Increased prevalence of MnSOD genetic polymorphism in endurance and power athletes

Abstract

The purpose of the current study was to determine the frequency distribution of manganese superoxide dismutase (MnSOD) Val-9Ala polymorphism (rs1799725) among 195 trained endurance and power athletes and 240 healthy controls. Genomic DNA was extracted using a standard protocol. Genotyping of the MnSOD Val-9Ala polymorphism was performed using polymerase chain reaction (PCR). Results showed a higher proportion of the Val/Ala and Ala/Ala genotype, and a lower proportion of Val/Val genotype, in the athletes group compared with that of the controls. The Ala allele frequency was significantly higher (p < 0.001) in the athletes group (46%) compared with that in the control (29%). Interestingly, there was no difference between the endurance and power athletes. In addition, the frequency of Ala/Ala genotype was significantly higher (p < 0.05) among top (international and Olympic-level) athletes (29%) compared with that among national-level endurance and power athletes (17%). We conclude that 1) the Ala allele is more frequent in athletes than in controls; and 2) the higher frequency of the Ala allele was noted in both endurance and power athletes compared with that in controls, suggesting that the positive association between the Ala allele and athletic performance may be related to ROS-related angiogenesis, mitochondrial biosynthesis, and muscle hypertrophy, and not to MnSOD aerobic properties.     

Polymorphism in the manganese superoxide dismutase gene

Oxidative stress and mitochondrial damage occur in sepsis. Manganese superoxide dismutase (MnSOD) provides the main defence against oxidative stress within mitochondria. Ala9Val is a single nucleotide polymorphism (SNP) in the MnSOD gene, predicted to affect intra-mitochondrial transport of the enzyme. We found a significant difference in the genotype frequency between healthy subjects (n = 100) and patients with sepsis (n = 40, p = 0.009). For assessment of functionality ten healthy subjects of each homozygous genotype (A/A or V/V) were studied. Peripheral blood mononuclear cells were separated and incubated for 18 h with lipopolysaccharide (LPS), followed by analysis of mitochondrial and cytosolic fractions. There was no difference between genotypes in MnSOD activity and cytochrome c concentration, and minor differences in total antioxidant capacity (TAC) and mitochondrial membrane potential, which did not affect response to LPS. Despite predictions from structural enzyme studies that mitochondrial trafficking would be affected by the Ala9Val polymorphism of the MnSOD gene had little functional effect.     

Manganese superoxide dismutase (MnSOD) genetic polymorphism is associated with risk of early-onset prostate cancer

Prostate cancer continues to be the most frequently diagnosed neoplasm, and the second leading cause of cancer-related mortality in men. Oxidative stress may enhance prostatic carcinogenesis. Manganese superoxide dismutase (MnSOD) is the only known superoxide scavenger in mitochondria. It plays a key role in antioxidant defense as mitochondria are important for oxidative metabolism coupled to the electron transport chain and oxidative phosphorylation and hence, ROS production. A T-->C single nucleotide substitution, resulting in a Val-->Ala change at position 9 (Ala-9Val), which alters the secondary structure of the protein, has been noted to affect transport of MnSOD into the mitochondria. We have determined the MnSOD genotype in 85 prostate cancer cases and 151 control subjects. Ala-9Val polymorphism was determined using real time polymerase chain reaction (PCR) amplification with fluorescently labeled primers. No significant difference was found in prostate cancer susceptibility in the subjects with Ala/Ala and Val/Ala genotype compared with Val/Val genotype (Odds ratio (OR), 1.3; 95% confidence interval (95% CI), 0.69-2.42; p = 0.416). We did not observe an association of the MnSOD genotype or allele frequency between subgroups of cases divided by disease status (aggressive vs. non-aggressive prostate cancer). However, in the analyses stratified by the age at diagnosis we have observed that men homozygous for Ala had a 5.2-fold increased risk of early-onset prostate cancer (under age of 65) compared to men homozygous for Val allele (p = 0.05). These data suggest that Ala/Ala MnSOD genotype in the Macedonian population could have an influence on early onset of prostate cancer, but no impact on the subsequent development of the disease.     

