Superoxide Dismutase Gene Polymorphism Research Articles

In vitro effects of Ala16Val manganese superoxide dismutase gene polymorphism on human white blood cells exposed to methylmercury

Environmental contamination by methylmercury (MeHg) is an enormous public health problem in world regions such as Amazonia. MeHg toxic effects seem to be influenced by environmental and genetic factors. However, few studies have evaluated the genetic influences of MeHg toxicity in humans. Therefore, the aim of this study was to evaluate the genetic influence of Ala16Val manganese superoxide dismutase gene polymorphism (Ala16Val-MnSOD) on the cytotoxic effects of in vitro human leukocytes exposed to MeHg. Subjects were selected from 100 individuals aged 26.4 ± 7.3 years genotyped to Ala16Val-MnSOD polymorphism (AA = 6, VV = 6, and AV = 12) to perform in vitro testing using white blood cells (WBCs). Reactive oxygen species production was measured using 2',7'-dichlorofluorescein diacetate fluorimetric assay, and cell viability was measured using MTT assay on WBC samples from the same subjects that were both exposed and not exposed to MeHg (2.5 µM for 6 h). The results showed that AA- and VV-WBCs exposed to MeHg did not display increased reactive oxygen species levels compared to those in cells that were not exposed. However, AV-leukocytes exposed to MeHg displayed increased ROS levels. Cellular viability comparison among genotypes exposed to MeHg showed that the viability of AA-WBCs was lower than that of VV-WBC, with mean values of 3.46 ± 0.13 and 3.08 ± 0.77 (standard error), respectively (P = 0.033), whereas heterozygous cells (AV) displayed intermediate values. This difference was likely due to the higher basal H2O2 production of AA-WBCs compared to that of other genotypes. These results suggest that the Ala16Val-MnSOD polymorphism has toxicogenetic effects in human cells exposed to MeHg.

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

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

Inflammatory cytokines in vitro production are associated with Ala16Val superoxide dismutase gene polymorphism of peripheral blood mononuclear cells

Obesity is considered a chronic low-grade inflammatory state associated with a chronic oxidative stress caused by superoxide production (O2-). The superoxide dismutase manganese dependent (SOD2) catalyzes O2- in H2O2 into mitochondria and is encoded by a single gene that presents a common polymorphism that results in the replacement of alanine (A) with a valine (V) in the 16 codon. This polymorphism has been implicated in a decreased efficiency of SOD2 transport into targeted mitochondria in V allele carriers. Previous studies described an association between VV genotype and metabolic diseases, including obesity and diabetes. However, the causal mechanisms to explain this association need to be more elucidated. We postulated that the polymorphism could influence the inflammatory response. To test our hypothesis, we evaluated the in vitro cytokines production by human peripheral blood mononuclear cells (PBMCs) carrier’s different Ala16Val-SOD2 genotypes (IL-1, IL-6, IL-10, TNF-α, IFN-γ). Additionally, we evaluated if the culture medium glucose, enriched insulin, could influence the cytokine production. Higher levels of proinflammatory cytokines were observed in VV-PBMCs when compared to AA-PBMCs. However, the culture medium glucose and enriched insulin did not affect cytokine production. The results suggest that Ala16Val-SOD2 gene polymorphism could trigger the PBMCs proinflammatory cytokines level. However, discerning if a similar mechanism occurs in fat cells is an open question.

Association of Alanine-Valine Manganese Superoxide Dismutase Gene Polymorphism and Microheterogeneity Manganese Superoxide Dismutase Activity in Breast Cancer and Benign Breast Tissue

PurposeAlthough the etiology of breast cancer is multifactorial, oxidative stress plays an important role in carcinogenesis. In this study, manganese superoxide dismutase (MnSOD) gene polymorphism and activity were evaluated in benign and breast cancer tissue.MethodsOne hundred and one females were enrolled in this study, 65 who were histopathologically diagnosed with breast cancer and 46 who were benign patients. MnSOD enzyme activity was determined using an indirect competitive inhibition assay and MnSOD gene polymorphism using poly merase chain reaction and agarose gel electrophoresis.ResultsMnSOD enzymatic activity (79.83±42.14) was lower in breast cancer tissue compared to benign tumors (236.18±46.37). At the same time, MnSOD enzymatic activity among Ala/Val patients was significantly lower in breast cancer tissue (39.19±7.33) than in Val/Val malignant breast tumors tissue (96.9±22.9). MnSOD enzymatic activity was significantly lower in Val/Val cancer tissue (96.9±22.9) than in benign tissue (255.44±42.7).ConclusionBreast cancer tumors contain less MnSOD than benign breast samples. Patients with Ala/Val polymorphism had reduced MnSOD activity compared to patients with Val/Val breast cancer. Ala/Val gene polymorphism may be a risk factor associated with more advanced breast cancer stage. MnSOD gene polymorphism Ala/Val may be a risk factor associated with more advanced breast cancer stage, and reduction of MnSOD activity may be a mechanism of the progression of benign to malignant tumors. Further investigations are needed to evaluate the role of MnSOD in breast cancer progression.

