Glutathione Peroxidase 1 Pro198Leu Polymorphism Research Articles

Glutathione Peroxidase-1 Pro198Leu Variant in Tuberculosis-infected Type2 Diabetes Mellitus Patients at Pulmonary Polyclinic Medan

BACKGROUND: Glutathione peroxidase-1 (GPx-1) is an antioxidant that plays an important to the body protection system against oxidative stress. The GPx-1 polymorphism that has been identified in individual with several diseases. AIM: This study aimed to observe the distribution of GPx-1 Pro198Leu variant in tuberculosis (TB)-infected Type 2 diabetes mellitus (T2DM) patients at pulmonary polyclinic Medan. GPx-1 Pro198Leu polymorphism was genotyped in 40 T2DM patients that also infected by TB. MATERIALS AND METHODS: Analysis of GPx-1 Pro198Leu polymorphism was done using polymerase chain reaction (PCR) and restriction fragment length polymorphism. The PCR products were digested 4 h at 37°C with Apa1 restriction enzyme. The result of Apa1 enzyme digestion was visualized with 4% agarose. RESULTS: From 40 TB-infected T2DM patients, the frequency of genotypes CC,CT, and TT were, respectively, 82.5%, 17.5%, and 0%. The frequency of C allele was higher than T allele, i.e. 91.3% and 8.7%. CONCLUSION: It was concluded that in TB-infected T2DM patients at pulmonary polyclinic Medan, the GPx-1 Pro198Leu polymorphism has CC variant higher than CT, whereas the TT genotype was not found. The frequency of the C allele is higher than the T allele.

The GPX1 Pro198Leu polymorphism in gastric cancer patients with and without Helicobacter pylori infection

Helicobacter pylori infection could induce oxidative stress. Oxidative stress is involved in the pathogenesis of gastric diseases. Glutathione peroxidase 1 (GPX1), is part of the enzymatic antioxidant defense, preventing oxidative damage. The aim of the present study was to assess the association of GPX1 Pro198Leu genotypes with gastric cancer in patients with and without H. pylori infection in a population of Northern Iran. The present case-control study consisted of 50 patients with gastric cancer and 78 cancer-free subjects as controls. Extraction of DNA was performed on bioptic samples and the GPX1 genotypes were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The frequencies of GPX1 Pro/Pro, Pro/Leu and Leu/Leu genotypes in controls were 21.8, 71.8 and 6.4%, respectively. However, in gastric cancer patients, the frequencies of 34, 56 and 10% were observed for Pro/Pro, Pro/Leu and Leu/Leu genotypes, respectively (p = 0.185). In 38 (76%) patients infected with H. pylori, the frequencies of Pro and Leu alleles were 94.7 and 3.3%, respectively. There was a higher frequency of combined genotype of Pro/Leu + Leu/Leu (94.7%) in H. pylori positive patients than that in patients without H. pylori infection (75%, p = 0.047). The presence of this genotype tended to increase the risk of H. pylori related gastric cancer by 5.88–fold (p = 0.069) in our population. Our findings indicated the absence of association between the GPX1 Pro198Leu polymorphism and the risk of gastric cancer in an Iranian population. However, we detected an association between H. pylori related gastric cancer with GPX1 Pro/Leu + Leu/Leu genotype.

Case control feasibility study assessing the association between severity of coronary artery disease with Glutathione Peroxidase-1 (GPX-1) and GPX-1 polymorphism (Pro198Leu).

BackgroundGlutathione peroxidase-1 (GPX-1) activity was reported to be useful marker for monitoring cardiovascular disease. However, accurate assessment of coronary artery disease (CAD) using GPX-1 polymorphism is limited for South Asian population. Present study aim to assess GPX-1activity and GPX-1 polymorphismin patients with coronary artery disease (CAD) who were confirmed with coronary angiography findings and in apparently healthy subjects.MethodsCase control study was carried out with 85 patients (58 males and 27 females) 40–60 years of age confirmed as having CAD on coronary angiography findings and 85 age and sex matched healthy volunteers as controls. Blood samples were analyzed for erythrocyte GPX-1 activity and GPX-1 polymorphism in both groups and the severity of CAD was assessed using coronary angiography scoring system based on vessel, stenosis and extent score.ResultsCoronary angiography scores indicated that erythrocyteGPX-1 cutoff value of 23.9 U/gHb showed a high sensitivity and negative predictive value in ruling out major vessel disease. The GPX-1 Pro198Leu (CT) polymorphism was higher in patients with CAD (25.3 %) when compared to controls (10.7 %). Pro198Leu (CT) genotype showed a 2.84 fold risk for CAD [odds ratio 2.84 (95 % CI 1.15–6.98), p = 0.019].ConclusionCoronary angiography findings indicated that individuals possessing Pro198Leu (CT) polymorphism were found to be associated with low erythrocyte GPX-1 activity and increased susceptibility for CAD.

