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.
Highlights
Diabetes mellitus is associated with increased mortality rates [1,2]
A logistic regression analysis confirmed the inverse association of the T-allele with the prevalence of previous myocardial infarction
Individuals who had a myocardial infarction, compared to those who did not, were older, had a longer duration of diabetes, higher systolic blood pressure, lower Estimation of the glomerular filtration rate (eGFR), and were more likely to be of the male sex and to be taking antihypertensive and lipids lowering drugs
Summary
Diabetes mellitus is associated with increased mortality rates [1,2]. Despite significant improvement of medical care during late decades, life expectancy of patients with type 1 or type 2 diabetes remains reduced as compared to age- and sex-matched nondiabetic subjects [1,2]. Cardiovascular disease is the leading cause of mortality and morbidity in patients with diabetes [1,2], and diabetic patients have a 3-fold higher risk than nondiabetic individuals of developing atherosclerosis and its clinical complications [1,3]. Advanced oxidation protein products (AOPP) and 8-iso-prostaglandin (isoprostane) were identified as markers of oxidative stress in patients with heart disease [10,11]. In the present study we investigated associations of allelic variation in the SOD3 gene with the risk of myocardial infarction, cardiovascular death and all-cause mortality in two prospective cohorts of type 1 diabetic patients and one prospective cohort of type 2 diabetic patients. Extracellular superoxide dismutase (EC-SOD, SOD3) is a major extracellular antioxidant enzyme and is highly expressed in arterial walls. We investigated association of SOD3 gene variants, plasma concentrations of EC-SOD, AOPP and isoprostane with myocardial infarction and mortality in diabetic patients
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