Association between Gene Polymorphism of Manganese Superoxide Dismutase and Prostate Cancer Risk

Manganese superoxide dismutase (MnSOD) is the most effective antioxidant enzyme in mitochondria and protects cells from reactive oxygen species‐induced oxidative damage. The aim of this study was to investigate the association between MnSOD Ala‐9Val gene polymorphism and prostate cancer (PCa) risk in Turkish men with prostate cancer. 33 patients with PCa and 81 control individuals were included in the study. We observed an association between MnSOD Ala/Ala frequency and a higher PCa risk. In addition, we found that the increased risk of early‐onset PCa (under age of 65) in the men homozygous for Ala allele was higher than the men homozygous for Val allele. However, we determined that MnSOD Ala‐9Val genotype was not associated with the aggressiveness of the disease. The results of our study suggest that MnSOD Ala/Ala genotype may influence on early‐onset of PCa patients, but no effect on subsequent development of the disease in Turkish men. However, our study has a limitation that is small numbers of individuals for cases and controls. Therefore, the presented study limited our statistical power to fully investigate the gene polymorphism on cancer risk. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:213‐218, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21472     

Genetic polymorphism of manganese superoxide dismutase (MnSOD) and breast cancer susceptibility

Within mitochondria, manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species (ROS). An alanine-9valine (Ala-9Val) polymorphism in the mitochondrial targeting sequence of MnSOD has been described and has recently been associated with risk of human breast cancer. Our present case-control study was performed to explore the association between MnSOD genetic polymorphism and individual susceptibility to breast cancer. Ala-9Val polymorphism in the signal sequence of the protein for MnSOD was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a study population. There was no significant difference in risk for breast cancer development between patients positive and negative for the MnSOD Ala allele with adjusted odds ratio (OR): 0.86 (95% confidence interval (CI(0.43 to 1.72). When MnSOD Ala was combined with either cytochrome P450 1B1 CYP1B1*1 and catechol O-methyltransferase COMT-L (V158M) genotypes, the risk for developing breast cancer was significantly increased in patients with a body mass index (BMI) greater than 24 kg m(-2) (OR: 1.42 (95%CI=1.04-1.93)).     

Ethnic variation in the mitochondrial targeting sequence polymorphism of MnSOD.

In contrast to CuZn superoxide dismutase (SOD), only a very limited number of mutations have been described in MnSOD. One interesting example is a polymorphism (Ala-9Val) in the mitochondrial targeting sequence of this radical-scavenging enzyme. We have studied the Ala-9Val polymorphism in various ethnic groups by means of the oligonucleotide ligation assay. There were significant variations in this unique polymorphism between three different language groups: Baltic (Lithuanians), Finnic (Finns and Saamis) and Germanic (Swedes). The Ala frequency in an Asiatic population (Chinese) was significantly lower than in most European populations. This polymorphism may affect the mitochondrial targeting rate of MnSOD which may result in mitochondrial damage with implication in various late-onset neurological diseases.     

Polymorphism in the manganese superoxide dismutase gene

Oxidative stress and mitochondrial damage occur in sepsis. Manganese superoxide dismutase (MnSOD) provides the main defence against oxidative stress within mitochondria. Ala9Val is a single nucleotide polymorphism (SNP) in the MnSOD gene, predicted to affect intra-mitochondrial transport of the enzyme. We found a significant difference in the genotype frequency between healthy subjects (n = 100) and patients with sepsis (n = 40, p = 0.009). For assessment of functionality ten healthy subjects of each homozygous genotype (A/A or V/V) were studied. Peripheral blood mononuclear cells were separated and incubated for 18 h with lipopolysaccharide (LPS), followed by analysis of mitochondrial and cytosolic fractions. There was no difference between genotypes in MnSOD activity and cytochrome c concentration, and minor differences in total antioxidant capacity (TAC) and mitochondrial membrane potential, which did not affect response to LPS. Despite predictions from structural enzyme studies that mitochondrial trafficking would be affected by the Ala9Val polymorphism of the MnSOD gene had little functional effect.     

