Manganese Superoxide Dismutase Polymorphism Research Articles

SOD2 in platelets: with age comes responsibility

SOD2 in platelets: with age comes responsibility

The structure-function relationships and physiological roles of MnSOD mutants.

In this review, we focus on understanding the structure–function relationships of numerous manganese superoxide dismutase (MnSOD) mutants to investigate the role that various amino acids play to maintain enzyme quaternary structure or the active site structure, catalytic potential and metal homeostasis in MnSOD, which is essential to maintain enzyme activity. We also observe how polymorphisms of MnSOD are linked to pathologies and how post-translational modifications affect the antioxidant properties of MnSOD. Understanding how modified forms of MnSOD may act as tumor promoters or suppressors by altering the redox status in the body, ultimately aid in generating novel therapies that exploit the therapeutic potential of mutant MnSODs or pave the way for the development of synthetic SOD mimics.

Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients.

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

Association of plasma manganese and MnSOD rs4880 polymorphism with nonalcoholic fatty liver disease

BACKGROUND AND AIM: Manganese is both an essential micronutrient and a known toxicant, and plays crucial roles in normal metabolism. However, few researchers have focused on the association between manganese and nonalcoholic fatty liver disease (NAFLD), and it is unclear whether this association differs according to manganese superoxide dismutase (MnSOD) genetic variations. We aimed to explore the association between plasma manganese and NAFLD as well as whether the association could be modified by MnSOD polymorphisms. METHODS: We performed a 1:1 matched case-control study in 1838 Chinese Han subjects, who were determined according to the NAFLD diagnosis and treatment guidelines of the Chinese Medical Association. Plasma manganese levels were detected by inductively coupled plasma mass spectrometry, and MassArray system was applied for MnSOD rs4880 polymorphism genotyping. RESULTS:The medians of plasma manganese concentrations were 3.80 and 3.38 μg/L for controls and NAFLD, respectively. After multivariable adjustment, the correlation between plasma manganese levels and NAFLD still existed and showed a negatively correlated dose-effect relationship. The ORs (95% CIs) of NAFLD across quartiles of plasma manganese were 1.00 (reference), 0.78 (0.58–1.07), 0.58 (0.41–0.81), 0.55 (0.39–0.77) (P-trend 0.001). For each SD increment in plasma manganese, the risk of NAFLD decreased by 20% (adjusted OR = 0.80, 95% CI: 0.71–0.91). In the restrict cubic spline analysis, we observed the odds of NAFLD were decreased with the increment of manganese concentration and reached a plateau at around 4.50 µg/L. Compared with the rs4880 TT genotype, the associations between CT, CC, CT + CC genotypes and NAFLD were not significant, and we did not observe interaction effects of plasma manganese and MnSOD rs4880 polymorphisms on NAFLD. CONCLUSIONS:Our results suggested a significantly negative association between plasma manganese levels and NAFLD, and the association was not modified by the MnSOD rs4880 polymorphism. KEYWORDS: Heavy metals, Epidemiology, Obesity and metabolic disorders

Association of Val16Ala Polymorphism of Manganese Superoxide Dismutase (MnSOD) with Food Intake and Cardiometabolic Risk Factors in the Elderly in Primary Care in Porto Alegre.

The aging process causes physiological changes on its own. The combination of an unhealthy lifestyle with the presence of genetic polymorphisms, such as the Val16Ala of the antioxidant enzyme manganese-dependent superoxide dismutase (MnSOD) may contribute to a greater occurrence of cardiometabolic risk factors. This study aimed to verify the association of Val16Ala-MnSOD polymorphism with food intake, caloric expenditure, and cardiometabolic risk factors in the elderly. A cross-sectional study with a sample size of 270 elderly individuals assisted in primary health care in the city of Porto Alegre, RS, Brazil. Val16Ala polymorphism, glucose, lipid profile, insulin, HOMA-IR, blood pressure, waist circumference, PCR-us, IL-6, food consumption, and caloric expenditure were evaluated. The average age of the elderly was 68.6 ± 7.6 years. There were statistically significant differences regarding the consumption of two or more servings of fruits and vegetables daily between the elderly VV versus AV (P=0.017). There were also statistically significant differences regarding the consumption of two or more daily servings of legumes and eggs between the elderly AA versus VV (P=0.002). The median of insulin was higher in the elderly AA versus AV (P=0.025) and the median of HOMA-IR was higher in the elderly VV versus AV (P=0.029). AA elderly individuals had higher means of high-density lipoprotein (HDL-c), compared to AV (P=0.029). The results suggest that Val16Ala -MnSOD polymorphism is associated with the consumption of fruits, vegetables, legumes, and eggs, as well as with cardiometabolic risk factors in the elderly.

