Superoxide Dismutase Polymorphism Research Articles

Association of SNP (RS4880) in SOD-2 Gene with Diabetic Nephropathy

Objective: To find an association between SNP (rs4880) in SOD-2 gene with Diabetic Nephropathy. Study Design: Case Control Study. Place & Duration of study: Department of Biochemistry and Molecular Biology, Army Medical College Rawalpindi and Armed Forces Institute of Urology, Rawalpindi Pakistan, from Nov 2020 to Mar 2021. Methodology: A total of 60 people were enrolled including 30 healthy individuals and 30 patients of diabetic nephropathy. Both males and females aged 35-85 years were enrolled. Baseline biochemical tests were performed to ascertain diagnosis and exclude comorbidities. DNA was extracted using kit method and sequence of interest was amplified using PCR. Amplified product of genomic DNA of each individual was subjected to restriction fragment length polymorphism (RFLP) analysis. Data was analyzed using SPSS version 22. Results: The frequency of TT genotype (40%) was higher among type 2 Diabetes Mellitus (T2DM) patients with nephropathy than CT (33.3%) and CC (26.6%) genotypes however the odds ratio for TT with 95% confidence interval (CI) was 2.53(0.69- 9.25) with p=0.35 which is statistically non-significant. The association value for genotypes was 1.29 (p-value=0.52) hence not significant. Conclusion: There was no significant association present between SNP (rs4880) in SOD-2 gene which causes Val16Ala polymorphism in superoxide dismutase 2 gene, with nephropathy in type 2 Diabetes Mellitus (T2DM) patients.

Dietary carotenoid intake and dental fluorosis in relation to SOD2 (rs 11968525) polymorphisms in Guizhou, China.

Genetic and dietary factors are important contributors to the development of dental fluorosis (DF). This study investigated the association between DF and dietary carotenoids, and explored whether the association was modified by polymorphisms of the antioxidant enzyme superoxide dismutase 2 (SOD2 rs11968525) in Guizhou, China. A cross-sectional study with a total of 899 adults aged 18-75 years were enrolled in the study. Face-to-face interviews were conducted to assess dietary habits using a validated 75 item food frequency questionnaire (FFQ). Sociodemographic and lifestyle information, and blood and urine samples were also collected. Genotypes were evaluated using TaqMan single nucleotide polymorphism (SNP) Genotyping Assay. There were significant dose-dependent inverse associations of the prevalence of DF with intake of α-carotene, β-carotene, lutein/zeaxanthin, lycopene and total carotenoids (p-trend ranged from <0.001-0.004). The odds ratios (ORs) and 95% confidence intervals (CIs) of DF comparing the highest against lowest quartile were 0.56 (0.35, 0.92) for α-carotene, 0.53 (0.35, 0.81) for β-carotene, 0.44 (0.27, 0.74) for lycopene, 0.35 (0.21, 0.58) for lutein/zeaxanthin in combination and 0.42 (0.25, 0.69) for total carotenoids (all p-trend<0.005). Intake of β-cryptoxanthin was not found to be related to DF. The inverse association of DF with dietary intake of α-carotene and β-carotene was more evident in individuals with the AG+AA genotype (p-interaction<0.05). Higher dietary carotenoids were associated with a lower occurrence of DF, polymorphisms in SOD2 (rs 11968525) modified the associations between dietary intake of carotene and DF. These findings provide evidence for precision prevention of fluorosis.

Polymorphism in Superoxide Dismutase, Catalase Genes and Their Role in Cervical Cancer Susceptibility among Rural Population of Maharashtra: Findings from A Hospital based Case Control Study

Background: The present study was planned to investigate the possible association between polymorphisms of superoxide dismutase, SOD1 (Cu,Zn-SOD), SOD2(Mn-SOD), SOD3(EC-SOD) and catalase genes and the risk of cervical cancer in rural population of Maharashtra. Methods: A case control study included 350 proven cervical cancer cases and 400 healthy age matched control women. Genotyping of isoforms of SOD and CAT were done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Results: When we studied genotype frequencies of codon 326 and 262 region of promoter of CAT gene, there was no significant association between A to T transition at codon 326 (p=0.45) and CAT C262T polymorphism (p=0.30) with susceptibility to cervical cancer. The variant G allele of SOD1 at codon 251 significantly increased in cervical cancer patients as compared with the control women (OR=3.02, 95% CI: 1.72-5.31; p&lt;0.0001). Conclusion: Findings from this investigation confirms conceivable association of A251G of SOD1 and G172A of SOD3 genes with risk of cervical cancer in women of Maharashtra.

