title: 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: 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.
authors: Kamel
authors: K
authors: Mohammedi
authors: Naïma
authors: N
authors: Bellili-Muñoz
authors: Stefan L
authors: SL
authors: Marklund
authors: Fathi
authors: F
authors: Driss
authors: Hervé
authors: H
authors: Le Nagard
authors: Thiago A
authors: TA
authors: Patente
authors: Frédéric
authors: F
authors: Fumeron
authors: Ronan
authors: R
authors: Roussel
authors: Samy
authors: S
authors: Hadjadj
authors: Michel
authors: M
authors: Marre
authors: Gilberto
authors: G
authors: Velho
mesh_terms: D000328:Adult; D000483:Alleles; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000235:genetics / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000401:mortality; D045604:Extracellular Fluid / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009026:Mortality / Q000639:trends; D009203:Myocardial Infarction / Q000097:blood* / Q000235:genetics / Q000401:mortality; D011446:Prospective Studies; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000097:blood* / Q000235:genetics
chemical_list: D015415:Biomarkers; C441642:SOD3 protein, human; D013482:Superoxide Dismutase