The effects of the genetic polymorphisms of antioxidant enzymes on susceptibility to papillary thyroid carcinoma.

Several lines of evidences have indicated that inflammation play an important role in the carcinogenesis. During the inflammatory processes, free radical species are produced from oxidative stress. In normal conditions, enzymatic and nonenzymatic antioxidants remove these products. Manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPx-1), and catalase (CAT) are three important enzymes. Therefore, this study aimed to evaluate the effects of MnSOD (SOD2), GPX-1, and CAT genetic polymorphisms on papillary thyroid carcinoma (PTC) susceptibility. A total of 134 patients with PTC and 151 healthy controls were recruited to participate in this study. All samples were genotyped for SOD2 rs4880, GPX1 1050450, and CAT rs7943316 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism method. The frequencies of the rs1050450, rs4880, and rs7943316 alleles and genotypes were not different between PTC patients and controls. However, the TC genotype of SOD2 rs4880 polymorphism was significantly higher in males compared to that in females in PTC patients (odds ratio [OR], 3.9 [95% CI, 1.5-11], p = .007). The rs4880 polymorphism was also associated with higher stages (III-IV) of PTC in dominant model. No significant correlation was found between GPX1-rs1050450 and CAT-rs7943316 polymorphisms and demographic, clinical, and pathological features of the disease. The SOD2 rs4880CT genotype was more frequent in males with PTC and patients with higher stages (III-IV) of disease (OR, 2.9 [95% CI, 1.1-7.7], p = .04). However, no significant association was found between GPX1-rs1050450 and CAT-rs7943316 variants and PTC or its demographic, clinical, and pathological features.

The effect of GPx-1 rs1050450 and MnSOD rs4880 polymorphisms on PE susceptibility: a case- control study.

Preeclampsia (PE) is a serious pregnancy complication whose etiology is not fully understood. However, previous reports have suggested that oxidative stress and genetic variants may contribute to the development of PE. This study aimed to examine the relationship between the Glutathione peroxidase-1(GPx-1) and Manganese Superoxide dismutase (MnSOD) polymorphisms and preeclampsia (PE) risk in Iranian women. Genotyping of the studied women, including 179 preeclamptic cases and 202 controls, for GPx-1 rs1050450 and MnSOD rs4880 polymorphisms was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our results showed a 1.7- to 1.6-fold increased risk of PE in the rs1050450 CT and CT + TT (dominant model) genotypes compared to CC genotype (OR = 1.7, 95%CI 1.1-2.7; P = 0.01 and OR = 1.6, 95%CI 1.1-2.4; P = 0.02; respectively). We also found a marked correlation between TC and CC genotypes of MnSOD rs4880 polymorphism and a 1.9- to 2.3-fold increase risk of PE (OR = 1.9, 95%CI 1.2-2.9; P = 0.005 and OR = 2.3, 95%CI 1-5.1; P = 0.04, respectively). The rs4880 MnSOD polymorphism was correlated with increased risk of PE in the allelic and dominant models (OR = 1.8, 95% CI 1.2-2.5, P = 0.002; OR = 1.9, 95%CI 1.3-3, P = 0.002, respectively). High frequency of TC/CC genotype of MnSOD rs4880 and CT genotypes of rs1050450 polymorphism in PE patients compared to controls showed the contribution of these variants to PE susceptibility.