Superoxide dismutase gene polymorphisms and functional activity in chronic obstructive pulmonary disease

To explore the association of genetic polymorphism of superoxide dismutase (SOD) and superoxide dismutase activity in chronic obstructive pulmonary disease. A total of 114 patients with COPD (the COPD group) and 80 healthy volunteers (the control group) were enrolled in this study. Peripheral blood was taken and whole blood cell genomic DNA was extracted. The genetic polymorphisms of Mn-SOD (G5774A) and EC-SOD G (-4466)T genes were determined by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Peripheral blood plasma was collected and the functional activity of SOD was determined by a SOD kit. The distribution of the Mn-SOD genotype frequencies (GG, AG, AA) between the patients [27.2% (31/114), 53.5% (61/114) and 19.3% (22/114)] and the controls [46.3% (37/80), 37.5% (30/80) and 16.2% (13/80)] were significantly different (χ(2) = 7.681, P < 0.05). The A allele gene frequencies of the patients (46.1%, 105/228) were significant higher than those of the controls (35.0%, 56/160), and subjects with the A allele gene of Mn-SOD were more likely to have COPD [OR = 1.585, 95%CI (1.045 - 2.404), P < 0.05]. The AA and AG genotypes of Mn-SOD were correlated with the most severe COPD (χ(2) = 12.345, P < 0.01). The distribution of the EC-SOD genotype frequencies (GG, GT, TT) was 76.3% (87/114), 22.8% (26/114), 0.9% (1/114) in the patients and 71.3% (57/80), 28.7% (23/80), 0% (0/80) in the controls. The allele gene frequencies of the EC-SOD (G, T) were 87.7% (200/228), 12.3% (28/228) in the patients and 85.6% (137/160), 14.4% (23/160) in the controls. There were no significant differences in the distribution of the different genotypes or allele gene frequencies between the patients and the controls in the EC-SOD genes (χ(2) = 0.631, P > 0.05; χ(2) = 0.36, P > 0.05). The SOD activity of COPD patients [(84 ± 17) kU/L] was significant lower than that of the healthy controls [(109 ± 15) kU/L]. Mn-SOD (G5774A) genetic polymorphism is related to the development of COPD. The Mn-SOD 5774A allele gene may be one of the predisposing genes for COPD. The AA and AG genotypes of Mn-SOD were correlated with the most severy COPD. The decrease of blood plasma SOD activity in COPD patients indicates a dysfunction of the oxidant/antioxidant defense system in the disease.

Oxidative stress in hypercholesterolemia and its association with Ala16Val superoxide dismutase gene polymorphism

Objectives To investigate the role of the oxidative stress and the antioxidant system as well as the influence of the manganese superoxide dismutase (Ala16Val) polymorphism on hypercholesterolemia. Design and methods Levels of glucose, lipid, high-sensitivity C reactive protein (hs-CRP), thiobarbituric acid reactive substances (TBARS), carbonyl protein, thiols, reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and vitamin C, vitamin E, as well as the presence of the manganese superoxide dismutase (Ala16Val) polymorphism were determined in 40 subjects with hypercholesterolemia and 40 controls. Results Lipid profile, hs-CRP, glucose, TBARS, carbonyl protein, CAT, and vitamin E were significantly higher in subjects with hypercholesterolemia. In contrast, GSH and SOD were lower. TBARS, carbonyl protein, thiols, CAT, and vitamin E were significantly higher in hypercholesterolemic subjects with VV genotype for MnSOD, while GSH, SOD, and vitamin C were lower in these subjects. Conclusions We suggest an association between the genotypes of MnSOD, hypercholesterolemia, and oxidative stress biomarkers.

