The V16A polymorphism in SOD2 is associated with increased risk of diabetic nephropathy and cardiovascular disease in type 1 diabetes

Aims/hypothesis: Hyperglycaemia increases oxidative stress and may thereby increase the risk of diabetic complications, including diabetic nephropathy. Cells are protected from oxidative damage by, for example, the manganese superoxide dismutase enzyme (MnSOD), but the functional polymorphism V16A affects the localisation of MnSOD and therefore its ability to scavenge superoxide radicals. In a Danish cohort of type 1 diabetes patients, we sought to confirm previous findings of association between the V allele and the risk of diabetic nephropathy and to investigate the influence of this polymorphism on the development of cardiovascular disease. Methods: Type 1 diabetes patients attending the Steno Diabetes Center, Gentofte, Denmark, between 1993 and 2001 were enrolled in this study. A total of 441 cases with diabetic nephropathy (albumin excretion ≥300 mg/24 h) and 314 controls with persistent normoalbuminuria (<30 mg/24 h), despite diabetes of duration ≥20 years, were identified. The median duration of diabetes was 35 years (range 12-73 years). Results: We confirmed the significant association between carrier status of the V allele and diabetic nephropathy. The association was independent of age at diabetes onset, HbA_1c, sex, smoking and diabetes duration (OR 1.7, 95% CI 1.2-2.4). The VV and AV genotypes considered together also predicted the risk of cardiovascular disease, independently of age at follow-up, HbA _1c, sex, smoking, systolic blood pressure, cholesterol and nephropathy status. The hazard ratio was 1.6 (95% CI 1.0-2.5). Conclusions/interpretation: The MnSOD V16A polymorphism is involved in the development of nephropathy caused by type 1 diabetes and seems to predict cardiovascular disease during follow-up.