Cyclooxygenase-2 Gene Polymorphisms Research Articles

Influence of Cyclooxygenase-2 (COX-2) gene promoter-1195 and allograft inflammatory factor-1 (AIF-1) polymorphisms on allograft outcome in Hispanic kidney transplant recipients

Cyclooxygenase-2 (COX-2) alleles have been associated with allograft outcomes in kidney transplant recipients; however, these alleles may be in linkage with other genes. Human allograft inflammatory factor-1 (AIF-1) is a cytoplasmic protein and is produced by macrophages. Its synthesis is regulated by several cytokines, including interferon gamma. We investigated whether polymorphisms of gene encoding COX-2 and AIF-1 were associated with allograft outcomes among Hispanic renal transplant recipients (RTRs). A total of 527 de novo RTRs of Hispanic ethnicity were included in this study transplanted at St. Vincent Medical Center (SVMC) during 2000-2009. Patients were genotyped for the following: COX-2 (-1195C>T rs689466, intron 6 rs2066826) and AlF1 (rs2269475). Analysis of the results showed that COX-2-1195 CC genotype (OR=1.92, CI%=1.00-3.67, p=0.04) were more frequent, but COX-2-1195 CT genotype was less frequent in kidney allograft acute rejection in comparison with control group (OR=0.59, CI%=0.38-0.91, p=0.017). The genetic variant TT/CT of the AIF-1 gene was associated with a lower risk of rejection (OR=0.63, CI%=0.41-0.98, p=0.038). No association of COX-2 (rs2066826) was observed with allograft rejection. We are unable to find statistically significant association between COX-2 and AIF-1 gene polymorphisms and allograft survival. The -1195C>T in the COX-2 promoter and AIF-1 gene polymorphisms could be a potential predictor of allograft rejection in our Hispanic kidney transplant recipients.

Su2127 Wild Homozygous VEGF-A and COX-2 Gene Polymorphisms Are Associated to Worst Prognosis in Patients With Colorectal Cancer (CRC)

Su2127 Wild Homozygous VEGF-A and COX-2 Gene Polymorphisms Are Associated to Worst Prognosis in Patients With Colorectal Cancer (CRC)

Abstract 4845: VEGF-A and Cox-2 gene polymorphisms and susceptibility to colorectal cancer in Brazilian population.

Abstract Background: Brazilian population displays very high levels of genomic diversity due to the multi-ethnicity, which have important clinical/genomic implications. The vascular endothelial growth factor-A (VEGF-A) and Cyclooxygenase-2 (Cox-2) polymorphisms have been implicated in colorectal cancer (CRC) risk, however, the results on the association between polymorphisms and cancer risk are conflicting. VEGF and Cox-2 polymorphisms might modify the levels of mRNA and protein expression and may have a considerable influence on disease phenotype. Aim: We carried out a case-control study to evaluate whether polymorphisms of VEGF-A and Cox-2 genes modulate the risk of developing CRC. We also aimed to investigate possible interactions between these genetic variations and environmental factors in CRC. Methods: We evaluated VEGF-A and Cox-2 genotypes obtained from a series of 230 CRC patients and 194 controls from the Hospital-based Brazilian population. DNA was isolated from leukocyte using extraction and purification kit PureLink, followed by amplification by polymerase chain reaction (PCR). Real-time analysis was used for genotyping of polymorphisms of VEGF-A and Cox-2, through the TaqMan ® SNP Genotyping Assay. There was no difference between the cases and controls regarding gender, age, ethnicity, and no individual or familial history of cancer was found in control cases. Results: We determined frequencies of four VEGF-A biallelic polymorphisms (-2578C>A, -460T>C, -634G>C, +936C>T), with twelve genotypes; and three Cox-2 polymorphisms (-1195A>G, -765G>C, 8437T>C,) with nine genotypes. The genotypes frequencies were similar in both case and control groups, and there was, therefore, no association between these genotypes and CRC risk. A high frequency of the wild genotype Cox-2 -765GG and 8437TT and polymorphic genotype Cox-2 -1195GG and VEGF-A -634CC was found in an Asiatic (mostly Japanese) population. Moreover, VEGF-A -2578C>A, and -460T>C were associated to familial history of cancer in the cases series. Tobacco consumption was marginally associated to Cox-2 -1195A>G genotype. Conclusion: VEGF-A and Cox-2 gene polymorphisms are not associated with an increased risk of CRC in a Brazilian population. We could demonstrate the genotype differences among ethnicity, and the association of these polymorphisms with some risk-factors for CRC. Citation Format: Michele T. P. Tomitão, Márcia S. Kubrusly, Guilherme C. Cotti, Evelise P. Zaidan, Adriana V. Safatle-Ribeiro, Suely K. N. Marie, Ivan Cecconello, Sergio C. Nahas, Ulysses Ribeiro. VEGF-A and Cox-2 gene polymorphisms and susceptibility to colorectal cancer in Brazilian population. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4845. doi:10.1158/1538-7445.AM2013-4845