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.

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.

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.

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

Genetic polymorphisms of superoxide dismutase-1 A251G and catalase C-262T with the risk of colorectal cancer.

Oxidative stress is significant in numerous types of disease including cancer. To protect cells and organs against reactive oxygen species (ROS), the body has evolved an antioxidant protection system that involved in the detoxification of ROS. Single nucleotide polymorphisms (SNP) of anti-oxidative enzymes may dramatically change the activity of the encoded proteins; therefore, certain alleles can be established as risk factors for some kind of multi-factorial diseases including cancer. In present study we investigate the possible association between polymorphisms of superoxide dismutase 1 (SOD1, OMIM: 147450) and catalase (CAT, OMIM: 115500) genes and the risk of colorectal cancer (CRC). The study included 204 colorectal cancer patients and 239 healthy control group matched for gender and age. Genotyping of SOD1 A251G and CAT C-262T were done by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. There was no significant association between CAT C-262T polymorphism and susceptibility to CRC (P>0.05). The carries of the G allele of SOD1 significantly showed higher prevalence in CRC patients compared with the control group (OR=1.84, 95% CI=1.13-2.98, P=0.013). We assessed the effect of combination of genotypes of the study polymorphisms on the risk of CRC. We found that the combination of AG+GG (SOD1) and CC (CAT) increases the risk of developing CRC (OR=2.38, 95% CI=1.25-4.52, P=0.008).

Influence of antioxidants' gene variants on risk of diabetes mellitus and its complications: a systematic review.

Oxidative stress has a key role in pathophysiology of type 2 diabetes mellitus (T2DM) and its complications as a most common health problem. Due to controversial evidence regarding the association between antioxidants' gene varients and T2DM, our aim was a systematic review of the current meta-analyses. All meta-analysis' studies which assessed the association of single nucleotide polymorphisms of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), glutathione S transferase (GST), nitric oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate oxidase (NOX) with T2DM and its complications were systematically extracted from PubMed, Scopus and Web of Science databases up to January 2016. Results are reported according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Among 131 articles recorded in initial search, 19 studies were in the topic just for eNOS (endothelial NOS), NOX, GST and SOD gene variants. G894T, 4b/a and T-786C variants (eNOS) were associated with DN (diabetic nephropathy). However no association between 4b/a variant and DR (diabetic retinopathy) was observed. Separate or combination of GSTM1 and GSTT1 null genotypes (GST gene) were associated with T2DM. GSTM1 and combination of GSTM1/GSTT1 null genotypes were associated with DN. Significant association between C242T variant (NOX) and T2DM or DN, and non-significant association with carotid atherosclerosis were seen. C allele of C47T variant (SOD) was protective against DN, DR and microvascular complications of diabetes. Finding gene polymorphisms involved in diabetes and its complications might be helpful in discovering new therapeutic approaches, as well as prevention which is currently as a main focus in personalized medicine.

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.

Genetic polymorphism of antioxidant enzymes in eosinophilic and non-eosinophilic nasal polyposis.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the paranasal sinuses, and its pathophysiology is not yet precisely known. It is suggested that oxygen free radicals play an important role in the pathogenesis of nasal polyposis. This study aimed to identify genetic polymorphisms of superoxide dismutase (SOD 2), catalase (CAT), and inducible nitric oxide synthase (iNOS) enzymes in eosinophilic CRSwNP and non-eosinophilic CRSwNP patients; the study also aimed to evaluate the effect of genetic polymorphism of antioxidant enzymes on CRSwNP etiopathogenesis. One hundred thirty patients, who received endoscopic sinus surgery due to CRSwNP, and 188 control individuals were included in this study. Nasal polyp tissues were divided into two groups histopathologically as eosinophilic CRSwNP and non-eosinophilic CRSwNP. Venous blood samples were taken from the patient and control groups. Polymorphisms in the Ala16Va1 gene, which is the most common variation of SOD-2 gene, and 21 A/T polymorphisms in catalase gene were evaluated with the restriction fragment length polymorphism method and -277 C/T polymorphism in the iNOS gene was evaluated with the DNA sequencing method. The GG genotype distribution for the (-277) A/G polymorphism in the iNOS gene was a statistically significant difference between eosinophilic CRSwNP and control groups (p<0.05). The CC genotype distribution for the SOD2 A16V (C/T) polymorphism was not statistically significant in all groups (p>0.05). The TT genotype distribution for the A/T polymorphism in catalase gene at position -21 was statistically significant differences in eosinophilic CRSwNP and control groups (p<0.05). Increased free oxygen radical levels, which are considered effective factors in the pathogenesis of CRSwNP, can occur due to genetic polymorphism of enzymes in the antioxidant system and genetic polymorphism of antioxidant enzymes in eosinophilic CRSwNP patients might contribute to the pathophysiology.

