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The functional -765G?C polymorphism of the COX-2 gene may reduce the risk of developing crohn's disease.

ABSTRACT: 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?/?, interferon-? and tumor necrosis factor-? 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 -765GG 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.

SUBMITTER: de Vries HS

PROVIDER: S-EPMC2991351 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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The functional -765G→C polymorphism of the COX-2 gene may reduce the risk of developing crohn's disease.

de Vries Hilbert S HS te Morsche Rene H M RH van Oijen Martijn G H MG Nagtegaal Iris D ID Peters Wilbert H M WH de Jong Dirk J DJ

PloS one 20101124 11

<h4>Background</h4>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-1α/β, interferon-γ and tumor necrosis factor-α produced by inflammatory cells.<h4>Aim</h4>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 inflammat ...[more]

PMID: 21124790

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Project description:BackgroundGenetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression.MethodsWe implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function.ResultsFAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems.ConclusionFAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.

Project description:Chronic rhinosinusitis with nasal polyps is strongly associated with other diseases, including asthma and allergy. The following study tested the association of the -765 G/C polymorphism of cyclooxygenase-2 (COX-2) encoding gene and the -14C/G polymorphism of protooncogen MET (MET) encoding gene with a risk of chronic rhinosinusitis with nasal polyps in a Polish population. One hundred ninety-five patients of chronic rhinosinusitis with nasal polyps as well as 200 sex-, age-, and ethnicity-matched control subjects without chronic sinusitis and nasal polyps were enrolled in this study. Among the group of patients, 63 subjects were diagnosed with allergy and 65 subjects with asthma, respectively. DNA was isolated from peripheral blood lymphocytes of patients as well as controls, and gene polymorphisms were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Ten percent of the samples have been confirmed by a second method single-strand conformation polymorphism (SSCP)-PCR. We reported that the -765 G/C COX-2 (odds ratio [OR] 7.79; 95% confidence interval [CI] 4.88-12.4, p<0.001) and the -14C/G MET (OR 2.83; 95% CI 1.74-4.61, p<0.001) were associated with an increased risk of chronic rhinosinusitis with nasal polyps among analyzed group of patients. Moreover, the group of patients without allergy or asthma indicated the association of the -765 C/G (OR 7.25; 95% CI 4.38-12.1, p<0.001 and OR 7.61; 95% CI 4.47-12.6, p<0.001) genotype of the COX-2 as wells as the -14C/G (OR 2.47; 95% CI 1.46-4.17, p<0.001 and OR 2.59; 95% CI 1.54-4.37, p<0.001) genotype of MET with an increased risk of chronic rhinosinusitis with nasal polyps. Finally, it was also found that the selected group of patients with allergy or asthma indicated a very strong association of the -765 G/C (OR 5.64; 95% CI 2.91-10.9 and OR 4.74; 95% CI 2.49-9.03, p<0.001, respectively) genotype of the COX-2 with an increased risk of chronic rhinosinusitis with nasal polyps. Thus, our results suggest that COX-2 and MET gene polymorphisms may have deep impact on the risk of rhinosinusitis nasal polyp formation, which may also depend on asthma or allergy. Our results showed that the -765 G/C polymorphism of COX-2 gene and the -14C/G polymorphism of the MET gene may be associated with the risk of chronic rhinosinusitis with nasal polyps in a Polish population.

Dataset Information

The functional -765G?C polymorphism of the COX-2 gene may reduce the risk of developing crohn's disease.

Publications

The functional -765G→C polymorphism of the COX-2 gene may reduce the risk of developing crohn's disease.

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