Manganese Superoxide Dismutase Ala16Val Polymorphism Research Articles

The manganese superoxide dismutase Val16Ala polymorphism is associated with decreased risk of diabetic nephropathy in Chinese patients with type 2 diabetes

The aim of the present study was to evaluate the relationship of the manganese superoxide dismutase (MnSOD) Val16Ala (V16A) polymorphism with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) in Chinese patients, a case-control study was performed. This case-control study included 172 non-diabetic (non-DM) subjects and 257 T2DM patients with or without DN. Among T2DM patients, 154 had DN [albumin excretion rate (AER) >or= 30 mg/24 h] and 103 did not (AER < 30 mg/24 h), but the latter with known diabetes duration >or=10 years. The DN patients were further divided into groups with microalbuminuria (DN-1; n = 92; 300 > AER >or= 30 mg/24 h) and overt albuminuria nephropathy (DN-2; n = 62; AER >or= 300 mg/24 h). PCR-restriction fragment length polymorphism (RFLP) was used to detect genotypes of the V16A polymorphism for all subjects. The genotypic distributions of the V16A polymorphism in non-DM and T2DM subjects were in Hardy-Weinberg equilibrium and Ala allelic frequencies did not differ (11.9% vs. 9.1%; P > 0.05). The AA+VA genotypic frequencies of DN patients were significantly lower than those of non-DN patients (11.6% vs. 24.3%; P = 0.008). Multiple logistic regression analysis revealed that except for HbA1C, triglyceride, and BMI, which were high risk factors for the development of DN, the AA+VA genotype of the MnSOD-V16A polymorphism was an independent protective factor from the development of DN (odds ratio = 0.42; 95% CI = 0.18-0.95; P = 0.037) in T2DM patients. Our results suggested that the MnSOD-V16A polymorphism is associated with decreased risk of diabetic nephropathy in Chinese patients with type 2 diabetes.

Manganese superoxide dismutase Ala16Val polymorphism is associated with the development of type 2 diabetes in Japanese-Americans

Aims Recent evidence indicates that oxidative stress may play an important role in the pathogenesis of insulin resistance and that gene polymorphism (Ala16Val) of manganese superoxide dismutase (MnSOD) may protect against reactive oxygen species (ROS) function. We aimed to test the hypothesis that the Ala16Val variant could be associated with the development of type 2 diabetes. Methods We examined 523 nondiabetic Japanese-Americans who underwent a 75 g oral glucose tolerance test (OGTT) and were followed for an average of 9.9 years. Cox proportional hazard analysis, stratified by category of OGTT, was used to determine whether the Ala16Val polymorphism was a risk factor in the development of type 2 diabetes. Results During the follow-up period, 65 subjects developed type 2 diabetes. Compared with Ala allele carriers, subjects with a Val homozygote showed significantly higher risk for developing diabetes (stratified hazard ratio = 2.05 [95% confidence interval 1.03–4.08]; P = 0.041) after adjustment for age, gender, systolic blood pressure, total cholesterol, body mass index, and homeostasis model assessment. Conclusions We demonstrated that the MnSOD Ala16Val polymorphism might be associated with development of type 2 diabetes among Japanese-Americans. These results suggest that insufficient ROS scavenging might be associated with a susceptibility to glucose intolerance.

Nitric Oxide Synthase and Superoxide Dismutase Gene Polymorphisms in Behçet Disease

To investigate the association of endothelial nitric oxide synthase (NOS), inducible NOS, manganese superoxide dismutase (SOD), and extracellular SOD gene polymorphisms with susceptibility to Behçet disease (BD) in Japan. Seventy-eight consecutive Japanese patients with BD and 107 healthy control subjects were genotyped by polymerase chain reaction or polymerase chain reaction-restriction fragment length polymorphism methods for endothelial NOS polymorphisms in intron 4, exon 7, and promoter region; inducible NOS polymorphisms in exon 16 and promoter region; manganese SOD Ala16Val polymorphism; and extracellular SOD Arg213Gly polymorphism. HLA-B*51 alleles, which have been found to be associated with BD, were also determined. The frequencies of manganese SOD Val16 increased significantly in patients with BD. The manganese SOD-Val/Val genotype and HLA-B*5101 had a synergistic role in controlling susceptibility to BD. There was no significant difference in the frequencies of endothelial NOS, inducible NOS, and extracellular SOD gene polymorphisms between patients with BD and control subjects. The manganese SOD Val16 allele is associated with the development of BD in Japan. Extracellular SOD, endothelial NOS, and inducible NOS gene polymorphisms do not constitute a risk factor for developing BD in Japan. The manganese SOD gene polymorphism seems to contribute to BD.