The roles of the GPX1 Pro198Leu and OGG1 Ser326Cys variants in coronary artery disease / GPX1 geni Pro198Leu ve OGG1 geni Ser326Cys varyantlarının koroner arter hastalığındaki rolleri

Abstract Objective: Coronary artery disease (CAD) is caused by plaque formation on inner walls of coronary arteries. Glutathione peroxidase-1 (GPX1), prevents oxidative damage by detoxifying hydrogen and lipid peroxides. GPX1 Pro198Leu polymorphism results in oxidant/antioxidant imbalance. 8-oxoguanine DNA glycosylase-1 (OGG1) is the key enzyme in DNA repair pathway. OGG1 Ser326Cys polymorphism leads to 8-oxoG accumulation and may play a role in cardiovascular diseases. Thus, our study aims to investigate GPX1 Pro198Leu and OGG1 Ser326Cys polymorphisms in CAD patients and the possible relationship of genotypes with serum lipids and CAD severity. Methods: A total of 169 CAD patients and 173 angiographically documented healthy controls were included in our study. The lesion severity in CAD patients was determined by Gensini scoring system. The genomic DNA was isolated from peripheral blood. Real-time polymerase chain reaction (RT-PCR) was used to genotype GPX1 Pro- 198Leu and OGG1 Ser326Cys polymorphisms. Results: Systolic and diastolic blood pressure, pulse, glucose, total- and LDL-cholesterol, triglycerides and waist circumference values were statistically significant between CAD patients and controls (p<0.05). No significant differences were observed in GPX1 Pro198Leu and OGG1 Ser- 326Cys genotype frequencies between CAD patients and controls (p=0.675, p=0.593; respectively). There was no significant differences between genotype frequencies of two SNPs and Gensini scores (p=0.317, p=0.911; respectively). Conclusion: Since no significant relation was observed in GPX1 Pro198Leu and OGG1 Ser326Cys genotype frequencies between CAD patients and controls, and no significant effect was determined between the two SNPs and Gensini scores, it was suggested that GPX1 Pro198Leu and OGG1 Ser- 326Cys polymorphisms do not seem to have an effect on CAD pathogenesis and lesion severity. This result may be due to the limited number of the sample size in the study group.

Pro198Leu polymorphism in the oxidative stress gene, glutathione peroxidase-1, is associated with a gender-specific risk for panic disorder

Objective. Panic disorder (PD) is an anxiety disorder characterized by sudden attacks of intense fear. Biochemical studies suggest that oxidative stress (OS) index is significantly higher in PD, and OS genes may participate in development of anxiety-like behavioral phenotypes. We aimed to investigate role of polymorphisms in OS gene, glutathione peroxidase-1 (GPX1), and DNA repair enzyme gene, 8-oxoguanine glycosylase-1 (OGG1), in PD patients. Methods. GPX1 Pro198Leu (rs1050450) and OGG1 Ser326Cys (rs1052133) polymorphisms of 127 patients with PD and 151 disease-free controls were analyzed with real-time polymerase chain reaction. Severity of PD symptoms was assessed by Panic and Agoraphobia Scale (PAS). Results. No significant relationship was found in genotype distributions of OGG1 Ser326Cys and GPX1 Pro198Leu polymorphisms between PD and control groups (p > 0.05). There was no significant relationship between OGG1 or GPX1 polymorphisms, and age of onset, agoraphobia, or PAS scores in PD group (p > 0.05). However, in GPX1 Pro198Leu polymorphism, C allele (Pro) was found to be more frequent in female subgroup of PD patients compared with that in males (p = 0.027). Conclusions. GPX1 Pro198Leu and OGG1 Ser326Cys polymorphisms were not associated with PD risk in Turkish patients. However, a gender-specific effect of GPX1 Pro198Leu C allele may be associated with PD development.

