Manganese Superoxide Dismutase Genotypes Research Articles

Associations between the phenotype and genotype of MnSOD and catalase in periodontal disease

BackgroundPeriodontal disease is an inflammatory disease in which pathogenic infections trigger a series of inflammatory responses and redox regulation. The hypothesis of this study was that a host’s redox regulation, as modified by genetic polymorphisms, may affect periodontal disease activities (including the plaque index (PlI), bleeding on probing (BOP), and pocket depth (PD)) during periodontal therapy.MethodsIn total, 175 patients diagnosed with periodontitis were recruited from the Department of Periodontology, Taipei Medical University Hospital. Both saliva samples and clinical measurements (PlI, BOP, and PD) were taken at the baseline and at 1 month after completing treatment. Salivary manganese superoxide dismutase (MnSOD) and catalase, and corresponding genetic polymorphisms (MnSOD, T47C, rs4880 and Catalase, C-262 T, rs1001179) were determined. The extent of change (Δ) of MnSOD or catalase was calculated by subtracting the concentration after completing treatment from that at the baseline.ResultsSubjects who carried the Catalase CC genotype had significantly higher salivary MnSOD or catalase levels. The MnSOD genotype had a significant effect on the percentage of PDs of 4~9 mm (p = 0.02), and salivary ΔMnSOD had a significant effect on the PlI (p = 0.03). The Catalase genotype had a significant effect on the PlI (p = 0.01~0.04), but the effect was not found for the mean PlI or PD. There was a significant interaction between the MnSOD genotype and salivary ΔMnSOD on PDs of 4~9 mm. After adjusting for gender, years of schooling, smoking status, and alcohol consumption, subjects with ΔMnSOD of < 0 μg/ml or Δcatalase of < 0 μg/ml had significantly higher 5.58- or 5.17-fold responses to scaling and root planing treatment.ConclusionsThe MnSOD T47C genotype interferes with the phenotype of salivary antioxidant level, alters MnSOD levels, and influences the PD recovery. MnSOD and catalase gene polymorphism associated with phenotype expression and susceptibility in periodontal root planing treatment responses.

Association of manganese superoxide dismutase Ala16Val polymorphism in the incidence of acute myocardial infarction in the Egyptians.

Background: Oxidative stress has been implicated in various diseases including atherosclerosis; the most common pathologic process underlying acute myocardial infarction (AMI). The manganese superoxide dismutase (MnSOD) antioxidant enzyme affords the major defense against reactive oxygen species (ROS) within the mitochondria. MnSOD Alanine16Valine (A16V) single nucleotide polymorphism (SNP) has been shown to decrease MnSOD detoxification activity. Aim: A case-control study was conducted to investigate the association between MnSOD A16V polymorphism and the incidence of AMI in the Egyptians, investigate the contribution of oxidative stress represented by hexanoyl lysine adduct (HEL), an oxidative stress biomarker, in the pathogenesis of AMI and finally correlate the MnSOD genotypes with HEL serum levels. Methods: A total of 200 Egyptian subjects were recruited for the study; 100 AMI patients and 100 control subjects. Genotypes of the MnSOD A16V polymorphism were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum HEL was measured by ELISA. Results: A significant difference in the distribution of the MnSOD A16V genotypes was observed; VV genotype was significantly higher in AMI than controls (p ≤ 0.0001). Also, studying the allele frequencies revealed that Val allele was significantly higher in AMI than controls (p ≤ 0.0001). Serum analysis showed higher levels of HEL in AMI patients (p = 0.0142). Furthermore, HEL levels were found to be significantly higher in VV genotype in AMI (p = 0.0273). Conclusions: Our study suggests that MnSOD A16V polymorphism is associated with increased risk of developing AMI in the Egyptians. Moreover, the VV genotype is associated with higher HEL levels.

Genetic variation and risk of DNA damage in peripheral blood lymphocytes of Iranian formaldehyde-exposed workers.

Formaldehyde (FA) has given positive results for the genetic damage evaluated in human peripheral blood lymphocytes. Polymorphism plays a special role in the toxicity of chemicals. DNA damage in blood cells was evaluated in workers who were occupationally exposed to FA. This study tested the association of alcohol dehydrogenase III (ADH3) and manganese-superoxide dismutase (Mn-SOD) gene polymorphism, with DNA damage of peripheral blood lymphocytes. Gene polymorphisms were evaluated in 54 workers from melamine dinnerware workshops and 34 workers from dairy production workshops. The control and exposed population were matched based on age, smoking, work history and socioeconomic status. DNA damage was evaluated by alkaline comet assay in the peripheral blood lymphocytes. ADH3 and Mn-SOD genotypes were determined in all workers using polymerase chain reaction-restriction fragment length polymorphism method. DNA damage of lymphocyte cells was significantly higher ( p < 0.001) in the exposed individuals in comparison with the control population. The examinations of the exposed group had revealed significantly higher ( p < 0.01) variant of Val/Val of Mn-SOD compared to control group. In workers with ADH32-2 variant, significantly higher levels of DNA damage ( p < 0.01) were observed than the control population with the same genotype. It could be concluded that enzymes involved in the metabolism of FA and oxidative stress controlling are two important effective parameters for DNA damage of peripheral blood lymphocytes in exposed people. These results are regarded as a pioneer investigation for the management of health risks assessment.