Association between the MnSOD Ala-9Val polymorphism and development of schizophrenia and abnormal involuntary movements in the Xhosa population

Reactive oxygen species (ROS)-mediated damage has been hypothesized to play a role in the development and poor outcome of schizophrenia, as well as the development of neuroleptic-induced abnormal involuntary movements. Recently, the functional polymorphism (Ala-9Val) in the manganese superoxide dismutase ( MnSOD) gene (part of the antioxidant defense mechanism) was found to be associated with schizophrenia in a Turkish population. This study was aimed at replicating this finding in a Xhosa population. In addition, the role of Ala-9Val in abnormal involuntary movement and tardive dyskinesia development in the Xhosa population was also investigated. The schizophrenic patient group ( n = 286) and a healthy control group ( n = 243) were genotyped for the Ala-9Val polymorphism using heteroduplex-single stranded conformational polymorphism (HEX-SSCP) analysis. No significant difference in genotype or allele frequency could be observed between the schizophrenia and control group ( P = 0.294 and P = 0.528 respectively). In addition no association could be found between the polymorphism and symptom severity (SANS and SAPS). The Xhosa schizophrenia patient group with abnormal involuntary movements ( n = 54) and a subgroup with tardive dyskinesia ( n = 30) was found to significantly differ in Ala-9Val genotype frequency ( P = 0.008 and P = 0.011 respectively) compared to the Xhosa schizophrenia patient group without abnormal involuntary movements ( n = 204). However, no significant difference was found for the allele frequencies ( P = 0.955 and P = 0.161). Further, using ANCOVA no association was found between AIMS score and genotype in the group with abnormal involuntary movements ( P = 0.1234). However, in the patient group with tardive dyskinesia an association was observed between genotype and AIMS score ( P = 0.0365). These results do not support a major role of the MnSOD Ala-9Val polymorphism in the development of schizophrenia or symptom severity in the Xhosa population. Yet it seems to be involved in the development of abnormal involuntary movements and tardive dyskinesia and may even modulate the severity of tardive dyskinesia.

Manganese superoxide dismutase Ala-9Val polymorphism, environmental modifiers, and risk of breast cancer in a German population

A functional polymorphism at codon 16 (Alanine-to-Valine) of manganese superoxide dismutase (MnSOD) has been hypothesized to increase the risk of breast cancer and to modify the effects of oxidative stress. However, study findings have been inconsistent and sample sizes often small. We used a large population-based age-matched case-control study in German Caucasian women up to age 50 to assess breast cancer risk associated with this polymorphism and to investigate interaction with other known risk factors related to oxidative stress, including alcohol intake, cigarette smoking, and diet. Data on a total of 614 cases and 1,080 controls were evaluated using multivariate conditional logistic models. No main effect between genotype and breast cancer was observed. However, risk was significantly increased for Ala carriers who consumed > or =19 g of alcohol per day, compared to women homozygous for the Val allele who did not drink (OR 2.1, 95% CI 1.1-3.9; p = 0.13 for interaction). No significant effect modification was observed for smoking or diet. The MnSOD Ala-9Val polymorphism may contribute to an increase in breast cancer risk in the context of high alcohol consumption, however the polymorphism is not an overall risk factor for breast cancer in this primarily premenopausal population.

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

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

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

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

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case–control study of African Americans and whites

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case-control study of African Americans and whites

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case-control study of African Americans and whites

Manganese superoxide dismutase Ala-9Val polymorphism and risk of breast cancer in a population-based case-control study of African Americans and whites.

IntroductionA polymorphism in the manganese superoxide dismutase (MnSOD) gene, Ala-9Val, has been examined in association with breast cancer risk in several epidemiologic studies. Results suggest that the Ala allele increases the risk of breast cancer and modifies the effects of environmental exposures that produce oxidative damage to DNA.MethodsWe examined the role of the MnSOD Ala-9Val polymorphism in a population-based case–control study of invasive and in situ breast cancer in North Carolina. Genotypes were evaluated for 2025 cases (760 African Americans and 1265 whites) and for 1812 controls (677 African Americans and 1135 whites).ResultsThe odds ratio for MnSOD Ala/Ala versus any MnSOD Val genotypes was not elevated in African Americans (odds ratio = 0.9, 95% confidence interval = 0.7–1.2) or in whites (odds ratio = 1.0, 95% confidence interval = 0.8–1.2). Greater than additive joint effects were observed for the Ala/Ala genotype and smoking, radiation to the chest, and occupational exposure to ionizing radiation. Antagonism was observed between the Ala/Ala genotype and the use of nonsteroidal anti-inflammatory drugs.ConclusionsThe MnSOD genotype may contribute to an increased risk of breast cancer in the presence of specific environmental exposures. These results provide further evidence for the importance of reactive oxygen species and of oxidative DNA damage in the etiology of breast cancer.