Plasma extracellular superoxide dismutase concentration, allelic variations in the SOD3 gene and risk of myocardial infarction and all-cause mortality in people with type 1 and type 2 diabetes

Abstract

BackgroundOxidative stress is involved in development of diabetes complications. Extracellular superoxide dismutase (EC-SOD, SOD3) is a major extracellular antioxidant enzyme and is highly expressed in arterial walls. Advanced oxidation protein products (AOPP) and 8-iso-prostaglandin (isoprostane) are markers of oxidative stress. We investigated association of SOD3 gene variants, plasma concentrations of EC-SOD, AOPP and isoprostane with myocardial infarction and mortality in diabetic patients.MethodsWe studied three cohorts designed to evaluate the vascular complications of diabetes: the GENEDIAB study (469 participants with type 1 diabetes at baseline; follow-up data for 259 participants), the GENESIS study (603 participants with type 1 diabetes at baseline; follow-up data for 525 participants) and the DIABHYCAR study (3137 participants with type 2 diabetes at baseline and follow-up). Duration of follow-up was 9, 5, and 5 years, respectively. Main outcome measures were incidence of myocardial infarction, and cardiovascular and total mortality during follow-up. Six single nucleotide polymorphisms in the SOD3 locus were genotyped in the three cohorts. Plasma concentrations of EC-SOD, AOPP, and isoprostane were measured in baseline samples of GENEDIAB participants.ResultsIn GENEDIAB/GENESIS pooled cohorts, the minor T-allele of rs2284659 variant was inversely associated with the prevalence at baseline (Odds Ratio 0.48, 95% CI 0.29–0.78, p = 0.004) and the incidence during follow-up of myocardial infarction (Hazard Ratio 0.58, 95% CI 0.40–0.83, p = 0.003) and with cardiovascular (HR 0.33, 95% CI 0.08–0.74, p = 0.004) and all-cause mortality (HR 0.44, 95% CI 0.21–0.73, p = 0.0006). The protective allele was associated with higher plasma EC-SOD and lower plasma AOPP concentrations in GENEDIAB. It was also inversely associated with incidence of myocardial infarction (HR 0.75, 95% CI 0.59–0.94, p = 0.01) and all-cause mortality (HR 0.87, 95% CI 0.79–0.97, p = 0.008) in DIABHYCAR.ConclusionsThe T-allele of rs2284659 in the promoter of SOD3 was associated with a more favorable plasma redox status and with better cardiovascular outcomes in diabetic patients. Our results suggest that EC-SOD plays an important role in the mechanisms of vascular protection against diabetes-related oxidative stress.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-014-0163-2) contains supplementary material, which is available to authorized users.

Relationship Between Plasma 8‐OH‐Deoxyguanosine and Cardiovascular Disease and Survival in Type 2 Diabetes Mellitus: Results From the ADVANCE Trial

“…In this study, we demonstrate that 8‐oxo‐2′‐dG, a marker of oxidative damage, is independently associated with all‐cause mortality and cardiovascular mortality in adults with longstanding type 2 diabetes mellitus who participated in the ADVANCE trial. This finding is consistent with smaller observational studies linking survival of patients with diabetes mellitus to other markers of oxidative stress, including oxidized RNA,10, 11 derivatives of reactive oxygen metabolite,19 advanced autoxidation products,2, 20 and F‐isoprostanes 2, 20. However, this is the first large prospective study to confirm an independent association between mortality and 8‐oxo‐2′‐dG in type 2 diabetes mellitus.…”

“…Hazard ratios for log‐linear effects of 8‐oxo‐2′‐dG levels on each of the 3 studied outcomes were obtained from weighted Cox regression models for case‐cohort analyses 18. Nonfatal outcomes were analyzed using a Fine and Gray competing risk model, treating death from any cause as the competing event 20. Results were expressed per unit SD of 8‐oxo‐2′‐dG (3.5 ng/mL).…”

Mitochondrial ROS control of cancer

“…Examples of these processes are the oxidant-scavenging activity that occurs through the superoxide dismutases (SOD), peroxidase, and catalase enzymatic systems at distinct cellular locations 94 . For instance, reactive O 2 •- is converted into H 2 O 2 , by superoxide dismutase (SOD)1 in the cytosol, by SOD2 in the mitochondrial matrix, and by SOD3 in the extracellular space 24,95 . Reduction of H 2 O 2 into H 2 O restricts reactive • OH formation through fenton chemistry and is regulated by both the catalase and the peroxidase systems such as the thioredoxin/ thioredoxin reductase/peroxiredoxin (Trx/TrxR/Prx) and the glutathione/glutathione peroxidase (GSH/GPx) systems 94 (Figure 2).…”

The copper‐zinc superoxide dismutase activity in selected diseases

“…Both aforementioned studies used PCR‐RFLP method for genotyping purposes. Research into a gene polymorphism in the promoter of SOD3 gene has revealed, that rs2284659 was associated with myocardial infarction, cardiovascular and all‐cause mortality in T1DM and T2DM patients …”