Polymorphisms of glutathione peroxidase 1 (GPX1 Pro198Leu) and catalase (CAT C-262T) in women with spontaneous abortion

About 10%–15% of conceptions are lost spontaneously prior to 20 weeks. Apart from the clinical problems, genetic variations have also been proposed as a susceptibility factor to miscarriage. Glutathione peroxidase 1 (GPX1) and catalase (CAT) encode two antioxidant enzymes that detoxify H2O2 and protect the cells from oxidative damage. A functional polymorphism at codon 198 of the GPX1 gene causes a C/T substitution in exon 2, which encodes for either proline or leucine (Pro198Leu). The CAT gene has a polymorphic site in the promoter region at position −262 (C-262T) which alters the expression and enzyme blood levels, leading to some pathological clinical conditions. In this study, we evaluated the association of these two polymorphisms with the risk of spontaneous abortion. Genomic DNA from 105 cases with spontaneous abortion and 90 healthy women were genotyped using allele-specific PCR (AS-PCR) and polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). The genetic distributions for GPX1 did not differ significantly between cases and controls (p = 0.680). However, C-262T polymorphism was significantly associated with the risk of the disease (OR, 5.50; 95% CI, 1.43–21.09; p = 0.012). In conclusion, this study indicates that CAT −262T/T genotype confers less susceptibility to spontaneous abortion, while GPX1 Pro198Leu polymorphism may not be correlated with the disease.

Single-nucleotide polymorphisms of GPX1 and MnSOD and susceptibility to bladder cancer: a systematic review and meta-analysis

Reactive oxygen species-related damage plays a critical role in carcinogenesis. Glutathione peroxidase 1 (GPX1) and mitochondrial superoxide dismutase (MnSOD) are two key antioxidant enzymes in the defense system against reactive oxygen species. This systematic review and meta-analysis was designed to evaluate the association of single-nucleotide polymorphisms in GPX1 and MnSOD genes with susceptibility to bladder cancer risk. Online databases of PubMed, Embase, China National Knowledge Infrastructure, and SinoMed were searched to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimated the association strength. The fixed effects model and random effects model were used to pool the data from different studies. By pooling all eligible studies, we found that the GPX1 Pro198Leu polymorphism was associated with a significantly increased risk of bladder cancer (Leu vs. Pro, OR = 2.111, 95% CI = 1.020-4.368, heterogeneity (p < 0.001); LeuPro/LeuLeu vs. ProPro, OR = 1.876, 95% CI = 1.011-3.480, heterogeneity (p < 0.001)). No significant association of MnSOD Ala-9Val polymorphism with cancer risk was observed (AlaVal/ValVal vs. AlaAla, OR = 0.966, 95% CI = 0.754-1.239, heterogeneity (p = 0.390); Vla vs. Ala, OR = 1.038, 95% CI = 0.782-1.377, heterogeneity (p = 0.015)). This systematic review and meta-analysis demonstrated that the GPX1 Pro198Leu polymorphism significantly increased susceptibility to bladder cancer, while the MnSOD Ala-9Val polymorphism was not associated with bladder cancer risk.

PROSTATE CANCER: EVIDENCE OF GENETIC AND ENVIRONMENTAL FACTORS, PARTICULARLY REGARDING OXIDATIVE STRESS

Prostate cancer (PCa) is the second most common cancer in men worldwide. However the etiology of this disease remains largely unclear. Both genetic and environmental factors seem to be involved in the pathogenesis. In the last years the role of reactive oxygen species (ROS) in deterioration of DNA, proteins, lipids of membrane cells has been demonstrated. Also external antioxidant factors such as vitamin C and vitamin E, melatonin, that intercept free radicals, play a role, preventing damage to cellular biomolecules. The antioxidant enzyme glutathione peroxidase 1 (GPX1) is a part of the enzymatic antioxidant defence, preventing oxidative damage to DNA, proteins and lipids by detoxifying hydrogen and lipid peroxides that may contribute to prostate cancer development. Some recent studies indicate an association between GPX1 Pro198Leu polymorphism and an increased risk of cancer. So the alimentary integration with an antioxidant agent such as ascorbate of potassium with ribose (PAR) can play an important rule in the prevention and also cure of prostatic cancer, opposing the effect of ROS, both in men carriers of the polymorphism the GPX1 Pro198Leu and in the general population after the demonstration on blood samples of an increase of the oxidative stress parameters.