Abstract LB-168: Differential response to genistein on prostate cancer cells expressing different MnSOD variants

Abstract Soy consumption may prevent prostate cancer (PCa) and be beneficial for patients with this malignancy. However, there are contradictory data on the anticancer effects of the soy isoflavone genistein, which has antioxidant properties and can affect cell proliferation and apoptosis of cancer cells through multiple mechanisms, including estrogen receptor-β mediation. Genistein also affects the expression of the manganese superoxide dismutase (MnSOD) gene and polymorphisms in this gene are related to risk of PCa. This study addressed the hypothesis that the effects of physiological concentrations of genistein on PCa cell proliferation and apoptosis are dependent on their MnSOD genotype and ER-β status, as well as on oxidative stress levels. In addition, we determined the effects of genistein on PCa cell proliferation and apoptosis at varying input levels of reactive oxygen species (O2.-), while controlling ER-β status and MnSOD genotype. PC-3 PCa cells transfected with different MnSOD genotypes (Ala/Ala and Val/Val) were cultured and treated with genistein at physiological concentrations (0, 0.01, 0.1, 0.5, 1, 5, 10 and 50 μM). After 24, 48 and 72 hours of incubation, we determined cytotoxicity, cell proliferation, apoptosis, and ER-β expression. Cell proliferation was induced at 0,5 μM genistein in PC-3 cells with MnSOD Val genotype and decreased at 2.5 μM in Ala genotype cells at 48 hours of treatment, which suggests 30-40% lower activity of Val genotype cells compared with the Ala variant, possibly increasing susceptibility to oxidative stress. ER-β expression levels were elevated by 48 hours of genistein treatment at 0.5 μM in Val genotype cells and were decreased at 2.5 μM in Ala cells. PARP protein expression levels, determined to investigate genistein’s effect on apoptosis in these cells, started to increase at 0.5 μM in Val cells and to decrease at 2.5 μM in Ala cells. These results suggest that PC-3 cells with Val genotype have increased oxidative stress and genistein at 0.5 μM induced proliferation in these cells. By contrast, genistein decreased proliferation of PC-3 cells with Ala genotype which have higher detoxification activity of superoxide radicals. Thus, genistein causes differential responses of cells with MnSOD variants, ER-β expression, and oxidative stress potential. This study help to understand the mechanisms of genistein's effects on PCa cells under physiological conditions and assess the impact of interactions of MnSOD genotype, ER-β presence, and ROS environment in the context of non-linear dose-response relationships contrasting potential benefit with possible harm of genistein. The results of this study may have important implications for PCa patients who consume soy in therapeutic and chemopreventive settings. Citation Format: Sule Terzioglu Usak, Maarten C. Bosland, Nur Özten Kandas. Differential response to genistein on prostate cancer cells expressing different MnSOD variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-168. doi:10.1158/1538-7445.AM2017-LB-168

Polymorphism variant of MnSOD A16V and risk of female infertility in northern Iran

ObjectiveInfertility is a disease of the reproductive system defined by inability to conceive after having regular unprotected intercourse. Both environmental and genetic factors can be involved in female infertility. Manganese superoxide dismutase (MnSOD) is a crucial mitochondrial antioxidant enzyme that has a key role in cellular defense against agents that induce oxidative stress. The present study was aimed to evaluate the MnSOD A16V gene polymorphism in female infertility in northern Iran. Materials and methodsSamples were obtained from 150 patients diagnosed with female infertility and 150 controls and genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. ResultsThe MnSOD genotype frequencies amongst the 150 cases were A/A = 27.3%, A/V = 69.4%, and V/V = 3.3%; the A and V allele frequencies were 62% and 38%, respectively. The MnSOD genotype frequencies amongst the 150 controls were A/A = 33.3%, A/V = 48.0%, and V/V = 18.7%; the A and V allele were 57% and 43%, respectively. We observed a significant difference in genotype distributions of MnSOD A16V polymorphism between patients and controls (p = 0.0001). ConclusionIt is suggested that the MnSOD A16V polymorphism may be associated with a risk of female infertility in northern Iran. More studies should be considered with a larger number of patients and controls to confirm our results.