Cox-2 gene variants in migraine

PurposeMigraine is a multifactorial and complex disorder, and any clear diagnostic marker to assess the status of the migraineurs has not been established, yet. Nonsteroidal anti-inflammatory drugs reduce production of prostanoids including PGE2 by inhibiting COX-1 and/or COX-2, and thereby suppress inflammatory pain in patients suffering from rheumatoid arthritis, osteoarthritis, and migraine. Thus, COX-2 regulation is important in the pathogenesis and treatment of migraine. We prospectively investigated COX-2-765G→C and COX-2-1195A→G gene polymorphisms which may account for an increased risk of migraine. MethodsThe present analyses are based on 144 case subjects with migraine disease and 123 non-case subjects. Genotyping of COX-2 gene polymorphisms (COX-2-765G→C, COX-2-1195A→G) was detected by PCR-RFLP. ResultsWe, for the first time, demonstrated positive association of COX-2 gene variants with an increased risk for development of migraine. Carriers of COX-2-765 C+ genotype in controls were higher than in the patients (57.7% and 36.1% respectively; P<0.0001) and the frequencies of G+ genotype in patients were higher than in the controls (97.9% and 88.6% respectively; P: 0.002). In addition, frequencies of COX-2-765 GG and GC genotypes in patients were higher than in the controls (P<0.0001, P<0.0001 respectively). It seems that COX-2-765 G+ genotype had increased and COX-2-765 C+ genotype had decreased risk for migraine. In COX-2-1195 polymorphism only AG genotype was statistically significantly different in patients than in the controls (P<0.05). ConclusionsOur findings have suggested that COX-2-765 G+ genotype could facilitate the development of migraine disease.

Association of COX-2 rs20417 with aspirin resistance

Aspirin is the most commonly used antiplatelet drug for treatment of a serious vascular event, most notably stroke and myocardial infarction. However, despite the demonstrated benefit of aspirin, significant fraction of aspirin-treated patients may be resistant to the antiplatelet effects of the drug. The possible mechanisms of aspirin resistance (AR) are multifactorial. A genetic basis for AR has been suggested to exist. Therefore, the present study was taken up to investigate the role of -765G/C polymorphism (rs20417) in the cyclooxygenase-2 (COX-2) gene with AR in stroke patients. Four hundred and fifty stroke patients and four hundred and forty age and sex matched healthy controls were involved in the study. Baseline clinical data were collected and follow-up telephone interviews were conducted with patients at 3months post event to determine stroke outcome using Modified Rankin Scale. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. The association between the genotypes and outcome was evaluated by stepwise multiple logistic regression analysis. The COX-2 CC and GC genotype showed a significant association with bad outcome. Therefore, the carriers of C allele of COX-2 -765G/C polymorphism are more prone to AR in comparison with non-carriers. These results support a potential role of -765G/C COX-2 gene polymorphism with AR in ischemic stroke patients.

Association study of polymorphisms in the cyclooxygenase-2 gene and Alzheimer’s disease risk in Chinese

To determine if polymorphisms (-765G/C, -1195G/A and 8473T/C) of the cyclooxygenase-2 (COX-2) gene can be associated with Alzheimer disease (AD). The frequency of the polymorphisms was determined in 244 cases and 226 controls. The results revealed that the distributions of COX-2 -765G/C and 8473T/C polymorphisms were statistically not significant between AD cases and controls. The genotype distributions and allele frequencies of COX-2 -1195G/A polymorphism in the cases were statistically significantly different from the controls (P < 0.05). The A/A distribution and A allele frequency were significantly lower in the AD group. COX-2 -1195AA carriers showed a one-third lower risk of developing AD as compared to those with -1195GG and GA genotypes (OR = 0.3, 95 % CI 0.194-0.465, P = 0.000). This study suggested that -1195G/A polymorphism of the COX-2 gene is associated with the risk of AD, and the A allele represents a protective factor in patients with AD.

