Cyclooxygenase-2 Polymorphisms Research Articles

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.

Genetics Polymorphisms in Cyclooxygenase-2 Associated with Esophageal Cancer Survival Treated with Preoperative Radiotherapy followed by Esophagectomy

Genetics Polymorphisms in Cyclooxygenase-2 Associated with Esophageal Cancer Survival Treated with Preoperative Radiotherapy followed by Esophagectomy

Cyclooxygenase‐2 gene promoter polymorphisms affect susceptibility to hepatitis C virus infection and disease progression

Because polymorphisms of cyclooxygenase-2 (COX-2) and osteopontin (OPN) promoter regions and a promoter/enhancer region of forkhead box protein 3 (FOXP3) gene are known to affect immune responses, we examined whether these polymorphisms can influence susceptibility to hepatitis C virus (HCV) infection and progression of liver disease. Peripheral blood samples were obtained from 104 Japanese patients with chronic HCV infection and 74 healthy Japanese donors. Polymerase chain reaction single-stranded conformational polymorphism analysis of genomic DNA was performed to determine the polymorphisms. The risk of persistent HCV infection was decreased in subjects with -1195GG genotype of the COX-2 promoter region. However, in patients with chronic HCV infection, the -1195GG genotype was associated with advanced-stage liver disease. A luciferase reporter assay performed to analyze the effect of single nucleotide polymorphisms (SNP) (-1195A or -1195G) in COX-2 gene on transcriptional activity using the HepG2, Huh7 and HeLa cell lines indicated that the -1195G genotype showed higher transcriptional activity than the -1195A genotype. SNP of OPN and FOXP3 did not differ between patients with chronic HCV infection and controls. However, the -443TT genotype of the OPN promoter region was associated with increased inflammatory activity of the liver. These results suggest that the -1195GG genotype of the COX-2 promoter region protects against HCV infection in the Japanese. However, once chronic infection is established, the -443TT genotype of the OPN promoter region and the -1195GG genotype of the COX-2 promoter are thought to promote inflammation and contribute to the progression of liver disease.

Prostaglandin-endoperoxide synthase genesCOX1 andCOX2 — novel modifiers of disease severity in cystic fibrosis patients

Cystic fibrosis (CF) is one of the most common autosomal recessive diseases among Caucasians caused by a mutation in the CFTR gene. However, the clinical outcome of CF pulmonary disease varies remarkably even in patients with the same CFTR genotype. This has led to a search for genetic modifiers located outside the CFTR gene. The aim of this study was to evaluate the effect of functional variants in prostaglandin-endoperoxide synthase genes (COX1 and COX2) on the severity of lung disease in CF patients. To the best of our knowledge, it is the first time when analysis of COX1 and COX2 as potential CF modifiers is provided. The study included 94 CF patients homozygous for F508del mutation of CFTR. To compare their clinical condition, several parameters were recorded, e.g. a unique clinical score: disease severity status (DSS). To analyse the effect of non-CFTR genetic polymorphisms on the clinical course of CF patients, the whole coding region of COX1 and selected COX2 polymorphisms were analysed. Statistical analysis of genotype-phenotype associations revealed a relationship between the heterozygosity status of identified polymorphisms and better lung function. These results mainly concern COX2 polymorphisms: -765G>C and 8473T>C. The COX1 and COX2 polymorphisms reducing COX protein levels had a positive effect on all analysed clinical parameters. This suggests an important role of these genes as protective modifiers of pulmonary disease in CF patients, due to inhibition of arachidonic acid conversion into prostaglandins, which probably reduces the inflammatory process.

Cyclooxygenase-2 (COX-2) polymorphisms and risk of inflammatory bowel disease in a Scottish and Danish case–control study