Manganese superoxide dismutase, glutathione peroxidase and catalase gene polymorphisms and clinical outcomes in acute kidney injury

Introduction The aim of this study was to evaluate the potential association of single gene polymorphisms of manganese superoxide dismutase (MnSOD), glutathione peroxidase 1 (GPX1) and catalase (CAT) with clinical outcomes of acute kidney injury (AKI). Materials and methods Ninety AKI patients and 101 healthy volunteers were included in the study. Determination of MnSOD rs4880, GPX1 rs1050450 and CAT rs769217 polymorphisms was performed using real-time polymerase chain reaction amplification. The duration of hospitalization of AKI patients, dialysis and intensive care requirements, sepsis, oliguria and in-hospital mortality rates were assessed. Results The MnSOD, GPX1 and CAT genotypes and allele frequencies of AKI patients did not differ significantly from those of healthy controls. In patients with a T allele in the ninth exon of the CAT gene, intensive care requirements were greater than those of patients with the CC genotype (p = 0.04). In addition, sepsis and in-hospital mortality were observed significantly more frequently in patients with a T allele in the ninth exon of the CAT gene (p = 0.03). Logistic regression analysis determined that bearing a T allele was the primary determinant of intensive care requirements and in-hospital mortality, independent of patient age, gender, presence of diabetes and dialysis requirements (OR 6.10, 95% CI 1.34–27.81, p = 0.02 and OR 10.25, 95% CI 1.13–92.80, p = 0.04, respectively). Conclusion Among AKI patients in the Turkish population, hospital morbidity and mortality were found to be more frequent in patients bearing a T allele of the rs769217 polymorphism of the CAT gene.

Association of MnSOD AA Genotype with the Progression of Prostate Cancer.

PurposeTo investigate whether manganese superoxide dismutase (MnSOD) genetic polymorphism is associated with the clinical significance of prostate cancer.Materials and MethodsProstates were obtained from 194 deceased men 45 years or older who did not have a history of prostate cancer. Serial sections and histological examinations of the prostate were performed. The MnSOD genotypes of the specimens were determined by polymerase chain reaction restriction fragment length polymorphism analysis.ResultsOf the 194 men, 31 and 26 had clinically insignificant and significant prostate cancer. Clinically significant cancer comprised 29% and 58% of the cancers in men <70 and >70 years old, respectively. The age-specific proportion of significant cancer significantly increased with the advance of age (p<0.001). MnSOD AA, as compared with the other genotypes (VA and VV together), was associated with significant prostate cancer across all ages, odds ratio (OR) 2.34, 95% confidence interval (CI) 0.99-5.49, and in men older than 69 years (OR 4.89, 95% CI 1.51-15.8), but not in men younger than 70 years. The genotype was not associated with clinically insignificant cancer regardless of age. The comparison between significant and insignificant cancer, the OR (95% CI) for MnSOD AA was 5.04 (1.05-24.2) (sensitivity 0.57, specificity 0.78, positive predictive value 0.78) in men older than 69 years.Conclusions MnSOD polymorphism is strongly associated with the clinical significance of prostate cancer in men older than 69 years, but not in men younger than 70 years suggesting that oxidative stress may be involved in the progression of the disease. MnSOD may be a clinically useful marker to predict the potential of progression of prostate cancer.

Spontaneous abortion and functional polymorphism (Val16Ala) in the manganese SOD gene

Spontaneous abortion is the most common complication of early pregnancy. Genetic factors have been hypothesised to play a role in spontaneous abortion. Since it is possible that the balance of oxidants and antioxidants can be affected by different genetic variants, gene polymorphisms have been proposed as a susceptibility factor that increases the chance of miscarriage. Manganese superoxide dismutase is an important antioxidant enzyme encoded by manganese superoxide dismutase (MnSOD) gene. The aim of this experiment was to assess whether Val16Ala polymorphism of MnSOD gene is associated with miscarriage in northern Iran. Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Statistical analyses were conducted using the χ2-test. The genetic distributions did not differ significantly between cases and controls, however slightly more Val/Val genotypes were found among the patients compared with control subjects (p = 0.059). No correlation was observed between susceptibility to abortion and MnSOD Val16Ala polymorphism. Larger population-based studies are needed for clarifying the relationship between abortion and MnSOD genotypes.