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.

Abstract 1047: Novel roles for manganese superoxide dismutase polymorphisms in prostate cancer

Abstract Prostate Cancer is the most common non-cutaneous cancer and second leading cause of cancer related death in American men. Epithelial Mesenchymal Transition (EMT), a key event in prostate cancer metastasis, is a process in which polarized epithelial cells undergo biochemical changes, allowing them to assume mesenchymal morphologies, enhancing invasiveness and migration. Reactive Oxygen Species (ROS) are chemically reactive molecules of cellular metabolism that induce oxidative stress, and increase levels of SNAI1 (Snail) transcription factor while also promoting EMT. In Phase II clinical trials, patients were treated with natural product, Muscadine Grape Skin Extract (MSKE), and patients with SOD2 Ala/Ala single nucleotide polymorphism (SNP) responded better than those with Val/Val SNP. Ala/Ala SNP is associated with higher dismutase activity [superoxide (O2-) to hydrogen peroxide (H2O2)] than Val/Val. We hypothesize that SOD2 Ala/Ala genotype is associated with increased H2O2 and EMT, potentially antagonized by MSKE in prostate cancer cells. Prostate cancer cell lines were analyzed for SOD2 SNPs by pyrosequencing. Site-directed mutagenesis was conducted to create the Ala/Ala and Val/Val SNP vectors. LNCaP prostate cancer cells were transiently and subsequently stably transfected with SOD2 Val/Val cDNA, as well as empty vector (Neo) control, and verified through western blot analysis. ROS activity was evaluated for baseline ROS activity. Our results showed that most prostate cancer cell lines were heterozygous for SOD2 SNP (Ala/Val), although several had extra copies, for example, LNCaP had Val/Val/Ala, suggesting multiple copy numbers. Only metastatic MDA PCa 2a and MDA PCa 2b contained Ala/Ala homozygous SNP. LNCaP cells transiently and stably transfected with Val/Val showed partial induction of EMT, concomitant with higher levels of Snail and Vimentin, as compared to LNCaP Neo control. Furthermore, data also suggested that transient transfection marginally affected ROS activity while stable transfection caused significant changes in ROS activity compared to LNCaP Neo cells. We have begun to stably transfect Ala/Ala cDNA into LNCaP cells and are interested to see the differences in ROS activity and EMT induction between the two clone cell types (LNCaP Ala/Ala and Val/Val). As previous data suggests, we believe that Ala/Ala will show a higher expression of SOD2 and mesenchymal markers Snail and Vimentin, demonstrating full induction of EMT. In future we will test ROS activity, EMT marker expression in response to treatment of LNCaP Ala/Ala and Val/Val cells with MSKE. These studies may uncover the differential functions and response to treatment of SOD2 SNPs. Acknowledgements: These studies were supported by the NIH/NIMHD/RCI Grant #5G12MD007590-31, NIH/NIGMS/RISE Grant #5R25GM060414, and https://www.thecommunityfoundation.org/ Citation Format: Janae D. Sweeney, Valerie Odero-Marah, Channing Paller. Novel roles for manganese superoxide dismutase polymorphisms in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1047.

Meta-analysis of the relationship between MnSOD polymorphism and cancer in the Turkish and Cypriot population

Abstract Objectives The association between manganese superoxide dismutase (MnSOD) p.Val16Ala polymorphism and cancer has been shown in various studies. The aim of this study is to investigate the relationship between MnSOD polymorphism (V/V, V/A, A/A) and cancer in the Turkish and Cypriot population through meta-analysis. Material and methods The present study included meta-analysis of 14 publications covering 2413 cancer patients and 2907 healthy control groups from 2005 to 2016. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using the random effect model of DerSimonian and Laird for each study. Publication bias was checked with funnel plot by Begg’s and Egger’s test statistics. Results Meta-analysis of MnSOD polymorphism was performed in the additive model (AV vs. VV; OR=1.133, 95% CI: 1.002–1.282), allele contrast (A vs. V; OR=1.016, 95% CI: 0.930–1.278), homozygote model (AA vs. VV; OR=0.983, 95% CI: 0.839–1.153), dominant model (AA+AV vs. VV; OR=1.090, 95% CI: 0.971–1.223) and recessive model (AA vs. AV+VV; OR=0.924, 95% CI: 0.803–1.064). The A/V genotype polymorphism was found be significant for cancer. Conclusion The frequency of the A/V heterozygote genotype of the MnSOD polymorphisms is found to be higher in the Cypriot and Turkish populations than any other genotype.

