Allelic variations in superoxide dismutase-1 (SOD1) gene and renal and cardiovascular morbidity and mortality in type 2 diabetic subjects

doi:10.1016/j.ymgme.2012.04.023

Molecular Genetics and Metabolism

Volume 106, Issue 3, July 2012, Pages 359-365

https://doi.org/10.1016/j.ymgme.2012.04.023 Get rights and content

Abstract

Background

Oxidative stress is involved in the pathophysiology of renal and cardiovascular complications of diabetes. Superoxide dismutase (SOD) enzymes play a major role in detoxification of reactive oxygen species and protection against oxidative stress. Associations of SOD1 gene variants with diabetic nephropathy were reported in patients with type 1 diabetes. We investigated associations of allelic variations in SOD1 gene with nephropathy and cardiovascular complications in patients with type 2 diabetes.

Methods

Seven SNPs in SOD1 region were analyzed in 3744 type 2 European Caucasian diabetic patients from the DIABHYCAR (a 6-year prospective study) and DIABHYCAR_GENE cohorts. Odds ratios or hazard ratios for prevalence and incidence of diabetic nephropathy and cardiovascular events were estimated.

Results

We observed an association of rs1041740 with the prevalence of microalbuminuria at baseline (OR 1.51, 95% CI 1.10–2.10, p = 0.01). No association with the incidence of renal events (doubling of the serum creatinine levels or the requirement of hemodialysis or renal transplantation) or cardiovascular events (myocardial infarction or stroke) was observed during follow-up. However, three variants were associated with increased risk of death from cardiovascular causes (sudden death, fatal myocardial infarction or stroke) during the follow-up: rs9974610 (HR 0.64, 95% CI 0.46–0.88, p = 0.005), rs10432782 (HR 1.71, 95% CI 1.16–2.48, p = 0.007) and rs1041740 (HR 1.78, 95% CI 1.10–2.78, p = 0.02).

Conclusions

Our results are consistent with a major role for SOD1 in the mechanisms of cardiovascular protection against oxidative stress in type 2 diabetic subjects.

Highlights

► Patients with type 2 diabetes followed prospectively for 6 years. ► Impact of superoxide dismutase-1 (SOD1) gene variants on vascular complications. ► Allelic association with the prevalence of microalbuminuria at baseline. ► Allelic associations with increased risk of death from cardiovascular causes. ► Results consistent with SOD1 protection against oxidative stress.

Introduction

Diabetic patients have a 3-fold higher risk than nondiabetic individuals of developing atherosclerosis and its clinical complications such as stroke, myocardial infarction, and peripheral vascular disease [1]. Cardiovascular disease accounts for up to 80% of the deaths of type 2 diabetic patients [2] and sudden death occurs frequently among diabetic patients [3]. Diabetic nephropathy is a leading cause of renal failure [4], [5] and is associated with increased risk of cardiovascular morbidity and mortality in type 1 and in type 2 diabetic patients [6], [7].

Reactive oxygen species (ROS), including free radicals such as superoxide and nonradical species such as hydrogen peroxide, are produced continuously in all cells as part of the normal cellular metabolism [8]. The major source of intracellular ROS is the mitochondrial respiratory chain, which produces large amounts of superoxide radicals [9]. Oxidative stress occurs when production of ROS exceeds local antioxidant capacity. In this situation, there is increased oxidation of proteins, lipids, carbohydrates and DNA, that can result in tissue and organ damage. Hyperglycemia increases the production of ROS and causes oxidative stress [10], [11]. Oxidative stress influences multiple pathways implicated in diabetic nephropathy [12], [13]. There is also compelling evidence that oxidative stress is associated with the metabolic syndrome and its components [14] and that it plays a key role in the pathophysiology of several cardiovascular diseases, including hypertension, myocardial infarction, stroke, and heart failure [15], [16].

Superoxide dismutases (SOD) are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide [17]. They play an important role in antioxidant mechanism in nearly all cells exposed to oxygen. Three isoforms of SOD are expressed in humans, encoded by different genes. SOD1 is mainly located in the cytoplasm, SOD2 in the mitochondria and SOD3 is extracellular. SOD1 accounts for ~ 85% of the total cellular SOD activity of most mammalian cells and is highly active in the human kidney and in the vascular wall [18], [19].

Associations of SOD1 gene variants with diabetic nephropathy have been observed in patients with type 1 diabetes [20], [21], but no data regarding associations with nephropathy and cardiovascular complications in type 2 diabetes is available. In this study, we assessed the impact of SOD1 allelic variation in the development and progression of diabetic nephropathy and in the morbidity and mortality of cardiovascular disease in individuals with type 2 diabetes followed prospectively for renal and cardiovascular events.

Section snippets

Participants

We studied unrelated French type 2 diabetic patients from the DIABHYCAR (n = 3137) and the DIABHYCAR_GENE (n = 607) cohorts. DIABHYCAR was a 6-year clinical trial conducted in men and women with type 2 diabetes selected on the basis of persistent microalbuminuria (urinary albumin excretion, UAE = 20–200 mg/l) or macroalbuminuria (UAE > 200 mg/l) without renal failure (plasma creatinine < 150 μmol/l) at baseline. The trial tested whether a low dose of ramipril, an angiotensin converting enzyme (ACE)

SOD1 variants and UAE status at baseline

In a first step, participants were divided into 3 groups according to UAE status at baseline: normal UAE (DIABHYCAR_GENE cohort), microalbuminuria and macroalbuminuria (DIABHYCAR cohort, both groups). Characteristics of participants are shown in Table 1. Subjects with microalbuminuria or with macroalbuminuria were younger, had a shorter duration of diabetes and were more often of male sex than subjects with normal UAE. Individuals with macroalbuminuria as compared to those with normal UAE had

Discussion

We have observed a modest association of rs1041740 of SOD1 with the prevalence of incipiens nephropathy (microalbuminuria) at baseline in a cohort of type 2 diabetic subjects followed prospectively for renal and cardiovascular events. No allelic association was observed with the prevalence of established nephropathy (macroalbuminuria) at baseline nor with the evolution of renal function during follow-up. Interestingly, no allelic association of SOD1 was observed with the incidence of

Acknowledgments

ALN was supported by a scholarship awarded by the Portuguese Society of Hypertension. This work was supported by a grant from the Association Diabète Risque Vasculaire (ADRV), France. The analysis and interpretation of the data have been done without the participation of these organizations.

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