Association between manganese superoxide dismutase gene polymorphism and breast cancer risk: A meta-analysis of 17,842 subjects

The aim of this meta-analysis was to explore the association between the manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk, and to investigate the interaction of this gene polymorphism with known risk factors for breast cancer. Crude odds ratios (ORs) with 95% confidence intervals (CIs) for breast cancer risk associated with co-dominant models [valine/alanine (Val/Ala) vs. Val/Val, Ala/Ala vs. Val/Val], a dominant model (Val/Ala + Ala/Ala vs. Val/Val) and a recessive model (Ala/Ala vs. Val/Ala + Val/Val) were statistically estimated. This meta‑analysis included 8,102 breast cancer cases and 9,740 controls from 14 published case-control studies. The data revealed no significant association between the MnSOD polymorphism and the risk of developing breast cancer. However, upon subgroup analyses, the risk was significantly increased in premenopausal women with the dominant model of the MnSOD gene polymorphism (OR, 1.15; 95% CI, 1.01-1.31). Statistically significant increased risks were also identified in women with the MnSOD genotypes containing the Ala allele who had a tobacco smoking history (OR, 1.17; 95% CI, 1.02-1.34), a higher body mass index (OR, 1.26; 95% CI, 1.02-1.56) or who used oral contraceptives (OR, 1.98; 95% CI, 1.34-2.93). By contrast, there was no significant association between breast cancer risk and alcohol consumption and ethnicity. This meta‑analysis demonstrated no statistically significant association between the MnSOD gene polymorphism and breast cancer susceptibility, except in premenopausal women with certain unhealthy lifestyle habbits.

An OGG1 polymorphism is associated with mitochondrial DNA content in pesticide-exposed fruit growers

Exposure to pesticides has the capacity to cause mitochondrial dysfunction. An increase mitochondrial DNA (mtDNA) content has also been suggested to relate with DNA damaging agent. In mitochondria, the manganese superoxide dismutase (MnSOD) is a scavenger of reactive oxygen species, and the 8-oxoguanine DNA glycosylase (OGG1) is the major DNA glycosylase for the repair of 8-oxoG lesions. However, the alteration of mtDNA content elicited by pesticide exposure in people with genetic variations in MnSOD or OGG1 has not been investigated. In this study, the mitochondrial to nuclear DNA ratio was quantified in the peripheral blood of 120 fruit growers who experienced pesticide exposure and 106 unexposed controls by real-time quantitative polymerase chain reaction (real-time qPCR). Questionnaires were administered to obtain demographic data and occupational history. The MnSOD and OGG1 genotypes were identified by the PCR based restriction fragment length polymorphism analysis. After adjusting for confounding effects, multiple regression model revealed that subjects experiencing high or low pesticide exposure had a greater mtDNA content than that of controls. The OGG1 Ser-Ser genotype was also associated with an increased mtDNA content. No association between MnSOD genotype and mtDNA content was revealed. Thus, subjects experiencing pesticide exposure had greater mtDNA content and the OGG1 genotype may modulate mtDNA content in pesticide-exposed fruit growers.

Expression and Genotype of Manganese Superoxide Dismutase (MnSOD) in Lung Cancer Cells of Smoker Patients

Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 Lung cancer is the most common cause of cancer-related deaths in men and women all over the world. Although &nbsp;the most common cause of lung cancer is long-term exposure to tobacco smoke, the role of genetic factor for the cell&nbsp; defense mechanism against lung cancer, such as MnSOD, should also be considered. MnSOD is the major antioxidant&nbsp; in matrix mitochondria, which plays a pivotal role in eliminating anion superoxide free radical generated from the&nbsp; tobacco smoke. The genotype of human MnSOD which is related to various cancers has been reported, but the&nbsp; correlation between the genotype and the enzyme activity remains unknown. The aim of this study is to analyze the&nbsp; expression (mRNA and enzyme specific activity) and genotype of MnSOD in lung cancer cells of smoker patients.&nbsp; Samples were normal and lung cancer cells of patients operated in Persahabatan Hospital from May to December 2008&nbsp; (3 patients), as well as lung cancer cells extracted from FFPE collection of Persahabatan Hospital. Leukocyte cells of 15&nbsp; healthy subjects aged more than 40 years with a history as a smoker for more than 10 years were used as controls.&nbsp; MnSOD gene expression was analyzed based on relative mRNA level and specific activity of MnSOD in lung cancer&nbsp; and leukocyte cells. The genotyping was performed using PCR-RFLP. The result showed that the lung cancer cells&nbsp; observed in this study have a Val/Val genotype frequency of 100%, thus Ala/Val genotype could not be found&nbsp; compared to the leukocyte cells of smoker controls (13.3%). The MnSOD specific activity in lung cancer of smoker&nbsp; patients is higher than in leukocyte cells of smoker controls. Result of MnSOD gene expression at the level of mRNA&nbsp; and protein activity was contradictory. Compared to the expression of MnSOD in the normal lung cells of patients, in&nbsp; the lung cancer cells the level of MnSOD mRNA was lower (0.382 times), whereas its specific activity was higher&nbsp; (1.988 times). Therefore, in this study we could conclude the role of MnSOD as tumor suppressor in lung cancer. The&nbsp; enhancement of MnSOD specific activity in lung cancer cells might be one of the cell responses against the exaggerated&nbsp; attack of ROS particularly in smokers. Further studies are required to analyze the correlation between MnSOD genotype&nbsp; and response or prognosis of cancer therapy.