The assessment of total antioxidant capacity and superoxide dismutase levels, and the possible role of manganese superoxide dismutase polymorphism in acromegaly.

Oxidative status is attributed to endothelial dysfunction and might be one of the key mechanisms of endothelial dysfunction in acromegaly. In this study, we aimed to investigate the effect of acromegaly on superoxide dismutase (SOD) and total antioxidant capacity (TAC) levels, and the possible influence of human manganese superoxide dismutase (MnSOD) polymorphism on these levels. 51 acromegaly patients and 57 age and sex matched healthy subjects were recruited to the study in Bezmialem Vakif University Hospital between 2011 and 2014. The median SOD and TAC levels were 42.7 (33-60) pg/mL and 1,313.7 (155-1,902) μM in acromegaly; and 46.3 (38-95) pg/mL and 1,607.3 (195-1,981) μM in healthy subjects (p < 0.001, p < 0.001). SOD levels were decreased in controlled and uncontrolled patients compared to healthy subjects (p = 0.05 and p = 0.002, respectively). Controlled and uncontrolled acromegaly displayed significantly decreased levels of TAC compared to healthy subjects (p < 0.05 and p < 0.001, respectively). SOD levels were not associated with MnSOD polymorphisms in acromegaly. In conclusion, this study showed that acromegaly was associated with decreased levels of SOD and TAC, and controlling the disease activity could not adequately improve these levels.

Polymorphism of MnSOD (Val16Ala) gene in pregnancies with blighted ovum: A case-control study

Blighted ovum is one of the most common reasons for abortion during the first three months of pregnancy. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme in the human immune system. The gene is located on 6q25 chromosome and acts on mitochondrial matrix. In the case of mutation or inactivity of this enzyme, mitochondrial and nuclear DNA will severely be destructed. The most common polymorphism of its gene is Val16Ala. The aim was to investigate a possible mutation in pregnant women who had abortion during the first trimester of pregnancy due to blighted ovum. In this case-control study, 34 women were entered as the case and control groups, respectively. Genome DNA was extracted from saliva samples and its genotype was determined using Tetra-primer amplification refractory mutation system polymerase chain reaction technique. In the case group, 16 (48%) cases had Val/Val genotype, 17 (50%) were heterozygote and had Val/Ala genotype, and 1 (2%) had Ala/Ala genotype. Among controls, 7 (22%) items had Val/Val genotype, 6 (17%) had Val/Ala genotype, and 21 (61%) had Ala/Ala genotype. The frequency of TT, CT, and CC genotypes was 48%, 50%, and 2% in case group and 22%, 17%, and 61% in control group, respectively. Statistical analysis revealed a significant relationship between Val16Ala polymorphism of MnSOD gene and blighted ovum (p= 0.0003). It has concluded that a significant relationship exists between Val16Ala polymorphism of MnSOD gene and blighted ovum.

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

Association between manganese superoxide dismutase (MnSOD) polymorphism and prostate cancer susceptibility: a meta-analysis.

