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

Cardiovasc Diabetol. 2015 Jan 15:14:845. doi: 10.1186/s12933-014-0163-2.

Abstract

Background: Oxidative 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.

Methods: We 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.

Results: In 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.

Conclusions: The 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.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles*
  • Biomarkers / blood
  • Cohort Studies
  • Diabetes Mellitus, Type 1 / blood*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / mortality
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / mortality
  • Extracellular Fluid / physiology
  • Female
  • Follow-Up Studies
  • Genetic Variation / genetics
  • Humans
  • Male
  • Middle Aged
  • Mortality / trends
  • Myocardial Infarction / blood*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / mortality
  • Prospective Studies
  • Risk Factors
  • Superoxide Dismutase / blood*
  • Superoxide Dismutase / genetics

Substances

  • Biomarkers
  • SOD3 protein, human
  • Superoxide Dismutase