Inflammatory bowel diseases (IBDs) are a result of interactions between luminal pathogens and the intestinal immune response. Cyclooxygenase-2 (COX-2) plays a key role in the regulation of the inflammatory response upon stimulation by luminal pathogens via Toll-like receptors. Genotypes of the COX-2/PTGS2/PGHS2 A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) polymorphisms were assessed in a Scottish and Danish case-control study including 732 Crohn's disease (CD) cases, 973 ulcerative colitis (UC) cases, and 1157 healthy controls using logistic regression. Carriers of the COX-2 A-1195G variant allele had increased risk of UC (odds ratio [OR], 95% confidence interval [CI] = 1.25 [1.02-1.54], P = 0.03) and of both UC and IBD among never smokers (OR [95% CI] = 1.47 [1.11-1.96], P = 0.01 and OR [95% CI] = 1.37 [1.06-1.77], P = 0.02, respectively). Furthermore, this variant genotype was associated with increased risk of diagnosis of UC before age 40 years and with extensive UC (OR [95% CI] = 1.34 [1.11-1.62], P = 0.002 and OR [95% CI] = 1.32 [1.03-1.69], P = 0.03, respectively). COX-2 A-1195G polymorphism was associated with the risk of UC, especially among never-smokers, suggesting that low activity of COX-2 may predispose to UC. Our results suggest that inclusion of smoking status may be essential for the evaluation of the role of genetic predisposition to IBD.

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.

Functional variants of COX-2 and risk of tobacco-related oral squamous cell carcinoma in high-risk Asian Indians

We assessed the association of COX-2 polymorphisms at promoter sites -1195, -765 and at 3'UTR (8473) in 193 patients with oral squamous cell carcinoma (OSCC) and 137 normal subjects by PCR-RFLP. Although no significant difference was observed in the frequency of COX-2 -1195G>A, -765G>C and 8473C>T single nucleotide polymorphisms (SNPs) between patients and controls, COX-2 -1195G/A genotype showed higher while -765G/C and 8473C/T showed lower prevalence in patients as compared to normal subjects. Logistic regression analysis of these three polymorphisms revealed a quantitative risk associated with -1195G>A SNP (OR 3.07 at 95%CI) while -765G>C and 8473C>T appeared to be protective. Results of the present study indicate that these three functional variants in the COX-2 regulatory region may contribute to risk modification of tobacco-related oral squamous cell carcinoma in Asian Indians.

Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for urinary bladder cancer in North India

Cyclooxygenase-2 (COX-2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of processes that are relevant to cancer development. It is involved in carcinogenesis, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. The gene for COX-2, designated as prostaglandin-endoperoxide synthase 2 (PTGS-2), carries polymorphisms, such as -765G>C, 1195G>A in the promoter region, and 8473T>C in the 3'-untranslated region (UTR), which have been associated with susceptibility to malignant disease. We undertook a case-control study of 212 urothelial bladder cancer (UBC) cases and 250 controls to investigate the association between COX-2 polymorphism and bladder cancer susceptibility, using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and also investigated gene-environment interactions. Cox-2 765G>C, a variant(C) allele carrier, was at an increased risk of UBC (odds ratio [OR] = 1.90; P = .004); however, -1195G>A; -1290A>G; and 3'UTR 8473T>C polymorphisms of COX-2 gene were not significantly associated with UBC. 765G>C also was associated with the invasive stage of a bladder tumor (OR = 2.73; P = .033). High risk for UBC also was observed with respect to COX-2 haplotypes C-765T8473A-1195A-1290 (OR = 3.47; P = .014). In case-only analysis, COX-2 765 variant allele carrier genotypes also showed an increased risk among former and current smokers (OR = 3.06; P = .041 and OR = 4.39; P = .032, respectively). COX-2 -765G>C polymorphism confers UBC susceptibility particularly in smokers and in patients with invasive tumors. 765C allele carrier genotypes also are influenced with a high risk of recurrence in Bacillus Calmette-Guérin-treated patients. Collectively, these findings confirm that the COX-2 -765G>C polymorphism is a risk factor for the development of bladder cancer and can provide a plausible mechanistic explanation. Further validation in large population-based studies is needed.

110 Gastric adenocarcinoma development in patients with atrophy or/and intestinal metaplasia: the role of COX-2 polymorphisms in a Northern Portuguese population

The present study showed that atherosclerotic lesions may be readily visualized in the thoracic aorta using transesophageal echocardiography. The absence of aortic plaque in the thoracic aorta rules out significant coronary artery obstruction, while the existence of the former appears to be a sensitive and specific predictor of the latter. The negative predictive value is the most interesting clinical finding of our study.