Association of the −14C/GMETand the −765G/CCOX-2Gene Polymorphisms with the Risk of Chronic Rhinosinusitis with Nasal Polyps in a Polish Population

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.

−765 G→C and −1195 A→G Promoter Variants of the Cyclooxygenase-2 Gene Decrease the Risk for Preeclampsia

Cyclooxygenase-2 (COX-2) is the inducible isoenzyme of COX that leads to increased production of prostaglandins and thromboxane, the mediators of inflammation. Controversial data regarding COX levels or activities in the placentas of women with preeclampsia have led us to examine whether a single nucleotide polymorphism (SNP) in the COX-2 gene is associated with the onset of preeclampsia. Two polymorphisms in the promoter region of COX-2 gene were examined by the polymerase chain reaction and restriction fragment length polymorphism in 128 controls and 74 preeclamptic patients. Genotype distribution and allelic frequencies for -765G→C polymorphism of COX-2 gene were significantly different between patients and controls (p=0.000 and p=0.042, respectively). The odds ratio (OR) for preeclampsia risk associated to the -765G allelic variant was 4.07 (95% confidence interval [CI]: 0.89-18.56). The AA genotype of the -1195 A→G variant was present at a significantly higher frequency among all preeclamptic subjects (p=0.000 χ(2): 13.4, OR: 3.44, 95% CI: 1.74-6.77). A moderate linkage was observed between the -765G and -1195A variants (D(0): 0.201; r(2): 0.003). These findings suggest that SNPs, -765G→C and -1195 A→G, on the promoter region of COX-2 gene may reduce the risk of preeclampsia, possibly by affecting the rate of gene expression.

Functional genetic variations of cyclooxygenase-2 and susceptibility to acute myeloid leukemia in a Chinese population

Cyclooxygenase-2 (COX-2) is a key enzyme involved in the synthesis of prostaglandins, which are known to play important roles in the proliferation and differentiation of leukemia cells, and inhibitors of COX-2 can suppress the proliferation and differentiation of human leukemia cell lines. Single-nucleotide polymorphisms (-765G/C: rs20417, -1195A/G: rs689466, and -1290A/G: rs689465) in the COX-2 promoter might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to cancer. In this case-control study, the genotypes of potential functional Single-nucleotide polymorphisms in COX-2 gene were determined with PCR-RFLP method in 446 patients and 725 controls. COX-2 mRNA level in Acute myeloid leukemia (AML) bone marrow and COX-2 protein level in serum samples were examined by real-time PCR and ELISA, respectively. It was found that carriers with -765CC genotypes had a 2.19-fold (95% CI = 1.24-3.88; P < 0.001) excess risk of developing AML compared with non-carriers. A greater risk of developing AML was observed for A(-1195) -C(-765) haplotype compared with G(-1195) -G(-765) haplotype. Moreover, individuals with -765C-containing genotypes had significantly increased COX-2 mRNA level and protein level compared with the -765G-containing counterparts. These findings indicate that -765G/C polymorphism in COX-2 may play a vital role in mediating individual susceptibility to AML.

Cyclooxygenase-2 polymorphisms and the risk of gastric cancer in various degrees of relationship in the Chinese Han population

A number of studies have shown that cyclooxygenase-2 (COX-2) gene polymorphisms were associated with gastric cancer. However, the results from different research groups have not been consistent. The present study aimed to investigate the association between polymorphisms of the cyclooxygenase-2 promoter region (-1195G>A, -765G>C) and gastric cancer patients with various degrees of relationship in the Chinese Han population. COX-2-1195G>A and COX-2-765G>C polymorphisms in 296 gastric cancer patients and 319 control family members were genotyped using polymerase chain reaction-restriction fragment length polymorphism. An increased risk of gastric cancer was observed in subjects with the COX-2-1195AA genotype (OR=2.03; 95% CI, 1.27-3.22), and the association strength decreased as the degree of relationship decreased. Stratification analysis revealed that the OR value of COX-2-1195AA genotype and A carriers exhibited synergy with Helicobacter pylori (H. pylori) infection (AA genotype: OR=2.96; 95% CI, 1.57-5.58; A carriers: OR=2.04; 95% CI, 1.18-3.52). No significant difference was found in each genotype of COX-2-765G>C between gastric cancer patients and control family members, as well as gastric cancer patients with various degrees of relationship. Our study demonstrated that the polymorphism of COX-2-1195AA genotype may be a risk factor for gastric cancer patients with various degrees of relationship among the Chinese Han population. H. pylori infection therefore may enhance the risk of gastric cancer in individuals with the COX-2-1195 AA genotype.