Genetic Polymorphism of Manganese Superoxide Dismutase is Associated with Childhood Asthma

Objective. Cellular defenses against allergens and reactive oxygen species (ROS) exposure are critical in the pathogenesis of asthma. CD14 is a receptor for various bacterial products, such as lipopolysaccharides (LPS), and is also a mediator of inflammatory processes. Manganese superoxide dismutase (MnSOD) is an ROS scavenger, and myeloperoxidase (MPO) can convert hydrogen peroxide into hypochlorous acid; thus, they are considered to be involved in inflammatory defense. The authors conducted a case-control study to evaluate the susceptibility to childhood asthma based on CD14, MnSOD, and MPO genes. Methods. The CD14 −260, MnSOD −9, and MPO −463 genotypes were identified by polymerase chain reactions for 116 asthmatic children and 232 healthy controls. Questionnaires were administered to obtain demographic characteristics. Allergen testing used common Taiwanese aeroallergens. Results. A higher level of parental education, family history of asthma, incense burning at home, allergen-test positive, and the MnSOD Val-Ala/Ala-Ala genotypes (matched relative risk = 2.0; 95% confidence interval = 1.0–4.2) were significantly associated with childhood asthma. Interactions between CD14, MnSOD, MPO genotypes and allergy status were significantly associated with asthma risk in these children (all p <.001). Furthermore, atopic cases with MnSOD Val-Ala/Ala-Ala (log eosinophil 2.66/mm3, log total serum immunoglobulin E [IgE] 2.48 IU/ml) or Val-Val (log eosinophil 2.61/mm3, log total serum IgE 2.63 IU/ml) genotypes had elevated eosinophil counts and total serum IgE levels as compared to nonatopic cases with MnSOD Val-Val genotype (log eosinophil 2.27/mm3, log total serum IgE 1.83 IU/ml). Conclusions. Susceptible MnSOD genotypes might modulate the development of asthma in Taiwanese children.

253 PATHOLOGICAL CHARACTERISTICS AND MANGANESE SUPEROXIDE DISMUTASE GENETIC POLYMORPHISM OF PROSTATE CANCER IN MEN 70 YEARS OR OLDER: AN AUTOPSY STUDY