Previous studies have investigated the relationship between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and prostate cancer susceptibility, but the results have remained controversial. This meta-analysis was therefore performed to clarify this association. The databases PubMed, Embase and Web of Science were searched for relevant available studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Publication bias was estimated using Begg's funnel plots and Egger's regression test. Trial sequential analysis was used to reduce the risk of type I error and estimate whether the evidence of the results was sufficient. Overall, a significant increased risk of prostate cancer was associated with MnSOD Val16Ala polymorphism for the heterozygote model (OR = 1.14; 95% CI, 1.05-1.24), homozygote model (OR = 1.18; 95% CI, 1.02-1.36), dominant model (OR = 1.24; 95% CI, 1.07-1.44) and recessive model (OR = 1.10; 95% CI, 0.96-1.24). In the subgroup analysis by genotyping method, the results were statistically significant for the TaqMan and PCR-RFLP methods. In addition, when stratified by sample size, statistically significant increased risks were found among both large samples and small samples. Furthermore, when stratified by source of control, significant results were detected in both population-based controls and hospital-based controls. By trial sequential analyses, these findings in the current study were shown to be based on sufficient evidence. This meta-analysis indicated that the Ala allele of the MnSOD gene polymorphism increases prostate cancer susceptibility.

Susceptibility of Patients with Manganese Superoxide Dismutase Ala16val Genetic Polymorphism to Type 2 Diabetes Mellitus and its Complications in a Sample of Lebanese Population

Oxidative stress has been frequently associated with the development of type 2 diabetes mellitus. Manganese superoxide dismutase (MnSOD) is one of the most important enzymes responsible for the defense against oxidative damage in the mitochondria. A polymorphism in the second exon of the MnSOD at position 16 that changes Ala into Val, induces changes in the structural conformation and mitochondrial transport of MnSOD. This polymorphism affects the scavenger activity of the enzyme and generates high reactive oxygen species which could exacerbate the development of type 2 diabetes and/or its complications. Relationship between MnSOD polymorphism and Type 2 diabetes mellitus and its complications remains uncertain.

Lack of Association Between Superoxide Dismutase Gene Polymorphism and Malignant Lymphoproliferative Disorders

Background: Superoxide dismutase is one of the most important antioxidant enzymes that protect cells against destructive eects of superoxide anion. Objectives: The aim of this study was to evaluate the association between the C47T polymorphism (rs4880) of the manganese su- peroxide dismutase (Mn-SOD) gene and the risk of malignant lymphoproliferative disorders (MLDs). Patients and Methods: Manganese superoxide dismutase polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 103 patients with MLDs and 103 healthy control subjects. Results: The frequencies of the CC, CT and TT genotypes were 29.1%, 51.5% and 19.4%, respectively, in patients with MLDs and 24.3%, 47.6% and 28.2%, respectively, in the control group. There were no statistical dierences in the genotype or allele frequency of rs4880 between cases and controls. Conclusions: According to the fact that Mn-SOD gene polymorphisms have been considered as a major risk factor in some ma- lignancies, this single center study did not find any association between the rs4880 polymorphism of the manganese superoxide dismutase gene and risk of MLDs.

Genetic Polymorphism of Manganese Superoxide Dismutase in Behçet's Disease.

This study aims to investigate the genetic association between single nucleotide mutation in mitochondrial manganese superoxide dismutase and a Behçet's disease (BD) population by using molecular techniques. Ninety-three BD patients (45 males, 48 females; mean age 33.15±8.99 years; range 17 to 65 years) and 125 controls (58 males, 67 females; mean age 28.33±7.31 years; range 18 to 62 years) were genotyped by polymerase chain reaction-restriction fragment length polymorphism method. The genotypic distributions in BD patients and controls were consistent with the Hardy-Weinberg equilibrium. Significant differences were observed between BD patients and controls in terms of genotypic distribution. Frequencies of alanine (Ala)/Ala, Ala/valine (Val), and Val/Val were 14.0% (n=13), 45.2% (n=42), and 40.9% (n=38) in BD patients and 21.6% (n=27), 53.6% (n=67), and 24.8% (n=31) in controls, respectively (p=0.033). The Val/Val genotype of the manganese superoxide dismutase gene is associated with the physiopathology of BD in a group of Turkish patients.

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.

A pilot study of the association of manganese superoxide dismutase and glutathione peroxidase 1 single gene polymorphisms with prostate cancer and serum prostate specific antigen levels.