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.

Interaction between PhIP from meat intake and polymorphism in superoxide dismutase 2 gene increases risk of oxidative stress

BackgroundHeterocyclic amines (HCA), especially 2‐Amino‐1‐methyl‐6‐phenylimiazo[4,5‐b]pyridine (PhIP) from meat intake have been linked to cancer due to oxidative stress generated during the metabolism. This process is mediated by detoxifying enzymes, as superoxide dismutase 2 (SOD2), which is encoded by a polymorphic gene. The presence of this polymorphism Val16Ala (rs4880) decreases the enzyme activity increasing oxidative stress and risk for chronic disease as cancer. The aim of the present study was to investigate if there is an interaction between PhIP from meat intake and SOD2 polymorphism on biomarkers of oxidative stress.MethodsWe performed a cross‐sectional study in adults and older adults from Brazil (n=239). PhIP intake was assessed using one 24‐hour dietary recall and a structured questionnaire with cooking methods and levels of meat doneness. It was used PCR‐based assays to detection SOD2 polymorphism. Malondialdehyde was measured in plasma after derivatization by thiobarbituric acid and separation on HPLC. Multiple linear regression models were performed to verify the association and interaction between PhIP intake and SOD2 on risk of oxidative stress. Sensitivity analyses were performed in a subsample (n=79) using a DNA adduct marker, 8oxodG measured by ELISA, as a dependent variable.ResultsThe frequency of the minor allele (C) was 45%. PhIP mean intake was 254ng/day (95% CI: 200;308ng/day). MDA concentration was associated with PhIP intake (β=0.04 P=0.004) after adjustment for energy and fruit intake, sex, age, BMI, race, physical activity, C reactive protein, global methylation, and smoking. We also noted a significant interaction between SOD2 polymorphism and PhIP intake on MDA (P=0.035). Subjects who had one or two risk alleles presented a significant relationship between PhIP and MDA concentration (β=0.06 P=0.01) compared with who had the wild‐type genotype (β=0.01 P=0.870). Moreover, we confirmed a significant interaction between SOD2 and PhIP intake on 8oxodG (P=0.022) after adjustment.ConclusionPhIP was associated with oxidative stress and interacted with polymorphism in SOD2 gene increasing oxidative stress and DNA adducts in a general population.Support or Funding InformationResearches relating to this abstract were funded by Municipal Health Secretariat of Sao Paulo, National Counsel of Technological and Scientific Development and Sao Paulo Research Foundation

POLYMORPHISM OF THE INTERLEUKIN-6, INTERLEUKIN-10, SUPEROXIDE DISMUTASE AND ANGIOTENSIN CONVERTING ENZYME GENES, AND THE RISK OF ATRIAL FIBRILLATION AFTER CARDIOSURGERY

Aim. To reveal the relation of gene polymorphisms of interleukin-6 (IL6, C174G), interleukin-10 (IL10, C592A), superoxide dismutase (SOD1, G8958A) and angiotensin converting enzyme (ACE, Alu Ins/Del) with postsurgery atrial fibrillation (PSAF) after coronary bypass grafting (CBG) in coronary heart disease patients (CHD). Material and methods. Totally, 80 CHD patients studied, had been admitted for CBG. Genotype assessed for IL6 C174G, IL10 C592A, SOD1 G8958A and ACE Alu Ins/Del. According to PSAF, patients were selected to 2 groups: 1 group — non- PSAF (56 patients, 78,6% males, mean age 61,0±7,5 years), 2 group — with PSAF (24 patients, 83,3% males, mean age 64,7±7,9 years). Results. Analysis of genetic polymorphisms showed the prevalence of СG IL6 C174G (57,2%) genotype, СС IL10 C592A (62,5%), GG SOD1 G8958A (87,5%), I/D ACE Alu Ins/Del (60,8%) among non-arrhythmic patients. In PSAF most prevalent were genotypes СG IL6 C174G (54,2%), СА IL10 C592A (54,2%), GG SOD1 G8958A (79,2%), I/D ACE Alu (58,4%). In multifactor regression analysis, odds ratio for PSAF in allele G IL6 C174G was 1,5 (95% CI, 0,69-3,44, р=0,29), for allele A IL10 C592A — 2,7 (95% CI, 1,2-6,9, р=0,04), for allele A SOD1 G8958A — 2,1 (95% CI, 0,7-6,2, р=0,19), for allele D gene ACE Alu Ins/Del — 0,9 (95% CI, 0,27-3,1, р=0,89). Conclusion. Therefore, presence of allele A of candidate gene IL10 C592A might force the onset of atrial fibrillation during early postsurgery period in coronary bypass.