Case–control association study of COX-2 gene polymorphism (− 765G>C) with sporadic colorectal cancer (CRC)

Case–control association study of COX-2 gene polymorphism (− 765G>C) with sporadic colorectal cancer (CRC)

Functional polymorphism of cyclooxygenase-2 gene (G–765C) in chronic obstructive pulmonary disease patients

Cyclooxygenase two (COX-2) is an important enzyme metabolizing arachidonic acid. In contrast to constitutive cyclooxygenase one (COX-1), COX-2 is induced by proinflammatory factors. Polymorphism -765 G/C in COX-2-encoding gene promoter is associated with development of Alzheimer's disease, depression, carcinoma of the pancreas in smokers, breast cancer and rheumatoid arthritis. It is interesting whether the -765 G/C polymorphism in COX-2-encoding gene promoter can be associated with COPD, a disease which is inflammatory in character. It is highly probable as the breast and pancreas cancers, whose associations with the analyzed polymorphism have been studied, are smoking-dependent tumors. Additionally, tobacco smoke has been demonstrated to induce COX-2 in the lungs. The study group consisted of 122 COPD patients (48 females, 74 males). The control group consisted of 149 healthy nonsmoking subjects (83 females, 66 males). Polymerase chain reaction/restriction fragment length polymorphism was used for genotyping. A statistically significant difference in genotype distribution was observed as a result of the comparison between healthy subjects and patients with COPD. The distribution of alleles in both groups conformed with Hardy-Weinberg equilibrium. In the group of COPD patients, GG allele was found in 79 subjects, GC in 36, and CC in 7 subjects (F = 0.094, P = 0.296927); in the control group, 73 subjects had GG allele, 68--GC and 8--CC (F = 0.12728, P = 0.120265). The allele frequency revealed differences between those groups, attaining the level of statistical significance (χ(2) = 29.043, df = 2, P = 0.0000. The carriers of -765 G allele are at 1.53-fold higher risk of developing COPD. The presence of GG genotype does not increase significantly the risk of the disease. It is also noteworthy that the carriers of CC or GC genotypes are at significantly lower risk of developing COPD than the group of subjects with GG genotype.

Association of matrix metalloproteinase (MMP-1, MMP-3 and MMP-9) and cyclooxygenase-2 gene polymorphisms and their proteins with chronic periodontitis

AimsThe objective of this study was to investigate the association amongst the single nucleotide polymorphisms of genes encoding for matrix metalloproteinase (MMP) 1, 3, 9 and cyclooxygenase-2 (COX-2) of subjects. Protein production of MMPs, COX-2 and Vascular Endothelial Growth Factor (VEGF) were also investigated. Methods280 chronic periodontitis patients and 250 periodontitis-free subjects were selected. DNA was extracted from blood samples of all patients, the polymorphic sites of the genes that encode for metalloproteinases and cyclooxygenase-2 were amplified using PCR, and digested with restriction enzymes. ELISA was used to determine the protein production of MMPs, COX-2 and VEGF. ResultsThe mean probing depth (PD) was 5.4mm and the clinical attachment loss (CAL) was 6.4mm in patients group with at least 2 years history. 2G/2G genotype of MMP-1, the periodontitis patients presented frequency of 28% and the control only showed 3%. 5A/5A genotype of MMP-3, the periodontitis patients presented higher frequency of 55% than the control 40%. C/C of genotype MMP-9, the periodontitis patients presented higher frequency of 51% than the control 17%. C/C of genotype COX-2, the periodontitis patients demonstrated 28% frequency and the control was 3%. ELISA analysis determined a significant difference (p<0.001) in protein production between patient and control samples for the bio-markers. 12 cases with suspicious genotype of MMPs and in COX-2 showed the serum level was the highest value between other C/C genotype. ConclusionsCombine genotype and serum expression of inflammatory mediators that may be a good bio-marker for diagnosis and prognosis of the periodontitis.