SOD2 gene polymorphism and response of oxidative stress parameters in young wrestlers to a three-month training

The aim of the study was to analyse the effect of Val 16Ala polymorphism in SOD2 gene on oxidative stress parameters and lipid profile of the blood during a three-month wrestling training. The study included 53 Polish young wrestlers. Blood samples were collected at the beginning of the programme and following three months of the training. The list of analysed parameters included erythrocyte and serum activities of superoxide dismutase (SOD), whole blood glutathione peroxidase (GPx) activity, total glutathione (tGSH) level, concentration of lipid hydroperoxides (LHs), total antioxidant capacity (TAC) and creatine kinase (CK) activity in the serum, as well as lipid profile parameters: triglycerides (TG), total cholesterol (TC), high-density (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Three-month training resulted in a decrease in CK activity, an increase in serum SOD activity, as well as in unfavourable changes in serum lipid profile: an increase in TC, LDL-C, and TG, and a decrease in HDL-C. Aside from CK activity, all these changes seemed to be associated with presence of Val allele. Prior to the training programme, subjects with Ala/Ala genotype presented with lower levels of LHs, lower whole blood GPx activity, and lower serum concentrations of TC than the individuals with Ala/Val genotype. Both prior to and after three-month training, higher levels of tGSH were observed in Val/Val genotype as compared to Ala/Val genotype carriers. Moreover, multiple regression analysis demonstrated that SOD2 genotype was a significant predictor of pre-training whole blood GPx activity and erythrocyte SOD activity (Val/Val?>?Ala/Val?>?Ala/Ala). Altogether, these findings suggest that Val 16Ala polymorphism in SOD2 gene contributes to individual variability in oxidative stress status and lipid profile of the blood in young wrestlers, and may modulate biochemical response to training.     

Evaluation of Genetic Polymorphisms in Patients with Multiple Chemical Sensitivity

Objective

Multiple chemical sensitivity (MCS) is a chronic medical condition characterized by symptoms that the affect an individual’s response to low-level chemical exposure. In this study, we identified a chemical sensitive population (CSP) and investigated the effect of genetic polymorphisms on their risk of chemical sensitivity.

Methods

A quick environment exposure sensitivity (QEESI) questionnaire was used to survey 324 Japanese male workers whose DNA samples had been collected and stored. The following genes, which encode enzymes affecting the metabolic activation of a large number of xenobiotic compounds, were selected and analyzed in order to determine their influence on genetic predisposition to CSP: cytochrome P450 (CYP) 2E1, N-acetyl transferase (NAT) 2, glutathione S-transferase (GST) M1, GSTT1, GSTP1, low Km aldehyde dehydrogenase (ALDH2), and superoxide dismutase (SOD) 2.

Results

Significant case-control distributed differences were observed in SOD2 polymorphisms and allele frequency distribution in high chemical sensitive subjects. Both the significant adjusted OR of 4.30 (95% CI, 1.23–15.03) and 4.53 (95% CI, 1.52-13.51) were observed in SOD2 Ala/Ala and Val/Ala compared to Val/Val and in SOD2 Ala/Ala compared to Val/Ala compared to Val/Val genetic analysis in the high chemical sensitivity case-control study.

Conclusions

We observed that high chemical sensitive individuals diagnosed by using Japanese criteria as MCS patients were more significantly associated with SOD2 polymorphisms.     

Genetic variants in antioxidant genes are associated with sperm DNA damage and risk of male infertility in a Chinese population