PROSTATE CANCER: EVIDENCE OF GENETIC AND ENVIRONMENTAL FACTORS, PARTICULARLY REGARDING OXIDATIVE STRESS

Prostate cancer (PCa) is the second most common cancer in men worldwide. However the etiology of this disease remains largely unclear. Both genetic and environmental factors seem to be involved in the pathogenesis. In the last years the role of reactive oxygen species (ROS) in deterioration of DNA, proteins, lipids of membrane cells has been demonstrated. Also external antioxidant factors such as vitamin C and vitamin E, melatonin, that intercept free radicals, play a role, preventing damage to cellular biomolecules. The antioxidant enzyme glutathione peroxidase 1 (GPX1) is a part of the enzymatic antioxidant defence, preventing oxidative damage to DNA, proteins and lipids by detoxifying hydrogen and lipid peroxides that may contribute to prostate cancer development. Some recent studies indicate an association between GPX1 Pro198Leu polymorphism and an increased risk of cancer. So the alimentary integration with an antioxidant agent such as ascorbate of potassium with ribose (PAR) can play an important rule in the prevention and also cure of prostatic cancer, opposing the effect of ROS, both in men carriers of the polymorphism the GPX1 Pro198Leu and in the general population after the demonstration on blood samples of an increase of the oxidative stress parameters.

Glutathione peroxidase 1 (GPX1) single nucleotide polymorphism Pro198→Leu: Association with life span and coronary artery disease

In this study we genotyped polymorphism in GPX1 Pro198Leu (C > T) rs 1050450 in four groups: patients with coronary artery disease, long-livers - above 90 years, early died peoples (before 55 years) from cardiovascular diseases and Russian population as control group. We have found significant higher allele T frequency in men with coronary artery disease -34.84% (Chi2 = 5.228, p = 0.022; OR = 1.46) and in early died men from cardiovascular diseases--38.16% (Chi2 = 6.461, p = 0.011; OR = 1.69) compared with control men--26.8%. Moreover, significantly higher genotype TT frequency has been shown in patients with coronary artery disease and myocardial infarction before age 50--19.44% in comparison with control group--7.28% (Chi2 = 9.55, p = 0.002). The TT frequency in long-livers (4.39%) was the lowest and significantly different from coronary artery disease group--12.79% (Chi2 = 8.07, p = 0.0045) and from coronary artery disease subgroup with myocardial infarction before 50--19.44% (Chi2 = 14.49, p = 0.0001). Thus our results indicate that allele T (Leu) of GPX1 Pro198Leu (C > T) polymorphism is unfavorable for successful ageing. It predisposes to coronary heart disease, earlier myocardial infarction (before age 50) and earlier death (before age 55).

Association of GPX1 polymorphism, GPX activity and prostate cancer risk.

Prostate cancer is the second most common cancer in men worldwide. Although the aetiology of this disease remains largely unclear, several lines of evidence suggest that oxidative stress plays a role in prostate carcinogenesis. The antioxidant enzyme glutathione peroxidase 1 (GPX1) is part of the enzymatic antioxidant defence, preventing oxidative damage to DNA, proteins and lipids by detoxifying hydrogen and lipid peroxides that may contribute to prostate cancer development. Some studies indicate an association between GPX1 Pro198Leu polymorphism and an increased risk of cancer. The purpose of the present study was to determine the possible association of GPX1 Pro198Leu polymorphism and erythrocyte GPX activity with the risk of developing prostate cancer and to clarify whether erythrocyte GPX activity levels were correlated with the GPX1 Pro198Leu genotype in the Turkish population. The GPX1 Pro198Leu genotype was determined in 33 prostate cancer patients and 91 control individuals. As evident from our results, there was no difference between genotype and/or allele frequencies in prostate cancer patients and controls. No significant difference was found in GPX1 genotype or allele frequency between aggressive and non-aggressive prostate cancer patients. It can be suggested with these findings that individual susceptibility of prostate cancer may be modulated by GPX1 polymorphism, but it needs further studies.