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History II1 Apr 2010253 PATHOLOGICAL CHARACTERISTICS AND MANGANESE SUPEROXIDE DISMUTASE GENETIC POLYMORPHISM OF PROSTATE CANCER IN MEN 70 YEARS OR OLDER: AN AUTOPSY STUDY Taro Iguchi, Ching Wang, Nicolas Delongchamps, Gustavo de la Roza, Yujiro Nitta, Toshihide Naganuma, Katsuyuki Kuratsukuri, Junji Uchida, Hidenori Kawashima, Gabriel Haas, and Tatsuya Nakatani Taro IguchiTaro Iguchi Osaka, Japan More articles by this author , Ching WangChing Wang Syracuse, NY More articles by this author , Nicolas DelongchampsNicolas Delongchamps Paris, France More articles by this author , Gustavo de la RozaGustavo de la Roza Syracuse, NY More articles by this author , Yujiro NittaYujiro Nitta Osaka, Japan More articles by this author , Toshihide NaganumaToshihide Naganuma Osaka, Japan More articles by this author , Katsuyuki KuratsukuriKatsuyuki Kuratsukuri Osaka, Japan More articles by this author , Junji UchidaJunji Uchida Osaka, Japan More articles by this author , Hidenori KawashimaHidenori Kawashima Osaka, Japan More articles by this author , Gabriel HaasGabriel Haas Syracuse, NY More articles by this author , and Tatsuya NakataniTatsuya Nakatani Osaka, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.312AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Increased life expectancy and the availability of less invasive treatment methods have led to an interest in the characterization of prostate cancer (PCa) in elderly men. Manganese superoxide dismutase (MnSOD) is an enzyme involved with oxidative stress. A polymorphism encoding for either valine (V) or alanine (A) at codon 16 of human MnSOD gene has been described. We previously reported that MnSOD AA genotypes were associated with PCa. We now investigated whether MnSOD genotypes are associated with clinically aggressive PCa in elderly men by using autopsy prostates where we can certainly account for all cancers present. METHODS A total of 194 prostates were from deceased men (age range 46-92 years) who have not been diagnosed with PCa in their lifetime were eligible for analysis. Prostates were processed whole-mounted at 5-mm intervals. Cancers were defined as clinically “significant” or “insignificant” based on established histological criteria. Genomic DNA was extracted from normal area of the prostate and MnSOD genotyping was performed using PCR restriction fragment length polymorphism analysis. RESULTS Fifty-seven out of 194 prostates had histological evidence of PCa. Thirty-three out of 74 prostates (45%) from men older than 69 had histological evidence of PCa. Twenty-six out of 137 (19%) from men younger than 70 had PCa. Clinically significant PCa were more common in old than in young men (64% vs 23%, p<0.05). MnSOD AA genotype was not associated with PCa (OR=1.90, 95%CI: 0.97-3.71, adjusted for age). In elderly men MnSOD AA genotype was strongly associated with “significant” PCa, but not in younger group (Table). On the other hand, MnSOD AA genotype was not associated with “insignificant” PCa regardless of age (Table). CONCLUSIONS Men older than 69 are more likely to have larger, higher grade, and clinically significant PCa as compared to younger men. MnSOD polymorphism is associated with aggressive PCa risk in elderly men. These results suggest that oxidative stress may be involved in the progression of PCa. Autopsy studies provide important information regarding the prevalence and genetic characteristics of PCa in SPECIFIC age groups. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e99-e100 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Taro Iguchi Osaka, Japan More articles by this author Ching Wang Syracuse, NY More articles by this author Nicolas Delongchamps Paris, France More articles by this author Gustavo de la Roza Syracuse, NY More articles by this author Yujiro Nitta Osaka, Japan More articles by this author Toshihide Naganuma Osaka, Japan More articles by this author Katsuyuki Kuratsukuri Osaka, Japan More articles by this author Junji Uchida Osaka, Japan More articles by this author Hidenori Kawashima Osaka, Japan More articles by this author Gabriel Haas Syracuse, NY More articles by this author Tatsuya Nakatani Osaka, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Age-Induced Reduction in Mitochondrial Manganese Superoxide Dismutase Activity and Tolerance of Macrophages Against Apoptosis Induced by Oxidized Low Density Lipoprotein

Oxidative stress is thought to play an important role in age-induced atherogenesis. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that is localized in mitochondria and protects macrophages against apoptosis induced by oxidized low density lipoprotein (oxLDL). We previously reported that genetic polymorphism of MnSOD modifies mitochondrial MnSOD (mtMnSOD) activity and increases the risk of coronary artery disease. In this study, we investigated the association of mtMnSOD activity with aging. Blood samples were taken from 69 healthy participants aged 20-52. The MnSOD genotype was analyzed using real-time polymerase chain reaction. Leukocyte mtMnSOD activity was measured by inhibition of WST-1. Macrophages were treated with oxLDL and the apoptotic cells were counted. mtMnSOD activity was inversely correlated with the age of the participant regardless of the MnSOD genotype. The percentage of apoptotic macrophages after incubation with oxLDL correlated with age. Thus, the percentage of apoptotic macrophages after incubation with oxLDL was inversely related to mtMnSOD activity. Lecithinized SOD, which can easily transfer into cells, improved the tolerance of macrophages against oxLDL. mtMnSOD activity decreases with age, thereby reducing the tolerance of macrophages against oxLDL-induced apoptosis. Our data may provide an important clue to clarify the mechanisms of age-induced atherosclerosis.

Association of the manganese superoxide dismutase polymorphism with vasospastic angina pectoris

Vasospastic angina (VSA) is closely related to endothelial dysfunction caused by oxidative damage. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that functions in mitochondria. There are two genetic variants of MnSOD arising from a substitution of an alanine for a valine in the signal peptide. We previously reported that the valine allele of MnSOD decreases the mitochondrial MnSOD (mtMnSOD) activity. Here, we investigated the association of the MnSOD polymorphism (Ala16Val) with VSA. Blood samples were collected from 618 healthy subjects who did not have any symptoms or other evidence suggesting angina pectoris, and 228 patients who underwent coronary angiography on suspicion of angina, and were diagnosed to have VSA by acetylcholine test. MnSOD genotype of each subject was determined by real-time polymerase chain reaction. The valine allele frequency was higher in the VSA patients (0.890) than in the healthy subjects (0.839) [odds ratio (OR)=1.55, p=0.0085]. In healthy subjects the MnSOD genotype distribution was as follows: alanine/alanine 1.9%, alanine/valine 28.3%, and valine/valine 69.8%, and in VSA patients the prevalence was: alanine/alanine 1.3%, alanine/valine 19.3%, and valine/valine 79.4%. Thus, the valine allele was closely associated with VSA (p=0.019). Multivariate logistic regression analysis showed valine/valine homozygosity to be an independent risk factor for VSA (OR=2.02, 95% CI 1.43, 2.85; p=0.0012). The valine variant of MnSOD signal peptide increases the risk of VSA.

