The Functional-765G→C Polymorphism of the COX-2 Gene May Reduce the Risk of Developing Crohn's Disease

Background: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the conversion of arachidonic acid into prostaglandins. COX-2 is mainly induced at sites of inflammation in response to proinflammatory cytokines such as interleukin-1 alpha/beta, interferon-gamma and tumor necrosis factor-alpha produced by inflammatory cells. Aim: The aim of this study was to investigate the possible modulating effect of the functional COX-2 polymorphisms -1195 A -> G and -765G -> C on the risk for development of inflammatory bowel disease (IBD) in a Dutch population. Methods: Genomic DNA of 525 patients with Crohn's disease (CD), 211 patients with ulcerative colitis (UC) and 973 healthy controls was genotyped for the -1195 A -> G (rs689466) and -765G -> C (rs20417) polymorphisms. Distribution of genotypes in patients and controls were compared and genotype-phenotype interactions were investigated. Results: The genotype distribution of the -1195A -> G polymorphism was not different between the patients with CD or UC and the control group. The -765GC genotype was more prevalent in CD patients compared to controls with an OR of 1.33 (95% CI 1.04-1.69, p < 0.05). The -765GC and -765CC genotype carriers showed a tendency to be less frequent in patients with CD compared to controls, with ORs of 0.78 (95% CI: 0.61-1.00) and 0.49 (95% CI 0.22-1.08), respectively. Combining homozygous and heterozygous patients with the -765C allele showed a reduced risk for developing CD, with an OR of 0.75 (95% CI: 0.59-0.96). In the context of this, the G(-1195)G(-765)/A(-1195)C(-765) diplotype was significantly less common in patients with CD compared to controls, with an OR of 0.62 (95% CI: 0.39-0.98). For UC however, such an effect was not observed. No correlation was found between COX-2 diplotypes and clinical characteristics of IBD. Conclusions: The -765G -> C polymorphism was associated with a reduced risk for developing Crohn's disease in a Dutch population.