Associations between glutathione peroxidase-1 Pro198Leu polymorphism, selenium status, and DNA damage levels in obese women after consumption of Brazil nuts

Objective Alterations in selenium (Se) status may result in suboptimal amounts of selenoproteins, which have been associated with increased oxidative stress levels. The Pro198Leu polymorphism at the glutathione peroxidase-1 (GPx1) gene is supposed to be functional. The response of Se status, GPx activity, and levels of DNA damage to a Se supplementation trial between the genotypes related to that polymorphism was investigated. Methods A randomized trial was conducted with 37 morbidly obese women. Participants consumed one Brazil nut, which provided approximately 290 μg of Se a day, for 8 wk. Blood Se concentrations, erythrocyte GPx activity, and DNA damage levels were measured at baseline and at 8 wk. The results were compared by genotypes. Results The genotype frequencies were 0.487, 0.378, and 0.135 for Pro/Pro (the wild-type genotype), Pro/Leu, and Leu/Leu, respectively. At baseline, 100% of the subjects were Se deficient, and after the supplementation, there was an improvement in plasma Se ( P < 0.001 for Pro/Pro and Pro/Leu, P < 0.05 for Leu/Leu), erythrocyte Se ( P = 0.00 for Pro/Pro and Pro/Leu, P < 0.05 for Leu/Leu), and GPx activity ( P = 0.00 for Pro/Pro, P < 0.00001 for Pro/Leu, P < 0.001 for Leu/Leu). In addition, the Pro/Pro group showed a decrease in DNA damage after Brazil nut consumption compared with baseline ( P < 0.005), and those levels were higher in Leu/Leu subjects compared with those with the wild-type genotype ( P < 0.05). Conclusion Consumption of one unit of Brazil nuts daily effectively increases Se status and increases GPx activity in obese women, regardless of GPx1 Pro198Leu polymorphism. However, the evaluated biomarkers showed distinct results in response to the supplementation when the polymorphism was considered.

Association between GPx1 Pro198Leu polymorphism, GPx1 activity and plasma selenium concentration in humans

Glutathione peroxidase 1 (GPx1) is an antioxidant selenoenzyme that protects the cells against reactive oxygen species. Its activity depends on the concentration of selenium (Se) which is present in the active centre of the enzyme. The genetic polymorphism of GPx1 encoding gene (GPx1) associated with the proline (Pro) to leucine (Leu) change at codon 198 is supposed to be functional. An in vitro study performed on human breast carcinoma cell line showed that GPx1Leu allele was associated with a lower responsiveness of the enzyme to Se added to the culture medium. Some authors observed a decrease in GPx1 activity associated with GPx1 Leu allele in humans; however, there were no findings on how GPx1 activity changes with Se concentration in individuals with different GPx1 genotypes. To assess whether GPx1 activity that depends on the Se status may be influenced by GPx1 polymorphism through studying this relationship in the blood of healthy individuals. The association between the Se status, GPx1 activity and GPx1 genotype was assessed in 405 individuals of Polish origin. GPx1 activity in red blood cells was measured by the spectrophotometric method by Paglia and Valentine, using t-butylhydroperoxide as the substrate. Plasma Se concentration was measured using graphite furnace atomic absorption spectrometry. GPx1 Pro198Leu polymorphism was determined with the Molecular Beacon Real-Time PCR assay. In the subjects examined, the mean plasma Se concentration was 54.4 +/- 14.2 mcg/L. The mean GPx1 activity was 15.1 +/- 4.7 U/g Hb. No difference regarding both the parameters was found between individuals with different GPx1 genotype. However, the association between GPx1 activity and Se concentration, analyzed separately for each genotype group, was not the same. The correlation coefficients amounted to r = 0.44 (p < 0.001) for Pro/Pro, r = 0.35 (p < 0.001) for Pro/Leu and r = 0.25 (p = 0.45) for Leu/Leu group, which indicates that the correlation strength was as follows: Pro/Pro > Pro/Leu > Leu/Leu. Notably, statistically significant difference in this relationship (analyzed as difference between correlation coefficients for linear trends) was found between genotypes Pro/Pro and Leu/Leu (p = 0.034). The findings of the present study provide evidence for the hypothesis based on in vitro studies which assumes that GPx1 Pro198Leu polymorphism has a functional significance for the human organism and that this functionality is associated with a different response of GPx1 activity to Se. They also point to the importance of the genetic background in the assessment of the Se status with the use of selenoprotein biomarkers such as GPx1 activity.