Polymorphisms of Superoxide Dismutase, Glutathione Peroxidase and Catalase Genes in Patients with Post-transplant Diabetes Mellitus

Post-transplant diabetes mellitus (PTDM) is a metabolic disorder that develops in response to a relative insulin deficiency in patients after organ transplantation treated with immunosuppressive drugs. Several studies have suggested that oxidative stress may be associated with diabetes and its complications. The aim of this study was to examine the association of polymorphisms in superoxide dismutase, catalase and glutathione peroxidase genes with PTDM in patients after kidney transplantation. The study included 159 patients receiving kidney transplants. PTDM was diagnosed in 21 patients. Analyzing the C599T (Pro200Leu) polymorphism in the GPX1 gene PTDM was diagnosed in 8.45% of patients with CC genotype, 13.43% with CT and in 28.57% with TT. Allele T was significantly more frequent among patients with PTDM compared to patients without PTDM (OR = 2.14, 95% CI = 1.11-4.12, p = 0.024). There were no associations between SOD1, SOD2 and CAT polymorphisms and PTDM. The present results suggest that Pro200Leu polymorphism of the GPX1 gene may be associated with the risk of PTDM development in renal graft recipients.

Association of manganese superoxide dismutase (MnSOD) gene polymorphism and prostate cancer risk

Association of manganese superoxide dismutase (MnSOD) gene polymorphism and prostate cancer risk

Association Between Manganese Superoxide Dismutase Gene Polymorphism and Risk of Prostate Cancer: A Meta-analysis

To examine the association between 2 mitochondrial manganese superoxide dismutase (MnSOD) genetic polymorphisms (Ala-9Val and Ala-16Val) and prostate cancer susceptibility. A comprehensive search was conducted to identify all case-control studies of MnSOD polymorphisms and prostate cancer risk. Statistical analysis was performed with the software program Stata, version 8.0, and Review Manage, version 4.2. A total of 9 eligible studies, including 3268 cases and 5907 controls, relating the MnSOD polymorphism to the risk of prostate cancer were identified. For the Ala-9Val polymorphism, 5 studies, including 889 cases and 1841 controls, found no significant associations between MnSOD polymorphism and the risk of developing prostate cancer in the recessive, dominant, and co-dominant models. In the sensitivity analysis, exclusion of the study with the controls not in Hardy-Weinberg equilibrium, no significant associations were also found in the recessive (odds ratio [OR] 1.29, 95% confidence interval [CI] 0.66-2.50), dominant (OR 1.35, 95% CI 0.84-2.17), and co-dominant (OR 1.33, 95% CI 0.87-2.01) models. For the Ala-16Val polymorphism, 4 studies, including 2379 cases and 4066 controls, found no significant association between MnSOD polymorphism and the risk of developing prostate cancer in both co-dominant (OR 1.08, 95% CI 1.00-1.16), recessive (OR 1.06, 95% CI 0.94-1.20) and dominant (OR 1.14, 95% CI 1.00-1.28) models. No significant association was found between the Ala-9Val and Ala-16Val polymorphisms in MnSOD and prostate cancer susceptibility.

Association between manganese superoxide dismutase (MnSOD) gene polymorphism and elderly obesity

Evidence suggests an association between obesity and oxidative stress caused by superoxide production. Since the dismutation of superoxide is catalyzed by superoxide dismutase enzymes, we tested the association between obesity and Ala16Val manganese-dependent superoxide dismutase gene (MnSOD) polymorphism. We analyzed 815 free-living community subjects (> or =60 years old) grouped into subjects who were either obese (BMI > or = 30 kg/m(2)) or non-obese (BMI < 25 kg/m(2)). Additionally, we investigated the possible interaction between the Ala16Val MnSOD gene polymorphism and obesity in the modulation of biochemical and nutritional variables. We found a positive association between MnSOD polymorphism and obesity, since higher VV frequency (28.2%) was observed in the obese group (P = 0.002, odds ratio 1.949, 95% CI: 1.223-3.008). This result was independent of sex, age, diabetes, dyslipidemia, hypertension, and metabolic syndrome. A possible biological explanation of the association described here could be a chronic state of superoxide enzyme imbalance present in VV carriers, which could affect differential metabolic pathways contributing to the obese state.

Additive effect between quinine oxidoreductase gene ( NQO1: Pro187Ser) and manganese superoxide dismutase gene ( MnSOD: Ala-9Val) polymorphisms on tardive dyskinesia in patients with schizophrenia

This study investigated whether there was an interaction between the NQO1 Pro187Ser and MnSOD Ala-9Val gene polymorphisms in the development of tardive dyskinesia (TD). The combined genotypes of T/T in NQO1 Pro187Ser and Val/Val in MnSOD Ala-9Val polymorphisms were found to be independently associated with a significantly higher risk of TD. However, further adequately powered studies will be needed to confirm these preliminary findings.

