Polymorphic differences in the SOD-2 gene may affect the pathogenesis of nephropathy in patients with diabetes and diabetic complications

The effective treatment of diabetes and the prevention of diabetic complications may be improved by a better understanding of the antioxidant function of intracellular defences against oxidative stress. Polymorphisms in antioxidant genes may determine cellular oxidative stress levels as a primary pathogenic role in diabetes and/or in its complications. SOD-2 was investigated in patients with type 1 diabetes mellitus (T1DM) to ascertain if specific genotypes have any protective influences in the pathogenic mechanisms in diabetes and/or in several different complications, including retinopathy, nephropathy and diabetic controls compared to normal healthy controls.

Method: 278 (136M:142F) T1DM patients and 135 (72M:63F) normal, healthy controls were investigated for SOD-2 polymorphism in the mitochondrial targeting sequence with Ala/Val (C-9T) substitution.

Results: A significant difference in the C-9-T genotype was observed between patients and normal controls but not between diabetic controls and patients with complications. There were significantly more of the diabetic control (DC, n=62) group (11.3%) than the patients with diabetic nephropathy (DN, n=73) (1.4%) with the CC genotype (p=0.03 and χ(2)=4.27, OR=9.16 (1.08<OR<204.03)). Further significance was found between normal healthy controls (11.4%) and patients with nephropathy (1.4%) with the genotype CC (p=0.03, χ(2)=4.68, OR=0.11 (0.00<OR<0.87)). No significant differences were found between these groups for the allelic frequency or between the different complication groups after correction for the number of groups. All groups were in Hardy Weinberg equilibrium.

Conclusion: The SNP in SOD-2 results in a substitution of C to T, which causes an amino acid change from alanine to valine. The variation in the SOD-2 leader signal affects the processing efficiency of the enzyme. A significantly greater proportion of the diabetic control group had the CC genotype suggesting antioxidant protection against diabetic nephropathy. The healthy control group also had a higher incidence of the protective genotype, which may suggest protective influences from the antioxidant gene in the CC form.