Potentially functional COX‐2 −1195G&gt;A polymorphism increases the risk of digestive system cancers: A meta‐analysis

Three potentially functional polymorphisms: -765G>C, -1195G>A, and 8473T>C in the cyclooxygenase-2 (COX-2) gene were identified and proposed to be associated with cancer susceptibility. The aim of this meta-analysis was to evaluate the association between these three polymorphisms and the risk of cancer in diverse populations. All case-control studies published up to November 2009 on the association between the three polymorphisms of COX-2 and cancer risk were identified by searching PubMed. The cancer risk associated with the three polymorphisms of the COX-2 gene was estimated for each study by OR together with its 95% confidence interval (CI), respectively. A total of 47 case-control studies were included, and variant genotypes GA/AA of -1195G>A were associated with a significantly increased cancer risk (GA/AA vs GG: odds ratio [OR], 1.29; 95% CI, 1.18-1.41; P(heterogeneity) = 0.113), and this significant association was mainly observed within cancers of the digestive system (e.g. colorectal, gastric, esophageal, oral, biliary tract, gallbladder, and pancreatic) without between-study heterogeneity (GA/AA vs GG: OR, 1.36; 95% CI; 1.23-1.51; P(heterogeneity) = 0.149). Furthermore, a stratification analysis showed that the risk of COX-2-1195G>A associated with cancers in the digestive system was more evident among Asians than Caucasians. However, for COX-2-765G>C and 8473T>C, no convincing association between the two polymorphisms and risk of cancer or cancer type was observed. The effect of three potentially functional polymorphisms (-765G>C, -1195G>A, and 8473T>C) in the COX-2 gene on cancer risk provided evidence that the COX-2-1195G>A polymorphism was significantly associated with increased risk of digestive system cancers, especially among Asian populations.

Polymorphisms in VEGF, eNOS, COX-2, and IL-8 as predictive markers of response to bevacizumab.

e13502 Background: There are no validated predictive markers for selecting patients who would respond to bevacizumab. Previous studies analyzed the role of SNPs in VEGF, eNOS, COX-2, IL-8, but no definite prognostic and predictive association has been established. We evaluated the association of genetic variability with outcome in patients (pts) treated with bevacizumab. Methods: Fifty metastatic pts affected by colorectal (35/50), breast (11/50), and kidney (4/50) cancer were included in this study. VEGF936 C/T and VEGF2578 C/A, eNOS894 G/T, eNOS786 T/C, COX-2 8473 C/T, IL-8 251 T/A polymorphisms were selected. All pts were treated with bevacizumab plus chemotherapy (colorectal and breast cancer) or IFN (renal cancer). Response rate was related to polymorphic gene expression. The relationship of TTP/OS to SNPs is too early because most pts are still alive. The association between response and genotypes was evaluated using the Chi-square test. Results: 29/50 (58%) pts had a partial response, one patient had a complete response and 20 (40%) pts a stable disease. 39/50 (78%) pts were VEGF936 CC (wt) and 11 (22%) VEGF936 CT. 20/50 (40%) pts were VEGF2578 CC (wt), 19 (38%) VEGF2578 CA and 11 (22%) VEGF2578 AA. 16/50 (32%) pts were eNOS894 GG (wt), 27 (54%) eNOS894 GT and 7 (14%) eNOS894 TT. 17/50 (34%) pts were eNOS786 TT (wt), 24 (48%) eNOS786 CT, 9 (18%) eNOS786 CC. All patients were COX-2 8473 CC (wt). The SNP IL-8 251 T/A was tested only in patients with colorectal cancer (35 pts) and 20/35 resulted IL-8 251 TT (wt), 6 pts were IL-8 251 TA and 9 pts IL-8 251 AA. The eNOS786 TT genotype (wt), compared to genotype CC, was associated with a best response to treatment in breast (RR 36.4% vs 18.2%; p=0.036) and colorectal cancer (RR 28.6% vs. 8.6%; p=0.04). The IL-8 251 TT genotype (wt), was associated with a best response to bevacizumab in colorectal cancer, when compared with the genotype AA (RR 25.7% vs 14.3%; p=0.04). Conclusions: With increasing number of antiangiogenic agents, the need of biomarkers is becoming critical, either due to hight cost of these treatments and to response variability. Our preliminary results suggest that the study of SNPs of some genes involved in angiogenesis might be useful in improving the selection of potentially responsive pts. No significant financial relationships to disclose.