GPX1 Pro 198Leu polymorphism, erythrocyte GPX activity, interaction with alcohol consumption and smoking, and risk of colorectal cancer

GPX1 encoding the enzyme glutathione peroxidase 1 (GPX1) and h OGG1 encoding the 8-oxoguanine glycosylase 1 (OGG1) may counteract oxidative stress and resulting DNA damage associated with lifestyle-related exposures. We examined whether the polymorphisms GPX1 Pro 198Leu and OGG1 Ser 326Cys or low erythrocyte GPX enzyme activity in pre-diagnostic blood samples are associated with colorectal cancer risk, and assessed possible interactions between the polymorphisms or enzyme activity and various lifestyle factors in relation to colorectal cancer risk. Additionally, we studied whether the GPX1 Pro 198Leu polymorphism and several lifestyle factors predict GPX activity in erythrocytes. The present study was nested within the prospective “Diet, Cancer and Health” study of 57,053 Danes including 375 colorectal cancer cases and a comparison group of 779 individuals matched on gender. Biomaterial was sampled and information on lifestyle factors was obtained from questionnaires filled in at enrolment in 1993–1997. GPX1 Pro 198Leu, h OGG1 Ser 326Cys and erythrocyte GPX enzyme activity were not associated with risk of colorectal cancer. We observed a higher risk associated with alcohol consumption and smoking among homozygous GPX1 198Leu carriers, with incidence rate ratios for colorectal cancer of 1.45 (95% CI: 1.17–1.81, P = 0.02) per 10 g alcohol intake per day and 2.56 (95% CI: 0.99–6.61, P = 0.02) among ever smokers compared with never smokers at enrolment. Erythrocyte GPX activity was influenced by the GPX1 Pro 198Leu genotype, gender, smoking intensity, and intake of fruits and vegetables. Our results indicate that lifestyle-related oxidative stress may be a risk factor for colorectal cancer among subjects with a lowered defence.

Glutathione peroxidase 1 (GPX1) genetic polymorphism, erythrocyte GPX activity, and prostate cancer risk.

Glutathione peroxidase 1 (GPX1) is a ubiquitously expressed selenium-dependent enzyme that protects cells against oxidative damage by reducing hydrogen peroxide and a wide range of organic peroxides. Some epidemiological studies have correlated low GPX activity or particular GPX1 polymorphisms with enhanced risk of cancer, although these correlations have not been consistently observed in all populations. Therefore, we conducted the present study to evaluate the possible association of GPX1 Pro198Leu polymorphism and erythrocyte GPX activity with the risk of developing prostate cancer and to clarify whether erythrocyte GPX activity levels were correlated with the GPX1 Pro198Leu genotype in the Macedonian population. The GPX1 Pro198Leu genotype was determined in 82 prostate cancer cases and 123 control individuals. We found an overall protective effect of the variant Leu allele of the GPX1 polymorphism on the prostate cancer risk. Heterozygous carriers of the variant Leu allele had a significantly lower risk of prostate cancer compared with homozygous wild-type individuals (OR, 0.38; 95% CI, 0.20-0.75; P = 0.004). Erythrocyte GPX activity was analyzed in 73 cases and 91 controls. The erythrocyte GPX activity in the cancer group was lower than in the healthy controls. Additionally, we compared the erythrocyte GPX activity in the control group of 90 subjects and found no significant differences by genotype. These findings suggest that individual susceptibility of prostate cancer may be modulated by GPX1 polymorphism and that the combination of genetic factors involved in oxidative response with environmental carcinogens may play an important role in prostate carcinogenesis.