IntroductionThe aim of the study was to evaluate the potential association of single gene polymorphisms of the antioxidant enzymes manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPX1) with prostate cancer (PCa).Material and methodsManganese superoxide dismutase and glutathione peroxidase 1 genotypes and allele frequencies in 49 prostate cancer cases (PCa group) and 98 control subjects were determined. Analysis of genotypes in control group individuals were performed in two subgroups according to serum prostate-specific antigen levels: the control group (n = 49), with prostate specific antigen (PSA) level < 4 ng/ml; and the nonPCa-high PSA control group (n = 49), with serum PSA > 4 ng/ml. Determination of MnSOD Ala-9Val and GPX1 Pro198Leu polymorphisms was performed using real-time polymerase chain reaction amplification.ResultsNo association was found between GPX1 polymorphisms and PCa in all groups (p > 0.05). In the PCa group, the frequency of homozygote Val allele carriers was significantly higher in comparison to nonPCa-high PSA control cases. Therefore, Val/Val genotype was found significantly suspicious for PCa risk (OR = 2.48; 95% CI: 1.37–4.48; p = 0.002). Furthermore, an overall protective effect of the Ala allele of the MnSOD polymorphism on PCa risk was detected. These findings in this small Turkish population suggested that individual risk of PCa may be modulated by MnSOD polymorphism especially in patients with high PSA, but GPX1 polymorphism seemed to have no effect on PCa risk.ConclusionsThe presence of genetic variants of antioxidant enzymes could have a potential influence on genesis of prostatic malignancy.

Abstract 5576: MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients

Abstract Purpose: The SOD2 gene encodes manganese superoxide dismutase (MnSOD) and is critical for superoxide anion detoxification. Variants in SOD2 have been associated with noise-induced hearing loss, and animal models suggest MnSOD expression is up-regulated in the cochlea after treatment with platinum-based chemotherapeutic agents. Therefore, we examined the role of SOD2 variants on ototoxicity among cisplatin-treated childhood medulloblastoma patients. Methods: Peripheral blood samples were obtained from 100 patients treated for pediatric medulloblastoma or supratentorial primitive neuroectodermal tumor at Texas Children's Cancer Center or MD Anderson Cancer Center between 1982 and 2009. Demographic, clinical, and treatment information was abstracted from patient medical records. A diagnosis of ototoxicity was assigned to patients whose medical records indicated they had received cisplatin chemotherapy and required the use of a hearing aid ≥1 year following the completion of primary therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip (San Diego, CA). A linkage disequilibrium-based single nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative common variants (minor allele frequency ≥5%). The association between each SNP and ototoxicity was assessed using multivariable logistic regression, assuming a log-additive model. Adjusted models included confounders (age at diagnosis, gender, craniospinal radiotherapy dose, cisplatin dose, amifostine therapy, and ethnicity) selected using a change in estimate approach. Results: Study participants were primarily male (73.2%) and non-Hispanic white (42.3%) with a mean age at diagnosis of 7.3 years. Of the 71 eligible patients with available information, 26 (36.6%) suffered from cisplatin-related ototoxicity. Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, rs4880) identified by the LD-based selection strategy were available in the genotyped data. After correcting for multiple comparisons, the C allele of the rs4880 variant was significantly associated with ototoxicity (OR = 3.00; 95% CI: 1.32-6.82) in adjusted models. Conclusions: In this study, the SOD2 rs4880 variant was associated with ototoxicity. The rs4880 T&amp;gt;C substitution results in a Val&amp;gt;Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. Specifically, the Ala-variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore oxidative stress may be an important mechanism in therapy-related cochlear damage. Characterizing genetic predictors of ototoxicity susceptibility may aid in prevention strategies and potentially identify novel antioxidant therapeutic targets. Citation Format: Austin L. Brown, Philip J. Lupo, Mehmet F. Okcu, Ching C. Lau, Surya P. Rednam, Michael E. Scheurer. MnSOD polymorphism is associated with ototoxicity in pediatric medulloblastoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2015-5576