Antioxidant Enzyme Gene Polymorphisms in Japanese Migraine Patients with Medication Overuse Headache

AIM: We investigated the association of an antioxidant enzyme gene polymorphisms and the medication overuse in migraine patients using cross-sectional method. METHODS: In total, 47 migraine patients (6 males and 41 females; 36.4±10.3 years) and 22 medication overuse headache patients with migraine (1 male and 21 females; 39.6±9.9 years) participated in this study. The gene polymorphisms of superoxide dismutase (rs4880), catalase (rs1001179), and glutathione peroxidase-1 (rs1050450) were analyzed by polymerase chain reaction -restriction fragment length polymorphism methods. RESULTS: No significant differences were observed in the genotype distributions of superoxide dismutase, catalase, and glutathione peroxidase-1 between migraine and medication overuse headache patients. CONCLUSION: The results of this study showed no association between antioxidant enzyme gene polymorphisms and the complication of medication overuse headache in migraine patients.

Correlations between polymorphisms of extracellular superoxide dismutase, aldehyde dehydrogenase-2 genes, as well as drinking behavior and pancreatic cancer.

To investigate the correlation between drinking behavior combined with polymorphisms of extracellular superoxide dismutase (EC-SOD) and aldehyde dehydrogenase-2 (ALDH2) genes and pancreatic cancer. The genetic polymorphisms of EC-SOD and ALDH2 were analyzed by polymerase chain reaction restriction fragment length polymorphism in the peripheral blood leukocytes obtained from 680 pancreatic cancer cases and 680 non-cancer controls. Subsequently the frequency of genotype was compared between the pancreatic cancer patients and the healthy controls.The relationship of drinking with pancreatic cancer was analyzed. The frequencies of EC-SOD (C/G) and ALDH2 variant genotypes were 37.35% and 68.82% respectively in the pancreatic cancer cases, and were significantly higher than those in the healthy controls (21.03% and 44.56%, all P<0.01). People who carried EC-SOD (C/G) (OR=2.24, 95% CI= 1.81-4.03, P<0.01) or ALDH2 variant genotypes (OR=2.75, 95% CI=1.92-4.47, P<0.01) had a high risk to develop pancreatic cancer. Those who carried EC-SOD (C/G) genotype combined with ALDH2 variant genotype had a high risk for pancreatic cancer (29.56% vs. 6.76%, OR=7.69, 95% CI=3.58-10.51, P<0.01). The drinking rate of the pancreatic cancer group (64.12%) was significantly higher than that of the control group (40.15%; OR=2.66, 95% CI=1.30-4.42, P<0.01). An interaction between drinking and EC-SOD (C/G)/ALDH2 variant genotypes increased the risk of occurrence of pancreatic cancer (OR=25.00, 95% CI= 11.87-35.64, P<0.01). EC-SOD (C/G), ALDH2 variant genotypes and drinking might be the risk factors of pancreatic cancer.

A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution.

The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single-nucleotide polymorphism in EC-SOD (rs1799895) leads to an arginine to glycine amino acid substitution at position 213 (R213G) in the heparin-binding domain. In recent human genetic association studies, this single-nucleotide polymorphism attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease. Capitalizing on the complete sequence homology between human and mouse in the heparin-binding domain, we created an analogous R213G single-nucleotide polymorphism knockin mouse. The R213G single-nucleotide polymorphism did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (eg, bronchoalveolar lavage fluid and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension). We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases.