To test the hypothesis that polymorphisms in antioxidant genes are more susceptible to sperm DNA damage and male infertility, we examined 11 single-nucleotide polymorphisms from six antioxidant genes (GPX1, CAT, PON1, NQO1, SOD2/MnSOD, and SOD3) in 580 infertility cases and 580 controls from a Chinese population-based case-control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform. Sperm DNA fragmentation was detected using the Tdt-mediated dUTP nick-end labeling assay, and the level of 8-hydroxydeoxyguanosine (8-OHdG) in sperm DNA was measured using immunofluorescence. The adjusted odds ratio and 95% confidence interval (CI) were estimated using unconditional logistic regression. The results indicated that the PON1 Arg192Glu (rs662) and SOD2 Val16Ala (rs4880) variant genotypes were associated with a significantly higher risk of male infertility. In addition, subjects carrying variant genotypes of both loci had a twofold (95% CI, 1.42-2.90) increase in the risk of male infertility, indicating a significant gene-gene interaction between these two loci (P for multiplicative interaction=0.045). Moreover, linear regression analysis showed that individuals carrying the PON1 Arg192Glu (rs662) or SOD2 Val16Ala (rs4880) variants have significantly higher levels of sperm DNA fragmentation and 8-OHdG. These data suggest that genetic variations in antioxidant genes may contribute to oxidative sperm DNA damage and male infertility.     

The impact of OGG1, MTH1 and MnSOD gene polymorphisms on 8-hydroxy-2′-deoxyguanosine and cellular superoxide dismutase activity in myocardial ischemia–reperfusion

Ischemia–reperfusion (I/R) injury, by inducing oxidative DNA damage, is one of the leading causes of increased patient morbidity and mortality in coronary artery by-pass grafting (CABG) surgery. 8-Hydroxyguanine (8-OHG) is an important oxidative base lesion. The 8-oxoguanine glycosylase (hOGG1) and hMTH1, which have several polymorphisms, remove 8-OHdG from the nucleotide pool. We investigated whether there are any correlations the biomarkers of oxidative stress (superoxide dismutase; SOD and 8-OHdG in serum) with genotype for two DNA repair genes (OGG1 and MTH1) and an antioxidant enzyme gene (manganese superoxide dismutase; MnSOD). Therefore, we measured DNA damage (8-hydroxy-2-deoxyguanosine; 8-OHdG) and endogenous antioxidant activity (SOD) at five different time points (T1, before anesthesia; T2, after anesthesia; T3, after ischemia; T4, after reperfusion and T5, after surgery). and also, MnSOD and MutT homolog 1 (MTH1) genes polymorphisms were genotyped by polymerase chain reaction–restricted fragment length polymorphism (PCR–RFLP) in patients undergoing coronary artery by-pass grafting (CABG) surgery. No statistically significant differences were detected in the levels of 8-OHdG and SOD in serum in terms of OGG1 Ser326Cys, MTH1 Val83Met and MnSOD Ala16Val genetic polymorphisms. Our results suggest that OGG1, MTH1 and MnSOD gene polymorphisms are not genetic risk factors for I/R injury.     

Analysis of mitochondrial targeting sequence and coding region polymorphisms of the manganese superoxide dismutase gene in German Parkinson disease patients

Two polymorphisms of the MnSOD gene, Ile58Thr and Ala9Val, have been associated with Parkinson disease (PD). The Ile58Thr amino acid exchange affects the stability at the tetrameric interface of the enzyme and reduces the enzymatic activity of MnSOD while the Ala/Val substitution at position -9 of the mitochondrial targeting sequence (MTS) may lead to misdirected intracellular trafficking. We have analyzed 63 German Caucasian PD patients for possible sequence variation in the MTS as well as in exon 3 of the MnSOD gene. All 63 PD patients analyzed exhibited a T at nucleotide position 5777 in exon 3 of the MnSOD gene corresponding to ATA, or Ile at the peptide level, and no other sequence variants were found. In addition, both alleles of the Ala9Val polymorphism in the MTS of MnSOD were equally distributed between German PD patients and controls excluding this gene variant as a risk factor for PD in Caucasian subjects.     