Glutathione peroxidase 1 Pro198Leu variant contributes to the metabolic syndrome in men in a large Japanese cohort

BackgroundThere has been much interest in the role of free radicals and oxidative stress in the pathogenesis of metabolic syndrome (MetS). Cellular antioxidant enzymes such as glutathione peroxidase 1 (GPX1) play a central role in the control of reactive oxygen species. ObjectiveWe examined whether GPX1 polymorphism (Pro198Leu) is associated with MetS as well as with each component of MetS. DesignThe study was a cross-sectional analysis of randomly selected, community-dwelling Japanese persons aged 40–70 y (1128 M, 1105 F). ResultsThe genotype frequencies for the GPX1 Pro198Leu polymorphism in this cohort were 0.846, 0.151, and 0.003 for CC, CT, and TT, respectively. The CT/TT genotypes had significantly higher waist-hip ratios, triacylglycerol concentrations, homeostasis model assessment for β-cell function, and systolic and diastolic blood pressures in men (P = 0.045, 0.012, 0.011, 0.004, and 0.003, respectively) than did the CC genotype; the CC/TT genotypes also had higher insulin in both sexes (P = 0.019 for men, P = 0.010 for women) and higher body fat mass (P = 0.027) and homeostasis model assessment for insulin resistance (P = 0.008) in women. The CT/TT genotypes showed significant association with higher prevalence of MetS as defined by 2 commonly used criteria in men [odds ratio (OR): 2.02; 95% CI: 1.30, 3.15 by the International Diabetes Federation criteria; OR: 1.49; 95% CI: 1.02, 2.18 by the modified National Cholesterol Education Program criteria) but not in women. The CT/TT genotypes showed a higher prevalence of central obesity (OR: 1.93; 95% CI: 1.31, 2.85) and hypertriglyceridemia (OR: 1.52; 95% CI: 1.08, 2.15) in men but not in women; there were no differences in other components of MetS between the CC and CT/TT genotypes in either sex. ConclusionGPX1 Pro198Leu variants are associated with the prevalence of MetS in Japanese men but not in women.

Associations Between GPX1 Pro198Leu Polymorphism and Erythrocyte GPX Activity and Risk of Colorectal Cancer

ISEE-476 Objective: GPX1 encodes the enzyme glutathione peroxidase 1 (GPX1), which may counteract oxidative DNA damage caused by reactive oxygen species from environmental and lifestyle sources. We examined prospectively whether the GPX1 Pro198Leu polymorphism or low enzyme activity in erythrocytes increases the risk of colorectal cancer, and assessed the interactions between the polymorphism/enzyme activity and dietary components or smoking in risk of colorectal cancer. Material and Methods: We identified 375 cases and selected a comparison group of 779 individuals matched on gender, all nested in the prospective “Diet, Cancer and Health” study of 57,053 Danes. Genotype was determined by endpoint reading on a Sequence Detection system ABI 7500. GPX enzyme activity was measured on a Roche/Hitachi 912 analyzer. Information on dietary components and smoking was obtained from questionnaires filled in at enrolment in 1993 to 1997. Results: We found no association between the GPX1 polymorphism and colorectal cancer, but observed statistically significant interaction (P = 0.01) between the polymorphism and alcohol consumption with an incidence rate ratio (IRR) of colorectal cancer of 1.47 (95% CI: 1.17–1.84) per 10 g alcohol intake per day among homozygous 198Leu carriers. Among these subjects IRR was 1.67 (CI: 1.06–2.65) per 10 g tobacco per day (P = 0.06). We found correlation between the GPX1 polymorphism and enzyme activity (P = 0.05). GPX activity was not associated with colorectal cancer. The activity was negatively correlated with smoking intensity (r = −0.12, P < 0.0001) and positively correlated with intake of fruits and vegetables (r = 0.09, P = 0.0012). No association was observed between GPX activity and alcohol consumption. Conclusions: Interaction was observed between alcohol consumption and the GPX1 Pro198Leu polymorphism in relation to colorectal cancer, which suggests that an adverse association between alcohol and colorectal cancer may be strongest among homozygous 198Leu carriers. GPX activity correlated with the polymorphism. Smoking intensity and intake of fruit and vegetables were predictors for GPX activity.

