IBD.