Manganese superoxide dismutase gene polymorphism, MnSOD plasma levels and risk of epithelial ovarian cancer

We aimed to confirm any relation between the manganese-containing superoxide dismutase (MnSOD) polymorphism and risk of ovarian carcinoma as well as to demonstrate any relation between the MnSOD mitochondrial signal sequence polymorphism and plasma MnSOD enzyme levels in women with ovarian carcinoma and healthy subjects. In a population-based case - control study, we compared 55 cases with ovarian carcinoma and 51 controls regarding the occurrence of the C/T (alanine/valine, A/V) substitution at the -9 position in the mitochondrial signal sequence of the MnSOD gene. Polymerase chain reaction, restriction fragment length polymorphism and Nu-Sieve agarose gel electrophoresis were utilized to perform genotyping. Additionally, MnSOD plasma levels were measured using enzyme-linked immunosorbent assay methodology. There were no statistically significant elevated risks associated with V or A alleles. No statistically significant association between the alleles and plasma MnSOD levels were found. Overall plasma MnSOD levels were found to be significantly higher in the patient group. Although in this study, patients with ovarian carcinoma had significantly higher plasma MnSOD levels than the control group (P<0.001), no influence of the allelic distribution on plasma MnSOD levels could be detected in either group. Our results are in disagreement with earlier findings that there was an association between the A allele and increased risk for ovarian carcinoma. Thus, an extended study for a possible association between the MnSOD diallelic polymorphism and risk of ovarian cancer may be warranted.

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

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

Manganese Superoxide Dismutase Gene Polymorphism (V16A) is Associated with Diabetic Retinopathy in Slovene (Caucasians) Type 2 Diabetes Patients

Substantial data indicate that oxidative stress is involved in the development of diabetic retinopathy. Two candidate genes that affect the oxidative stress are manganese mitochondrial superoxide dismutase (Mn-SOD) and endothelial nitric oxide synthase (eNOS). The aim of the present study was to examine the role of the V16A polymorphism of the Mn-SOD gene and the 4a/b polymorphism of the eNOS gene in the development of diabetic retinopathy in Caucasians with type 2 diabetes. In this cross sectional case-control study 426 unrelated Slovene subjects (Caucasians) with type 2 diabetes mellitus were enrolled: 283 patients with diabetic retinopathy and the control group of 143 subjects with type 2 diabetes of duration of more than 10 years who had no clinical signs of diabetic retinopathy. A significantly higher frequency of the VV genotype of the V16A polymorphism of the Mn-SOD was found in patients with diabetic retinopathy compared to those without diabetic retinopathy (OR=2.1, 95% CI = 1.2–3.4; p = 0.006), whereas the 4a/b polymorphism of the eNOS gene failed to yield an association with diabetic retinopathy.We may conclude that the VV genotype of the V16A polymorphism of the Mn-SOD gene was associated with diabetic retinopathy in Caucasians with type 2 diabetes, therefore it might be used as a genetic marker of diabetic retinopathy in Caucasians.

Manganese superoxide dismutase (MnSOD: Ala–9Val) gene polymorphism may not be associated with schizophrenia and tardive dyskinesia

There has been increasing evidence that the alteration of antioxidant enzymes such as manganese superoxide dismutase (MnSOD) might be implicated in the development of schizophrenia and/or tardive dyskinesia (TD). This study investigated the association of a MnSOD gene ( MnSOD) polymorphism (Ala–9Val) with schizophrenia as well as its involvement in TD. Patients with schizophrenia ( n = 262) and healthy controls ( n = 263) were enrolled in this study and genotyped by a polymerase chain reaction-based method. The distribution of the MnSOD genotypes and alleles was not significantly different between patients and controls. Logistic regression analysis also failed to reveal any association between MnSOD genotypes and TD. Taken together, these results suggest that the MnSOD polymorphism does not contribute to the development of schizophrenia and/or TD, at least in the Korean population.

Association of manganese superoxide dismutase gene polymorphism (Ala-9Val) and breast cancer in males and females

INTRODUCTION: One of the several metabolic pathways involved in breast carcinogenesis is the human polymorphism in the mitochondrial targeting sequence Ala-9Val of the manganese superoxide dismutase (MnSOD) gene, which has been previously associated with increased risk of breast cancer in females. Since there is no previous report on this polymorphism in male breast cancer, the objective of this study is to analyze MnSOD polymorphism in a population of males and females with breast cancer from the southernmost state of Brazil, compared to healthy controls. METHODS: A case-control study of one hundred patients affected by breast cancer (11 men and 89 women) and 370 healthy age-adjusted database controls was performed. DNA was extracted from paraffin-embedded tumoral tissue. MnSOD polymorphism was determined by PCR-RFLP techniques using restriction enzyme Hae III. Chi-square test was used to compare MnSOD frequency distribution. RESULTS: MnSOD genotypic frequencies in all patients with breast cancer were AA = 15%; AV = 56%; VV = 29% and controls AA = 6.5%; AV = 68.1% and VV = 25.4%. Both male and female patients with breast cancer presented significantly higher AA frequencies compared to controls (p = 0.035), suggesting strong association of this genotype with breast cancer. A 2.15-fold (95% confidence interval [CI] 1.393-4.541) risk of breast cancer was found among individuals carrying the MnSOD AA allele-containing genotypes compared with the MnSOD VV and AV genotypes. DISCUSSION: These results confirm the already established association of MnSOD AA genotype with female breast cancer and further indicate a similar frequency distribution and increased risk in the male population.