MnSOD and GPx-1 polymorphisms in relation to local recurrence in patients with rectal cancer treated with chemoradiation

3604 Background: Manganese superoxide dismutase (MnSOD) and Glutathione peroxidase-1 (GPx-1) are two enzymes that scavenge ROS (reactive oxygen species) such as superoxide and hydrogen peroxide and protect cells from oxidative damage. MnSOD reduces superoxide to oxygen and hydrogen peroxide, and GPx-1 reduces hydrogen peroxide to water. Radiation therapy produces an excess of ROS, which results in DNA damage, cellular destruction, and tumor degradation. In vitro and in vivo studies show that increasing the levels of MnSOD and GPx-1 lowers the level of ROS in the cell. Therefore, the activity levels of MnSOD and GPx-1 may be directly related to the efficacy of chemoradiation treatment and hence may influence risk of local recurrence. We tested whether two functional polymorphisms, an Ala-9Val SNP in the mitochondrial targeting sequence of the MnSOD gene and a Pro/Leu SNP at codon 197 near the C-terminus of the GPx-1 protein will correlate with local recurrence in chemoradiation-treated rectal cancer patients. Methods: DNA was extracted from rectal tissue and blood from 92 patients with locally advanced rectal cancer treated with neoadjuvant or adjuvant chemoradiation, of which 38 had local recurrence and 54 had no recurrence. MnSOD Ala-9Val polymorphism and GPx-1 Pro-198Leu polymorphism were tested using PCR-RFLP method. Results: A combined analysis of the genotypes showed patients carrying at least one unfavorable genotype (homozygous Ala for MnSOD and homozygous Leu for GPx-1) had a greater risk of recurrence (relative risk: 2.36, 95% CI) when compared to patients possessing no unfavorable genotypes (p=0.01). Individually, MnSOD and GPx-1 showed trends for tumor recurrence (p=0.087 for GPx-1 and p=0.13 for MnSOD). Conclusions: The data suggest that polymorphisms in free radical scavengers MnSOD and GPx-1 are potential prognostic markers for local recurrence in rectal cancer and may predict chemoradiation efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron NCI; NIH; Roche; Lilly; Pharmacia; Bayer; Bristol-Myers Squibb; Chiron; Aventis; Genentech; ImClone; Cellpathway; Newbiotics; Sanofi

MnSOD and GPx-1 polymorphisms in relation to local recurrence in patients with rectal cancer treated with chemoradiation

3604 Background: Manganese superoxide dismutase (MnSOD) and Glutathione peroxidase-1 (GPx-1) are two enzymes that scavenge ROS (reactive oxygen species) such as superoxide and hydrogen peroxide and protect cells from oxidative damage. MnSOD reduces superoxide to oxygen and hydrogen peroxide, and GPx-1 reduces hydrogen peroxide to water. Radiation therapy produces an excess of ROS, which results in DNA damage, cellular destruction, and tumor degradation. In vitro and in vivo studies show that increasing the levels of MnSOD and GPx-1 lowers the level of ROS in the cell. Therefore, the activity levels of MnSOD and GPx-1 may be directly related to the efficacy of chemoradiation treatment and hence may influence risk of local recurrence. We tested whether two functional polymorphisms, an Ala-9Val SNP in the mitochondrial targeting sequence of the MnSOD gene and a Pro/Leu SNP at codon 197 near the C-terminus of the GPx-1 protein will correlate with local recurrence in chemoradiation-treated rectal cancer patients. Methods: DNA was extracted from rectal tissue and blood from 92 patients with locally advanced rectal cancer treated with neoadjuvant or adjuvant chemoradiation, of which 38 had local recurrence and 54 had no recurrence. MnSOD Ala-9Val polymorphism and GPx-1 Pro-198Leu polymorphism were tested using PCR-RFLP method. Results: A combined analysis of the genotypes showed patients carrying at least one unfavorable genotype (homozygous Ala for MnSOD and homozygous Leu for GPx-1) had a greater risk of recurrence (relative risk: 2.36, 95% CI) when compared to patients possessing no unfavorable genotypes (p=0.01). Individually, MnSOD and GPx-1 showed trends for tumor recurrence (p=0.087 for GPx-1 and p=0.13 for MnSOD). Conclusions: The data suggest that polymorphisms in free radical scavengers MnSOD and GPx-1 are potential prognostic markers for local recurrence in rectal cancer and may predict chemoradiation efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron NCI; NIH; Roche; Lilly; Pharmacia; Bayer; Bristol-Myers Squibb; Chiron; Aventis; Genentech; ImClone; Cellpathway; Newbiotics; Sanofi