Manganese Superoxide Dismutase (SOD2) Polymorphisms, Plasma Advanced Oxidation Protein Products (AOPP) Concentration and Risk of Kidney Complications in Subjects with Type 1 Diabetes

AimsOxidative stress is involved in the pathophysiology of diabetic nephropathy. Manganese superoxide dismutase (SOD2) catalyses the dismutation of superoxide, regulates the metabolism of reactive oxygen species in the mitochondria and is highly expressed in the kidney. Plasma concentration of advanced oxidation protein products (AOPP), a marker of oxidative stress, was found to be increased in patients with kidney disease. We investigated associations of SOD2 allelic variations, plasma SOD activity and AOPP concentration with diabetic nephropathy in type 1 diabetic subjects.MethodsEight SNPs in the SOD2 region were analysed in 1285 Caucasian subjects with type 1 diabetes from the SURGENE prospective study (n = 340; 10-year follow-up), GENESIS (n = 501) and GENEDIAB (n = 444) cross-sectional studies. Baseline plasma concentration of AOPP and SOD activity were measured in GENEDIAB participants. Hazard ratio (HR) and odds ratio (OR) were determined for incidence and prevalence of nephropathy. Analyses were adjusted or stratified by retinopathy stages.ResultsIn the SURGENE cohort, the T-allele of rs4880 (V16A) was associated with the incidence of renal events (new cases, or the progression to a more severe stage of nephropathy; HR 1.99, 95% CI 1.24–3.12, p = 0.004) and with the decline in estimated glomerular filtration rate (eGFR) during follow-up. Similar associations were observed for rs2758329 and rs8031. Associations were replicated in GENESIS/GENEDIAB cohorts, in the subset of participants without proliferative retinopathy, and were confirmed by haplotype analyses. Risk allele and haplotype were also associated with higher plasma AOPP concentration and lower SOD activity.Conclusions SOD2 allelic variations were associated with the incidence and the progression of diabetic nephropathy, with a faster decline in eGFR and with plasma AOPP concentration and SOD activity in subjects with type 1 diabetes. These results are consistent with a role for SOD2 in the protection against oxidative stress and kidney disease in type 1 diabetes.

Polymorphic differences in SOD‐2 may influence HCV viral clearance

Hepatitis C virus (HCV) is a pathogen causing chronic hepatitis, cirrhosis, and liver cancer occurring in about 3% of the world's population. Most individuals infected with HCV develop persistent viremia. Oxidative stress may play an important role in the pathogenesis of a number of diseases including HCV infection and diabetes mellitus. Polymorphisms in the antioxidant genes may determine cellular oxidative stress levels as a primary pathogenic role in HCV and/or in its complications. Patients with HCV and normal, healthy controls were investigated for a superoxide dismutase (SOD-2) polymorphism in the mitochondrial targeting sequence with Ala/Val (C-9T) substitution. Polymorphisms in antioxidant gene SOD-2 were carried out by PCR, restriction fragment length polymorphism assays and by polyacrylamide gel electrophoresis. For the SOD-2 polymorphism, the RNA positive group showed a higher percentage of "CT" genotype than the RNA negative group (89.3% vs. 66.1%, P = 0.001, χ(2) = 11.9). The RNA negative group had more TT genotypes than the RNA positive group (27.4% vs. 6.80%, P = 0.01, χ(2) = 11.6). The exposed uninfected group had an increased frequency of the "CT" genotype (86.2% vs. 66.1%, P = 0.02, χ(2) = 5.5). The RNA positives had a higher frequency of the "CT" from the normal controls (72.1% vs. 89.2%, P = 0.005, χ(2) = 7.8).

The Role of Genetic Polymorphisms in Antioxidant Enzymes and Potential Antioxidant Therapies in Neonatal Lung Disease

Oxidative stress is involved in the development of newborn lung diseases, such as bronchopulmonary dysplasia and persistent pulmonary hypertension of the newborn. The activity of antioxidant enzymes (AOEs), which is impaired as a result of prematurity and oxidative injury, may be further affected by specific genetic polymorphisms or an unfavorable combination of more of them. Genetic polymorphisms of superoxide dismutase and catalase were recently demonstrated to be protective or risk factors for the main complications of prematurity. A lot of research focused on the potential of different antioxidant strategies in the prevention and treatment of lung diseases of the newborn, providing promising results in experimental models. The effect of different genetic polymorphisms on protein synthesis and activity has been poorly detailed in the newborn, hindering to derive conclusive results from the observed associations with adverse outcomes. Therapeutic strategies that aimed at enhancing the activity of AOEs were poorly studied in clinical settings and partially failed to produce clinical benefits. The clarification of the effects of genetic polymorphisms on the proteomics of the newborn is mandatory, as well as the assessment of a larger number of polymorphisms with a possible correlation with adverse outcome. Moreover, antioxidant treatments should be carefully translated to clinical settings, after further details on optimal doses, administration techniques, and adverse effects are provided. Finally, the study of genetic polymorphisms could help select a specific high-risk population, who may particularly benefit from targeted antioxidant strategies.