Alcohol consumption and breast tumor mitochondrial DNA mutations.

Mitochondrial DNA (mtDNA) mutations are frequent in breast tumors, but the etiology of these mutations is unknown. We hypothesized that these mutations are associated with exposures that affect oxidative stress such as alcohol metabolism. Using archived tumor blocks from incident breast cancer cases in a case control study, the Western New York Exposures and Breast Cancer (WEB) study, analysis of mtDNA mutations was conducted on 128 breast cancer cases selected based on extremes of alcohol intake. Temporal temperature gradient gel electrophoresis (TTGE) was used to screen the entire mtDNA genome and sequencing was completed for all TTGE positive samples. Case-case comparisons were completed using unconditional logistic regression to determine the relative prevalence of the mutations by exposures including alcohol consumption, manganese superoxide dismutase (MnSOD) genotype, nutrient intake related to oxidative stress and established breast cancer risk factors. Somatic mtDNA mutations were found in 60 of the 128 tumors examined. There were no differences in the prevalence of mtDNA mutations by alcohol consumption, MnSOD genotype or dietary intake. The likelihood of mtDNA mutations was reduced among those with a positive family history for breast cancer (OR = 0.33, CI = 0.12-0.92), among postmenopausal women who used hormone replacement therapy (OR = 0.46, CI = 0.19-1.08, P = 0.08) and was increased for ER negative tumors (OR = 2.05, CI = 0.95-4.43, P = 0.07). Consistent with previous studies, we found that mtDNA mutations are a frequent occurrence in breast tumors. An understanding of the etiology of mtDNA mutations may provide insight into breast carcinogenesis.

Manganese superoxide dismutase: effect of the ala16val polymorphism on protein, activity, and mRNA levels in human breast cancer cell lines and stably transfected mouse embryonic fibroblasts

The manganese superoxide dismutase (MnSOD) ala16val polymorphism has been associated with various diseases including breast cancer. In the present study, we investigated levels of MnSOD protein, enzymatic activity, and mRNA with respect to MnSOD genotype in several human breast carcinoma cell lines and in mouse embryonic fibroblasts (MEF), developed from the MnSOD knockout mouse, stably expressing human MnSOD-ala and MnSOD-val. In human breast cell lines, the MnSOD-ala allele was associated with increased levels of MnSOD protein and MnSOD protein per unit mRNA. In the MEF transformants, MnSOD activity correlated fairly well with MnSOD protein levels. MnSOD mRNA expression was significantly lower in MnSOD-ala versus MnSOD-val lines. MnSOD protein and activity levels were not related to MnSOD genotype in the transformed MEF, although, as observed in the human breast cell lines, the MEF human MnSOD-ala lines produced significantly more human MnSOD protein per unit mRNA than the human MnSOD-val lines. This suggests that there is more efficient production of MnSOD-ala protein compared to MnSOD-val protein. Examination of several indicators of reactive oxygen species levels, including superoxide and hydrogen peroxide, in wild-type MEF and in MEF expressing similar elevated amounts of MnSOD-ala or val activity did not show differences related to the levels of MnSOD protein expression. In conclusion, in both human breast carcinoma cell lines and MEF cell lines stably transfected with human MnSOD, the MnSOD-ala allele was associated with increased production of MnSOD protein per unit mRNA indicating a possible imbalance in MnSOD protein production from the MnSOD-val mRNA.

Functional polymorphism in manganese superoxide dismutase and antioxidant status: Their interactions on the risk of cervical intraepithelial neoplasia and cervical cancer

Objective Manganese superoxide dismutase (MnSOD), the primary antioxidant enzyme in mitochondria, plays a key role in protecting cells from oxidative stress. Furthermore, the MnSOD rs4880 polymorphism is associated with enzyme activity. The authors evaluated the interaction between MnSOD genotypes and cervical carcinogenesis risk and the modulating effects of serum antioxidant nutrient status (β-carotene, lycopene, zeaxanthin/lutein, retinol, α-tocopherol and γ-tocopherol). Methods Cases and controls for this study were recruited between June 2006 and July 2007 (263 controls, 84 cervical intraepithelial neoplasia (CIN), 94 CIN 2/3, and 99 cases of cervical cancer). The MnSOD polymorphism at rs4880T/C was examined using SNaPshot assays. Serum antioxidant vitamin concentrations were measured by reverse-phase gradient high-pressure liquid chromatography. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated after adjusting for age, menopause, parity, oral contraceptive use, smoking and alcohol consumption. Results No association was found between the MnSOD rs4880 polymorphism and cervical cancer. However, genotypes significantly modified the risk of cervical cancer in association with the serum statuses of micronutrients ( P interaction < 0.05 for β-carotene, lycopene, zeaxanthin/lutein, α-tocopherol, and γ-tocopherol). Decreased CIN1 risk in association with the MnSOD rs4880 variant genotype was also observed particularly for subjects with higher β-carotene and γ-tocopherol levels. Similar results were observed for lycopene and α-tocopherol in relation to the risk of CIN2/3. Conclusion Our findings suggest that a higher antioxidant micronutrients status may decrease the risk of CIN and cervical cancer and modify the effect of the MnSOD polymorphism on disease risk.