The MnSOD Ala16Val SNP: Relevance to human diseases and interaction with environmental factors

Abstract

The relevance of reactive oxygen species (ROS) production relies on the dual role shown by these molecules in aerobes. ROS are known to modulate several physiological phenomena, such as immune response and cell growth and differentiation; on the other hand, uncontrolled ROS production may cause important tissue and cell damage, such as deoxyribonucleic acid oxidation, lipid peroxidation, and protein carbonylation. The manganese superoxide dismutase (MnSOD) antioxidant enzyme affords the major defense against ROS within the mitochondria, which is considered the main ROS production locus in aerobes. Structural and/or functional single nucleotide polymorphisms (SNP) within the MnSOD encoding gene may be relevant for ROS detoxification. Specifically, the MnSOD Ala16Val SNP has been shown to alter the enzyme localization and mitochondrial transportation, affecting the redox status balance. Oxidative stress may contribute to the development of type 2 diabetes, cardiovascular diseases, various inflammatory conditions, or cancer. The Ala16Val MnSOD SNP has been associated with these and other chronic diseases; however, inconsistent findings between studies have made difficult drawing definitive conclusions. Environmental factors, such as dietary antioxidant intake and exercise have been shown to affect ROS metabolism through antioxidant enzyme regulation and may contribute to explain inconsistencies in the literature. Nevertheless, whether environmental factors may be associated to the Ala16Val genotypes in human diseases still needs to be clarified.     

SOD2 gene polymorphism and muscle damage markers in elite athletes

Abstract

Exercise-induced oxidative stress is a state that primarily occurs in athletes involved in high-intensity sports when pro-oxidants overwhelm the antioxidant defense system to oxidize proteins, lipids, and nucleic acids. During exercise, oxidative stress is linked to muscle metabolism and muscle damage, because exercise increases free radical production. The T allele of the Ala16Val (rs4880 C/T) polymorphism in the mitochondrial superoxide dismutase 2 (SOD2) gene has been reported to reduce SOD2 efficiency against oxidative stress. In the present study we tested the hypothesis that the SOD2 TT genotype would be underrepresented in elite athletes involved in high-intensity sports and associated with increased values of muscle and liver damage biomarkers. The study involved 2664 Caucasian (2262 Russian and 402 Polish) athletes. SOD2 genotype and allele frequencies were compared to 917 controls. Muscle and liver damage markers [creatine kinase (CK), creatinine, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP)] were examined in serum from 1444 Russian athletes. The frequency of the SOD2 TT genotype (18.6%) was significantly lower in power/strength athletes (n = 524) compared to controls (25.0%, p = 0.0076) or athletes involved in low-intensity sports (n = 180; 33.9%, p < 0.0001). Furthermore, the SOD2 T allele was significantly associated with increased activity of CK (females: p = 0.0144) and creatinine level (females: p = 0.0276; males: p = 0.0135) in athletes. Our data show that the SOD2 TT genotype might be unfavorable for high-intensity athletic events.     

Evaluation of gene polymorphisms in exercise-induced oxidative stress and damage

Abstract

Many potentially significant genetic variants related to oxidative stress have been identified and performance in endurance sports is a multi-factorial phenotype. Thus, it was decided to investigate the influences of the haptoglobin (Hp), MnSOD (Val9Ala), CAT (21A/T), GPX1 (Pro198Leu), ACE, glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) genes' polymorphisms on the oxidative stress and damage suffered by human athletes (runners). Blood samples taken immediately after a race were submitted to genotyping, comet and TBARS assays, biochemical analyses of creatine kinase (CK), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). MnSOD significantly influenced results of CK and a possible association between Hp1F-1S and Hp1S-2 genotypes with a superior TBARS values was found. Higher or lower TBARS and CK values or DNA damage also depended on the interaction between Hp and ACE or GST genotypes, indicating that MnSOD and Hp polymorphisms can be determining factors in performance, at least for runners.     

Genetic polymorphism in the manganese superoxide dismutase gene is associated with an increased risk for hepatocellular carcinoma in HCV-infected Moroccan patients

Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. The main risk factors for its development are hepatitis B and C virus infections. Hepatitis B and C viruses induce chronic inflammation and oxidative stress that could predispose a cell to mutagenesis and proliferation. Manganese superoxide dismutase (MnSOD) catalyses the detoxification of free radicals, thus playing a crucial role in the protection against damage. A valine (Val) to alanine (Ala) substitution at amino acid 9, mapping within the mitochondrion-targeting sequence of the MnSOD gene, has been associated with an increased cancer risk. The aim of our study was to investigate a possible association of the Val/Ala-MnSOD polymorphism and HCC development in Moroccan patients. Genotypes were determined by means of PCR and RFLP analysis in 96 patients with HCC and 222 control subjects matched for age, sex, and ethnicity. Homozygous Ala/Ala carriers were 31% in the cases and 18% in the controls, which corresponds to an odds ratio (OR) of 2.89, with a 95% confidence interval (CI) of 1.47-5.68. Stratification into subgroups based on HCV infection status revealed an even more increased risk for homozygous Ala/Ala carriers with hepatitis C infection (38.2% in the cases versus 14.8% in the control subjects OR, 5.09; 95% CI, 1.76-14.66). Our findings provide further evidence of an association between the Ala-9Val MnSOD polymorphism and HCC occurrence in hepatitis C virus-infected Moroccan patients.     

Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism

We aimed to investigate the association between manganese superoxide dismutase (MnSOD) Ala-9-Val gene polymorphism and the initiation and/or progression of prostate cancer (PCa) as well as to evaluate its potential interactions with advanced age and smoking status. MnSOD Ala-9-Val gene polymorphism was carried out in 134 (mean age 64.1 ± 7.48) PCa patients and 159 (mean age 62.5 ± 7.53) healthy controls with serum prostate specific antigen (PSA) levels (<4 ng/ml) and normal digital rectal examination (DRE) findings in this prospectively designed study. PCa patients were classified as low stage disease (T₁ or T₂ and N₀M₀ stages) and high stage disease (T₃ or T₄ and N₀M₀ or N₁ or M₁ stages). Genotypes for MnSOD Ala-9-Val gene polymorphism were identified by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFPL). Despite lack of association between different genotypes of MnSOD Ala-9-Val gene polymorphism and the presence of PCa, patients with Ala/Ala genotype were at an increased risk of high stage disease compared with those with the Val/Val genotype [odds ratio (OR), 3.77; 95% CI, 1.30–10.94; P = 0.012]. However, no significant difference was observed in the distribution of each genotype among PCa patients, with respect to tumor grade. On the other hand, smoking status and aging did not seem to change the association between genotypes and PCa risk. Ala/Ala genotype of MnSOD polymorphism may have an effect on adverse features of PCa such as high stage disease.     

Higher frequency of septic shock in septic patients with the 47C allele (rs4880) of the SOD2 gene

Aim

To analyze the effect of the two different versions of the manganese superoxide dismutase gene (SOD2) on sepsis. The SOD2 gene presents the 47C > T single nucleotide polymorphism (SNP; ID: rs4880) which produces MnSOD with different activities. The − 9Val MnSOD (47T allele) is less efficient than the − 9Ala version (47C allele). During sepsis there are abundance of ROS, high SOD2 expression and excess of H₂O₂ synthesis. High concentrations of H₂O₂ could affect the sepsis scenario and/or the sepsis outcome.

Methods

We determined the 47C > T single nucleotide polymorphism (SNP) frequencies in 529 critically ill patients with or without sepsis, facing outcome. To collect information on population frequencies, we obtained a pilot 47C > T genotypic and allelic frequencies in a random group of 139 healthy subjects.

Results

We compared the 47C allele carriers (47CC + 47CT genotypes) with 47TT homozygotes and noticed a significant association between 47C allele carriers and septic shock in septic patients (P = 0.025). With an adjusted binary multivariate logistic regression, incorporating 47C > T SNP and the main clinical predictors, we showed high SOFA scores [P < 0.001, OR = 9.107 (95% CI = 5.319–15.592)] and 47C allele [P = 0.011, OR = 2.125 (95% CI = 1.190–3.794)] were significantly associated with septic shock outcome. With this information we presented a hypothesis suggesting that this negative outcome from sepsis is possibly explained by effects on cellular stress caused by 47C allele.

Conclusion

In our population there was a significant higher frequency of septic shock in septic patients with the 47C allele of the SOD2 gene. This higher 47C allele frequency in septic patients with negative outcome could be explained by effects of higher activity MnSOD on cellular stress during the sepsis.     