Impact of COX-2 rs5275 and rs20417 and GPIIIa rs5918 Polymorphisms on 90-Day Ischemic Stroke Functional Outcome: A Novel Finding

We hypothesized that polymorphisms in 5 genes related to thrombolytic and inflammation pathways will independently influence occurrence, severity, and 3-month functional outcome in patients with ischemic stroke. This was a case-control design with ischemic stroke patients recruited from 4 public hospitals (n = 640) and community controls (n = 627). Baseline clinical data were collected, and follow-up telephone interviews were conducted with 520 patients at 90 days postevent to determine stroke outcome using the Barthel Index (BI), Modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS). Blood samples were collected and genotyped for polymorphisms in platelet glycoprotein Ibα (GPIbα) rs224309 and rs6065, glycoprotein IIIa (GPIIIa) rs5918, tissue plasminogen activator (tPA) rs63020761, plasminogen activating inhibitor (PAI-1) rs72578597, and cyclooxygenase-2 (COX-2) rs5275 and rs20417. COX-2 polymorphism rs5275 demonstrated a significant association with poststroke mRS, with a dominant genetic model demonstrating the best fit (CC + TC) (adjusted odds ratio [aOR] = 1.61; P = .026). The COX-2 rs20417 C allele showed an association with GOS (aOR = 1.95; P = .012), and again a dominant genetic model demonstrated the best fit (CC + GC). GPIIIa rs5918 (A1A2) was associated with poststroke BI, with a dominant model demonstrating the best fit (A1A2 + A2A2) (aOR = 0.56; P = .014). There was a significant association between stroke severity and tPA rs63020761 TT allele (aOR = 1.96; 95% CI = 1.03-3.72; P = .040). This is the first study to demonstrate associations between stroke functional outcome and 2 COX-2 variants (rs20417 and rs5275) and a GPIIIa variant (rs5918).

Cyclooxygenase-2 polymorphisms and pancreatic cancer susceptibility

Objectives:DNA sequence variants in the cyclooxygenase-2 (COX-2) gene may lead to altered COX-2 production and/or activity, resulting in interindividual differences in susceptibility to pancreatic cancer. To test this hypothesis, we investigated the relationship between polymorphisms in the COX-2 ge

COX-2 polymorphisms and colorectal cancer risk: a strategy for chemoprevention

COX-2, the inducible isoenzyme, was found to be overexpressed in approximately 85% of colorectal adenocarcinomas, contributing to key steps in tumor development. COX-2 polymorphisms that might modify the levels of protein expression would be anticipated to have a substantial influence on disease phenotype. Therefore, we sought to understand the role of three COX-2 polymorphisms (-1195A>G, -765G>C, and 8473T>C) in colorectal cancer (CRC) onset. We conducted a hospital-based case-control study involving 117 consecutively enrolled CRC patients and 256 healthy individuals without any clinical evidence of cancer. The COX-2 polymorphisms' genotypes were characterized by PCR-restriction fragment length polymorphism or real-time PCR techniques. The -1195A>G polymorphism was associated with a 1.73-fold increased predisposition to CRC onset. In a stratified analysis, men and ever-smokers carrying -1195G allele (AG+GG) had an increased risk for CRC development (odds ratio: 2.58; 95% confidence intraval: 1.29-5.15 and odds ratio: 10.3; 95% confidence intraval: 3.37-31.2, respectively). More interestingly, men ever-smokers carrying -1195G allele appeared to have a nine-fold increased risk for CRC onset (95% CI: 2.94-27.6). No difference in the genotype's distribution was noticed between cases and controls for the remaining two polymorphisms. The -1195A>G COX-2 polymorphism seems to modulate the genetic susceptibility for CRC onset, especially in men ever-smokers. This genetically based higher-risk group definition may help shift the balance between risk and benefits for the use of COX-2 inhibitors in chemoprevention that is currently hampered by the adverse gastrointestinal and cardiovascular side-effects.

Polymorphisms in inflammatory genes, plasma antioxidants, and prostate cancer risk.

Presence of xenotropic murine leukemia virus-related virus and chronic inflammation in prostate tumor suggests that inflammation plays a role in prostate cancer etiology. This study investigated whether variants in inflammatory genes act alone or interact with plasma antioxidants to influence prostate cancer risk in a population-based case-control study in Central Arkansas. Cases (n = 193) were men, aged 40-80, diagnosed with prostate cancer in three major hospitals in 1998-2003, and controls (n = 197) were matched to cases by age, race, and county of residence. After adjustment for confounders, polymorphisms in COX-2 (rs689466) and IL-8 (rs4073) were not significantly associated with prostate cancer risk. However, apparent interactions were observed between these genetic variants and plasma antioxidants on the risk of this malignancy. The protective effect of the mutant allele of the COX-2 polymorphism was more pronounced among subjects with high plasma levels of beta-cryptoxanthin, lycopene, beta-carotene, or selenium (>or=median) [e.g., OR (95% CI): 0.37 (0.15, 0.86) (AG/GG vs. AA) for beta-cryptoxanthin]. Conversely, the promoting effect of the variant allele of the IL-8 polymorphism was more remarkable in subjects with low plasma levels of Lutein/zeaxanthin, beta-cryptoxanthin, and beta-carotene (<median) [e.g., OR (95% CI): 2.44 (1.08, 5.75) (AT/TT vs. AA) for beta-carotene]. We found that sequence variants in inflammatory genes interact with plasma antioxidants to modulate prostate cancer risk.