Manganese Superoxide Dismutase (MnSOD) Polymorphism, Alcohol, Cigarette Smoking and Risk of Oesophageal Cancer

Alcohol, tobacco smoke and Barrett's oesophagus as a consequence of gastro-oesophageal reflux are the main risk factors in oesophageal carcinogenesis. All risk factors may induce oxidative stress. Manganese superoxide dismutase (MnSOD) is one important repair enzyme for reactive oxidative stress (ROS)-induced damage. MnSOD polymorphisms in the -9 position of the signal sequence of the protein may lead to critical enzyme deficiency. The aim of the present study was to investigate the role of polymorphisms of MnSOD in patients with oesophageal cancer [n = 170, 61 patients with adenocarcinoma (AC), 109 patients with squamous cell carcinoma (SCC)] compared to heavy drinkers (n = 160) and healthy blood donors (n = 400). Genotyping was performed by PCR-RFLP analysis using genomic DNA extracted from whole blood. The Ala/Ala genotype was 27.7% in cancer patients (29.5% AC, 26.6% SCC), 23.1% in patients with heavy alcohol abuse and 12.5% in the group of healthy blood donors. These results were not statistically significant after multivariate analysis controlling for age, sex, alcohol, cigarettes and interactions (odds ratio 0.92, 95% confidence interval = 0.63-1.36, for cancer patients versus heavy drinkers; odds ratio 1.02, 95% confidence interval = 0.51-2.03, for cancer patients versus blood donors; analysis by logistic regression). Subjects with an Ala/Ala genotype (81.3 g/day) had a significantly higher alcohol intake than those with Val/Ala (63.9 g/day) or Val/Val (53.8 g/day) genotype (P < 0.00001 by the Kruskal-Wallis test). MnSOD polymorphisms play no role in the genetic predisposition to oesophageal cancer. However, our data suggest a complex gene-to-phenotype interaction between the MnSOD genotype and alcohol misuse.

Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk

The manganese superoxide dismutase (MnSOD) gene encodes an antioxidant enzyme (SOD2) that may protect cells from oxidative damage. The MnSOD allele with Val as amino acid 16 encodes a protein that has 30-40% lower activity compared with the MnSOD Ala variant, hence possibly increasing susceptibility to oxidative stress. On the other hand, some epidemiologic studies suggest that the Ala allele is associated with a higher risk of cancer, including prostate cancer. We conducted a nested case-control study in the Health Professionals Follow-up Study with 612 incident prostate cancer cases and 612 matched controls to investigate the role of the MnSOD gene Ala16Val polymorphism and its joint association with plasma carotenoid concentrations in relation to risk of total prostate cancer and aggressive prostate cancer (advanced stage or Gleason sum > or =7). The allele frequencies in the controls were 49.8% for Ala and 50.2% for Val. No association was found between the MnSOD genotype and risk of total and aggressive prostate cancer. Furthermore, no statistically significant interaction was observed between the MnSOD genotype and any of the plasma carotenoids in relation to risk of total and aggressive prostate cancer. In analyses in which we combined data from plasma and dietary carotenoids and created a quintile score to reflect long-term carotenoid status, a 3-fold [95% confidence interval: 1.37-7.02] increased risk of aggressive prostate cancer was observed among men with the Ala/Ala genotype in the presence of low long-term lycopene status (P-value, test for interaction = 0.02) as compared with men with the Ala/Val+Val/Val genotypes with low long-term lycopene status. In this cohort of mainly white men, the MnSOD gene Ala16Val polymorphism was not associated with total or aggressive prostate cancer risk. However, men with the MnSOD Ala/Ala genotype who had low long-term lycopene status had a higher risk of aggressive prostate cancer compared with individuals with the other genotypes. These results are consistent with findings from earlier studies that reported when antioxidant status is low, the MnSOD Ala/Ala genotype may be associated with an increased risk of aggressive prostate cancer.