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.

Neonatal manganese superoxide dismutase gene polymorphism, gestational length and respiratory distress syndrome in twin pregnancies

Oxidative stress is an important determinant of unfavorable pregnancy outcome. The enzyme, manganese superoxide dismutase (MnSOD), present in trophoblasts and endothelial cells in the placenta, protects cells against reactive oxygen species (ROS) that are produced as a consequence of tissue remodeling and inflammation. The removal of superoxide anions also prolongs the biological half-life of nitric oxide in the uterus and maintains uterine quiescence. A single nucleotide polymorphism (SNP) in the MnSOD gene at position 1183 results in an alanine (A) to valine (V) change in the protein and results in formation of an enzyme with reduced ROS-inactivating capacity.

Association of manganese superoxide dismutase gene polymorphism (V16A) with diabetic macular edema in Korean type 2 diabetic patients

This study was designed to investigate whether V16A polymorphism of the manganese superoxide dismutase (Mn-SOD) gene is associated with the development of type 2 diabetes mellitus and with progression of diabetic retinopathy (DR) and diabetic macular edema (DME). We simultaneously analyzed insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene in the 16th intron to avoid its confounding effect. A total of 192 nondiabetic subjects and 304 type 2 diabetic patients were included in the study. Diabetic retinopathy was classified as nonretinopathy, nonproliferative retinopathy, and proliferative retinopathy. Diabetic macular edema was defined as thickening of the retina and/or hard exudates within a 1-disk diameter of the center of the macula. Diabetic macular edema was further classified into focal, diffuse, and ischemic types. The A allele frequency of the Mn-SOD gene was not different between nondiabetic and type 2 diabetic subjects, between the normotensive and hypertensive groups, between the DR (−) and DR (+) groups, and among the stages of DR. In the DR (+) group, the DME (+) group had a lower A allele frequency than that of the DME (−) group. In the DME (+) group, focal, diffuse, and ischemic types were found in 8, 23, and 6 patients, respectively. The A allele frequency of each type was 0.188, 0.109, and 0.0. The D allele frequency of the angiotensin-converting enzyme gene did not differ in any of the comparisons. Clinical and laboratory parameters of the A allele carriers were not different from those of the noncarriers except for the prevalence of hypertension and DME. Hypertension, diabetic duration, and insulin therapy were related to DR. The A allele, hypertension, and insulin therapy were associated with DME. In conclusion, our results suggest that V16A polymorphism of the Mn-SOD gene is not related to the development of diabetes and progression of DR, but is associated with DME in Korean type 2 diabetic patients.

Gene × Gene interaction between MnSOD and GPX-1 and breast cancer risk: a nested case-control study

BackgroundGerm-line mutations in genes such as BRCA1, BRCA2, and ATM can cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population, and account for little of the incidence of sporadic breast cancer in the general population. Therefore, research has been focused on examining associations between common polymorphisms and breast cancer risk. To date, few associations have been described. This has led to the hypothesis that breast cancer is a complex disease, whereby a constellation of very low penetrance alleles need to be carried to present a risk phenotype. Polymorphisms in the manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPX-1) genes have been proposed as low penetrance alleles, and have not been clearly associated with breast cancer. We investigated whether variants at both polymorphisms, while not independently associated with breast cancer risk, could influence breast cancer risk when considered together.MethodsA case-control study nested within the Nurses' Health Study was performed comparing 1262 women diagnosed with breast cancer to 1533 disease free women. The MnSOD (Val16Ala, rs1799725) and GPX-1 (Pro198Leu, rs1050450) were genotyped via TaqMan assay. Disease risk was evaluated using logistic regression.ResultsWhile neither allele alone shows any change in breast cancer risk, an increase in the risk of breast cancer (OR 1.87, 95% CI 1.09 – 3.19) is observed in individuals who carry both the Ala16Ala genotype of MnSOD and the Leu198Leu genotype of GPX-1.ConclusionPolymorphisms in the GPX-1 and MnSOD genes are associated with an increased risk of breast cancer.