Allelic variations of superoxide dismutase 1 (SOD1) gene and diabetic nephropathy in type 2 diabetic patients

Abstract

Background and aims: Oxidative stress is involved in the pathophysiology of diabetic nephropathy (DN), and the enzyme superoxide dismutase 1 (SOD1) is essential for reactive oxygen species detoxification. Associations of SOD1 gene variants with DN have been reported in patients with type 1 diabetes. In this study, we assessed the impact of SOD1 allelic variation in the development and progression of DN in individuals with type 2 diabetes (T2DM) followed prospectively for renal events. Material and methods: 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 T2DM selected on the basis of persistent microalbuminuria (urinary albumin excretion, UAE=20-200 mg/l) or macroalbuminuria (UAE>200 mg/l) without renal failure at baseline. The trial tested whether a low dose of ramipril able to reduce UAE would also reduce cardiovascular and/or renal events. A renal event was defined as the doubling of the serum creatinine levels or the requirement of haemodialysis or renal transplantation during follow-up. It occurred in 77 cases (2.46%). Results were negative regarding the drug effect and were published previously. The DIABHYCAR-GENE cohort was recruited concomitantly to DIABHYCAR and included men and women with T2DM presenting with normal UAE (UAE<20 mg/l). Seven SNPs (rs2173962, rs9974610, rs10432782, rs2070424, rs1041740, rs17880135 and rs202449), giving information on ∼90% of the allelic variation of the haplotypic block containing SOD1 gene were analyzed. Genotype associations with DN were assessed by logistic regression analyses and by Cox proportional hazards survival regression analyses. Adjustments for clinical and biological parameters were carried out by including these parameters as covariables in the regressive model. The power to detect associations of the SNPs with DN at baseline and with incidence of renal events during follow-up was 0.98 and 0.74, respectively, for odds ratio or hazard ratio equal or higher than 1.5 and alpha=0.05. Results: In a first step, participants were divided into 3 groups according to UAE at baseline: normal UAE (DIABHYCAR-GENE cohort), microalbuminuria and macroalbuminuria (DIABHYCAR cohort, both groups). Allele and genotype frequencies of the seven SNPs were similar in the 3 groups. Next, we assessed the impact of allelic variations on the renal outcomes of the original DIABHYCAR study. We have not observed any association of the SNPs with the incidence of renal events during follow-up neither in univariate analyses nor in complex models adjusted for sex, age, BMI, duration of diabetes, HbA1c levels, presence of arterial hypertension, history of myocardial infarction, treatment with ACE inhibitors or treatment group in the original DIABHYCAR study. In these analyses, only HbA1c, BMI, arterial hypertension and history of myocardial infarction at baseline were significantly and independently associated with the incidence of renal events at follow-up. Conclusions: Allelic variations in the SOD1 gene were not associated with micro or macroalbuminuria nor with the deterioration of renal function in patients with T2DM followed prospectively for 6 years. These results suggest that SOD1 does not play a major role in the genetic determinants of DN in type 2 diabetes.