Cyclooxygenase-2 Genetic Variants Are Associated with Survival in Unresectable Locally Advanced Non–Small Cell Lung Cancer

Cyclooxygenase-2 (COX-2) plays important roles in the modulation of apoptosis, angiogenesis, immune response, and tumor invasion. Elevated COX-2 expression has been reported to be correlated with reduced survival after radiotherapy. This study examined whether genetic variations in the COX-2 gene are associated with different survival in inoperable locally advanced non-small cell lung cancer (NSCLC) treated with chemoradiotherapy or radiotherapy alone. One hundred and thirty-six patients with inoperable stage IIIA-B NSCLC receiving thoracic irradiation between 2004 and 2007 were recruited in this study. Five functional COX-2 polymorphisms were genotyped using DNA from blood lymphocytes. Kaplan-Meier methods were used to compare survival by different genotypes. Cox proportional hazards models were used to identify independently significant variables. During the median 22.4 months of follow-up, the favorable COX-2 -1195GA and GG genotypes were significantly correlated with better overall survival (20.2 months versus 15.7 months; P = 0.006; hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.39-0.86) and with longer progress-free survival (11.9 months versus 9.5 months; P = 0.034) compared with the -1195AA genotype. No significant associations were found among other COX-2 polymorphisms and clinical outcomes. In the multivariate Cox proportional hazards model, COX-2 -1195G/A polymorphism was independently associated with overall survival after adjusting the clinicopathologic factors (P = 0.008; HR, 0.58; 95% CI, 0.39-0.87). COX-2 -1195G/A polymorphism is a potential predictive marker of survival in locally advanced NSCLC patients treated with chemoradiotherapy or radiotherapy alone.

Study on the association of COX-2 genetic polymorphisms with risk of gastric cancer in high incidence Hexi area of Gansu province in China

To investigate the possible association of polymorphisms, cyclooxygenase-2 (COX-2) promoter region -899G>C, COX-2 codon 587G>A, with risk of gastric cancer in the high incidence Hexi area of Gansu province in China. Blood samples from 140 patients with gastric carcinoma and 125 normal persons were collected in Hexi area of Gansu province in China. Polymorphisms of COX-2 -899G>A and COX-2 587G>A were genotyped by PCR-TaqMan. For detection Helicobacter pylori infection, Warhin-Starry staining was used. Three kinds of polymorphisms of COX-2 -899G>C were GG, GC and CC. The frequencies in gastric cancer patients were 72.9, 21.4 and 5.7%, and the frequencies in controls were 84.0, 12.8 and 3.2%, respectively. COX-2 -899C carrier (GC + CC) increased risk of gastric carcinoma with an odds ratio 1.950 (95% CI: 1.067-3.586, P=0.029). The genotype of COX-2 587G>A polymorphism were GG, GA and AA. The frequencies in patients group were 86.4, 11.4 and 2.2%, and the frequencies in controls were 89.6, 9.6 and 0.8%, respectively. There was no significant difference between cases and controls in each genotype. Helicobacter pylori infection rate was 68.6% in patients group and 50.4% in healthy controls. Helicobacter pylori infection rate in gastric cancer patients was remarkably higher than that in normal people (OR: 2.147, 95% CI: 1.302-3.541, P=0.003). Stratification analysis was showed that COX-2 -899C carrier genotype with Helicobacter pylori infection was significantly higher in cases than that in healthy controls (OR: 4.000, 95% CI: 1.638-9.770). The polymorphism of COX-2 -899G>C could be a risk factor for gastric cancer in high incidence Hexi area of Gansu Province in China. COX-2 -899C carrier genotype and Helicobacter pylori positive infection may have a synergistic effect on gastric cancer in high incidence Hexi area of Gansu Province in China. However, the polymorphisms of COX-2 587G>A is no association with gastric cancer in the high incidence Hexi area of Gansu Province in China.