Effect of genetic polymorphisms of MnSOD and MPO on the relationship between PAH exposure and oxidative DNA damage

To investigate the effect of genetic polymorphisms on the oxidative damage caused by PAH exposure, we measured urinary 1-hydroxypyrene (1-OHP) and 8-hydroxydeoxyguanosine (8-OHdG) levels to determine exposure and oxidative injury in university students. After examining myeloperoxidase (MPO) and manganese superoxide dismutase (MnSOD) genotypes by PCR and RFLP, we evaluated the effects of these polymorphisms on the relationship between the urinary levels of 1-OHP and 8-OHdG. No significant relation was observed between log 1-OHP and 8-OHdG concentrations in the whole study group (p=0.182), or between urinary 8-OHdG levels and polymorphisms of MnSOD or MPO (p=0.539 and 0.993, respectively). However, significant differences of regression coefficient were found for the relation between urinary log 1-OHP and urinary 8-OHdG concentrations in the presence of different MnSOD or MPO genotypes by multiple regression after controlling for age, sex, body mass index, cotinine, and smoking. In those with the MnSOD Val/Ala or Ala/Ala genotypes this regression coefficient was 1.480 (p=0.040), whereas for the MnSOD Val/Val genotype it was 0.088 (p=0.859). The higher regression coefficient was obtained for the subject group with the MnSOD Val/Ala or Ala/Ala genotype in combination with the MPO G/G genotype (p=0.012). We suggest that the oxidative injury caused by PAH exposure is modulated by genetic polymorphisms such as MnSOD and MPO.     

Manganese superoxide dismutase dimorphism relationship with severity and prognosis in cardiogenic shock due to dilated cardiomyopathy

The aim was to determine (a) Ala-16Val-SOD2 dimorphisms; (b) allelic frequency and phenotype of a common Pro-Leu polymorphism in GPx1, in a cohort of patients with a cardiogenic shock (CS) due to dilated cardiomyopathy without acute coronary syndrome. Consecutive patients with de novo CS that worsened a dilated (DCM) or ischemic (ICM) cardiomyopathy. Congenital heart disease, pacemaker and other shock aetiologies were excluded. To determine oxidative stress (OS), this study evaluated lipid peroxidation, protein oxidation and erythrocyte GPx, SOD and catalase activities. Ala16Val-SOD2 (dbSNP: rs4880) and Pro198Leu-GPx1 (dbSNP: rs1050450) polymorphisms were studied by allelic discrimination using fluorogenic probes and the 5'nuclease (TaqMan) assay. Twenty-four patients (with ICM (n = 8) or DCM (n = 16), age = 57.5 ± 10.7 years, LVEF = 25.3 ± 8.5%, NT-proBNP levels = 8540 ± 1703 ng/L) were included during a 15 month follow-up. OS parameters were significantly higher in patients than in controls. Distribution of MnSOD genotypes was 47% Val/Val-variant, 29.5% Ala/Val and 23.5% Ala/Ala-variants. Severity of CS was more important in patients with Val/Val-variant and can be put in parallel with NT-proBNP levels (Val/Val-variant: 11 310 ± 3875 ng/L vs Ala/Ala-variant: 6486 ± 1375 ng/L and Ala/Val-variant: 6004 ± 2228 ng/L; p < 0.05) and hemodynamic support duration (144.6 vs Ala/Val-variant: 108.8 h and Ala/Ala-variant: 52.5 h; p < 0.05) with a positive correlation (Spearman rho = 0.72, p < 0.05). Moreover, Val/Val-variant significantly influenced the mortality (Spearman rho = 0.67, p < 0.05), but not the morbidity (p = 0.3). Distribution of GPx genotypes was 64% Pro/Pro, 18% Pro/Leu and 18% Leu/Leu. GPx-variants influenced neither GPx activities nor cardiac events. In conclusion, CS was associated with markers of increased OS. GPx polymorphism did not influence the GPx activity. Only the Val-encoding MnSOD allele was significantly correlated with the severity and prognosis of CS.