Role ofcyclooxygenase-2gene polymorphisms in pancreatic carcinogenesis

To evaluate the clinical significance of -765G/C and -1195G/A cyclooxygenase-2 (COX-2) gene polymorphisms in patients with pancreatic cancer (PC). The study included 201 patients: 85 with PC and 116 healthy controls. -765G/C and -1195G/A COX-2 gene polymorphisms were studied in DNA isolated from blood samples. The associations of the analyzed genotypes and clinical data at diagnosis were evaluated. We found an increased frequency of the homozygous -1195AA COX-2 genotype in patients with PC (53.7%) compared with the control group (21%) (P < 0.01). In contrast, the distribution of genotype and allele frequencies of the -765G/C COX-2 polymorphism in the PC patients were not different from those in control groups. A correlation between presence of homozygous -1195AA COX-2 genotype and tumor size > 3 cm was observed (P < 0.05). Analyzed polymorphisms were unrelated to the patients' sex and age, nor to the presence of regional or distant metastases. These preliminary results indicate that the -1195G/A COX-2 polymorphism may play an important role in PC prognosis and carcinogenesis.

Cox-2 gene polymorphism and IL-6 levels in coronary artery disease

Coronary artery disease is one of the leading causes of mortality and diabetes mellitus is one of its main risk factors due to microvascular and macrovascular complications, such as atherosclerosis. Atherosclerosis is now known to be an inflammatory process mediated by prostaglandins and several interleukins. As both are important in inflammatory processes, we examined Cox-2 (-765G > C) polymorphism and interleukin-6 levels in coronary artery disease patients compared to healthy controls. We also divided the patients into diabetic and non-diabetic groups to check the effects of diabetes mellitus separately. We found that the GG allele frequency was significantly higher in the patient group. Patients with the GG genotype had an approximately 2.78-fold higher risk of coronary artery disease. We also found that the Cox-2 (-765G > C) polymorphism is associated with lower interleukin-6 levels, which decreased in the order: GG > GC > CC.

Cyclooxygenase-2 gene and epithelial ovarian carcinoma risk

In this study, we aimed to investigate a possible association of the COX-2 polymorphisms (-765G→C and -1195A→G) and with the risk of developing epithelial ovarian carcinoma (EOC). COX-2 gene polymorphisms was investigated in 111 healthy women and 57 patients with EOC. Individuals who had -765 CG, -1195 AA genotype, and -765 C allele had increased risk for ovarian carcinoma (P < 0.01) and individuals with -765 GG, -1195 AG genotypes and -1195 G allele seem to be protected from ovarian carcinoma (P < 0.01). Haplotype analysis confirmed the association of COX-2 gene variants with ovarian carcinoma and revealed that the frequencies of -765C: -1195A haplotype frequencies was significantly higher in patients as compared with those of controls (P = 0.048). We state that there appears to be a modulating role for the COX-2 -1195A→G and -765G→C polymorphisms in the development of EOC. To the best of our knowledge, this is the first study to show such an association.

Interaction between COX-2 G-765C and smoking in relation to coronary artery disease in a Chinese Uighur population

Coronary artery disease (CAD) is a complex multifactorial and polygenic disorder where multiple environmental and genetic factors are involved simultaneously. The purpose of this study was to explore the relationship between the interaction of cyclooxygenase-2 (COX-2) gene polymorphism and smoking and CAD in a Uighur population. Using a case-control study of Chinese Uighur CAD patients (n=430) and healthy controls (n=470), we investigated the roles of G-765C polymorphism in the COX-2 gene (PTGS2) by the use of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The PTGS2 GG genotype was significantly more prevalent in CAD patients (84.6% vs. 78.3%; p=0.014). Multiple logistic regression analysis showed two independent risk factors: smoking (OR 1.89, 95% CI 1.01-5.24; p=0.008) and hypertension (OR 2.73, 95% CI 1.59-7.21; p=0.001). Moreover, there was a synergistic effect between smoking and the PTGS2 polymorphism and the occurrence of CAD (interaction p=0.009). The odds ratio (OR) estimated by the combined analysis of the PTGS2 GG genotype and smoking history (OR 4.09, 95% CI 2.7-9.3) was markedly higher than that estimated separately from the PTGS2 GG genotype (OR 1.28, 95% CI 0.8-1.9) or smoking (OR 2.51, 95% CI 1.5-5.7) alone. Plasma 6-keto-PGF1α, a stable metabolite of PGI(2), was lower in individuals with the PTGS2 GG genotype (p<0.05). Smoking could further lower plasma 6-keto-PGF1α concentrations in GG genotype carriers than non-smokers, especially in patients with CAD. The PTGS2 polymorphism and smoking were synergistically and significantly associated in Chinese Uighur patients with CAD.