The Effect of Genetic Polymorphisms of Cyclooxygenase 2 on Acute Pancreatitis in Turkey

The aims of our study were to determine if polymorphisms in the cyclooxygenase 2 (COX-2) gene is associated with acute pancreatitis (AP) and to evaluate if inflammation risk is associated with specific COX-2 gene haplotypes containing these polymorphisms. The COX-2 genotypes for 7 polymorphisms (rs5275, rs2206593, rs4648262, rs4648261, rs2066826, rs5277, rs2745557) were determined using polymerase chain reaction-restriction fragment length polymorphism analysis in 103 patients with AP and 92 healthy controls. Except for rs5275, the frequencies of COX-2 polymorphisms were both similar in patients with mild or severe pancreatitis, so were in pancreatitis patients and in controls. Only rs5275 was statistically significantly associated with AP risk. The association was seen with rs5275 (P = 0.03); specifically, patients carrying the TT genotype in comparison with patients carrying the CC genotype had a significantly lower risk of disease (odds ratio, 1.88; 95% confidence interval, 1.06-3.34). Haplotypes with nucleotide T at the -18491961 position (rs5275) and A at the 184915627 position (rs4648261) of COX-2 promoter seem to increase susceptibility (odds ratio, 2.46; 95% confidence interval, 1.15-5.29; P = 0.02). These findings suggest that the rs5275 polymorphism in the 3'-untranslated region of the COX-2 gene may be used as 1 marker for defining the risk of AP.

Abstract B123: Sequence variants in inflammatory genes, plasma antioxidants, and prostate cancer risk

Abstract Background: Presence of xenotropic murine leukemia virus-related virus and chronic inflammation in prostate tumor tissue suggests that inflammation plays a role in prostate cancer etiology. This study thus investigated whether variants in genes involved in inflammation influence alone or interact with plasma antioxidants to influence prostate cancer risk in a population-based case-control study in Central Arkansas. Methods: Cases (n=193) were men, ages 40–80 years, diagnosed with prostate cancer in three major hospitals in 1998–2003, and controls (n=197) were matched to cases by age, race, and county of residence. Results: After adjustment for confounders, polymorphisms in COX2 (rs689466) and IL-8 (rs4073) were not significantly associated with prostate cancer risk. However, significant interactions were observed between these genetic variants and plasma antioxidants on the risk of this malignancy. The protective effect of the mutant allele of the COX polymorphism was more pronounced among subjects with high plasma levels of β-cryptoxanthin, lycopene, β-carotene, or selenium (≥median) [e.g., OR (95% CI): 0.37 (0.15–0.86) (AG/GG vs. AA) for β-cryptoxanthin]. Conversely, the promoting effect of the variant allele of the IL-8 polymorphism was more remarkable in subjects with low plasma levels of Lutein/zeaxanthin, β-cryptoxanthin, and β-carotene (&amp;lt;median) [e.g., OR (95% CI): 2.44 (1.08–5.75) (AT/TT vs. AA) for β-carotene]. Conclusions: We found that genetic variants in inflammatory genes interact with plasma antioxidants to modulate the risk of prostate cancer. The results obtained from our study need to be replicated in large epidemiologic studies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B123.

Role of Cyclooxygenase-2 and 5-Lipoxygenase Polymorphisms in Alzheimer's Disease in a Population from Northern Italy: Implication for Pharmacogenomics

Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by cognitive deficit with progressive worsening of memory. Recent data indicate that neurons, as well as other brain cells, can express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. Moreover, it has been demonstrated that COX-2 and 5-LO enzymes play a considerable role in the pathophysiology of AD. In order to assess the possible role of COX-2 and 5-LO single nucleotide polymorphisms (SNPs) in AD, we examined their distribution in 341 AD patients and 190 controls from Northern Italy. A significant difference was observed in the distribution of the -765G COX-2 and -1708A 5-LO alleles between AD cases and controls (p=0.03 for -765G/C COX-2 SNP; and p=0.007 for -1708G/A 5-LO SNP). Hence, COX-2 -765G and 5-LO -1708A alleles were overrepresented in AD patients and underrepresented in controls. Our data suggest that these alleles of COX-2 and 5-LO could be risk factors for AD. These results seem of some importance for a pharmacogenomic approach.