Functional polymorphisms of cyclooxygenase-2 gene and risk for hepatocellular carcinoma

Cyclooxygenase-2 (COX-2) influences carcinogenesis through immune response suppression, apoptosis inhibition, regulation of angiogenesis and tumor cell invasion, and metastasis. It is now well established that COX-2 is overexpressed in many premalignant, malignant, and metastatic cancers, including hepatocellular carcinoma (HCC). DNA sequence variations in the COX-2 gene may lead to altered COX-2 production and/or activity, and so they cause inter-individual differences in the susceptibility to HCC. Functional coding region polymorphisms -1195A>G (rs689466), -765G>C (rs20417), and +8473T>C (rs5275) in the COX-2 gene have recently been shown to be associated with several human cancers but their association with HCC has yet to be investigated. We used hospital-based case-control study to assess the hypothesis that the functional COX-2 variation may affect individual susceptibility to the HCC. COX-2 polymorphisms were investigated in 129 confirmed subjects with HCC and 129 cancer-free control subjects matched on age, gender, smoking, and alcohol consumption using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The distribution of the COX-2 -1195A>G and +8473T>C genotypes were not significantly different between HCC cases and control. However, proportion of the COX-2 -765CC genotype which leads to a 30% reduction of the COX-2 promoter activity was significantly lower in patients with HCC (3.1%) when compared to control subjects (11.6%) (P < 0.05). Logistic regression analyses revealed that the COX-2 -765G>C variant genotype (-765CC) was associated with a significantly decreased risk of HCC compared with the -765GG wild-type homozygotes [P < 0.05, odds ratio (OR) = 0.25, 95% confidence interval (CI) = 0.08-0.79]. Our results suggest for the first time that the -765CC genotype of COX-2 -765G>C polymorphism, causing lower COX-2 gen expression, is a genetic protective factor for HCC. However, because this is the first report concerning the COX-2 -1195A>G, -765G>C, and +8473T>C polymorphisms and the risk of HCC, independent studies are needed to validate our findings.

Cyclooxygenase-2 gene and lung carcinoma risk

In this study, we aimed to investigate a possible association of the COX-2 polymorphisms with the risk of developing lung carcinoma. COX-2 (-765G→C; -1195A→G) gene polymorphisms were performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism in 118 healthy individuals and 231 patients with lung carcinoma. The present study was the first that addressed the role of the COX-2-765G→C and -1195A→G polymorphisms in lung carcinoma in Turkish population. In the present study, we found that the frequencies of GG, CC, and CG genotypes of COX-2-765G→C and AA, GG, and AG genotypes of -1195A→G in our control group were 0.22, 0.22, 0.55 and 0.59, 0.0, 0.40, respectively. These frequencies in patient group were 0.34, 0.07, 0.58 and 0.74, 0.04, 0.24, respectively. There were statistically significant differences in COX-2-765G→C (P=0.0002) and -1195A→G genotypes (P=0.007) between the controls and patients. We found that individuals carrying -765 GG genotype and -765 G allele of COX-2 or 1195 AA genotype of COX-2 and -765G: -1195A haplotype had an increased risk for the development of lung carcinoma. In contrast, individuals with -765 CC, -1195 AG genotypes and -1195 G allele of COX-2 seem to be protective from lung carcinoma. We suggest that the COX-2-765G→C and -1195A→G genotypes may be a risk factor for lung carcinoma.

Association of −765G&gt;C polymorphism of the COX-2 gene with recurrent embryo implantation failure in Southern Chilean women

Embryo implantation failure is considered an important cause of infertility in women undergoing assisted reproductive protocols. Recent studies demonstrated that the cyclooxygenase-2 (COX-2) enzyme is implicated in biosynthesis of prostaglandins and play an important role in the molecular implantation mechanisms. According to this evidence, we evaluated the potential association between the -765G>C (rs20417) polymorphism at the COX-2 gene and the implantation failure susceptibility in a sample of Chilean women. A total of 186 unrelated women matched by age were included in the present study, 106 patients (aged 31.9±4.17 y) with no history of successful pregnancy and a diagnosis of infertility undergoing assisted reproductive protocols and 80 healthy controls (aged 31.4 ± 4.05 y). The COX-2 -765G>C gene polymorphism was analyzed by PCR-RFLP. Genotype distribution and allelic frequencies for -765G>C polymorphism of COX-2 gene were significantly different between patients and controls (P=0.004 and P=0.002, respectively). The odds ratio for implantation failure associated to the -765C allelic variant was 2.14 (95% C.I., 1.35-3.39, P=0.00071). Our data suggest, by the first time, that the COX-2 -765G>C polymorphism is associated with recurrent implantation failure in Chilean women and may constituted a novel molecular biomarker of reproductive failure.