Genetically Low Antioxidant Protection and Risk of Cardiovascular Disease and Heart Failure in Diabetic Subjects

• SOD3 R213G heterozygosity was associated with a 2-fold higher risk of cardiovascular disease and heart failure.
• This association was observed in diabetic subjects, but not in non-diabetic subjects.
• This could provide further insight on the pathophysiology of cardiovascular disease and heart failure in diabetes.Diabetic patients have high risk of cardiovascular disease, possibly due to increased oxidative stress. The SOD3 enzyme is an important extracellular antioxidant in blood vessel walls. A rare mutation in the SOD3 gene causes the enzyme to diffuse from vessel walls into the blood stream. In diabetic subjects, we found a 2-fold higher risk of cardiovascular disease and heart failure among those with the rare SOD3 variant compared to those with the normal variant, with no effect of the variant among non-diabetic subjects. This could help provide further insight on the mechanisms underlying cardiovascular disease and heart failure in diabetes.

BackgroundHyperglycemia-induced oxidative stress is one mechanism believed to underlie diabetic vascular disease. We tested the hypothesis that diabetic subjects heterozygous for extracellular superoxide dismutase (SOD3) R213G, which entails lower antioxidant capacity in tissues, have increased risk of cardiovascular disease and heart failure.MethodsWe used the prospective Copenhagen General Population Study and Copenhagen City Heart Study and genotyped 95,871 individuals for the rs1799895 R213G variation in the SOD3 gene, of which 4498 had diabetes. We used national hospitalization and death registers to assess cardiovascular disease and heart failure.FindingsOut of 95,871 individuals, we identified 93,521 R213G non-carriers (213RR, 97.5%), 2336 heterozygotes (213RG, 2.4%) and 14 homozygotes (213GG, 0.01%). In diabetic subjects, the hazard ratio for cardiovascular disease in R213G heterozygotes compared to non-carriers was 2.32 (95% CI 1·44–3.75), with a corresponding hazard ratio in non-diabetic subjects of 0.97 (0·80–1.19) (p for interaction 0.002). For heart failure, the hazard ratios in R213G heterozygotes compared to non-carriers were 2.19 (1.28–3.76) in diabetic and 0.68 (0.49–0.92) in non-diabetic subjects (p for interaction < 0.001).InterpretationRisk of cardiovascular disease and heart failure was higher in R213G heterozygotes versus non-carriers in diabetic subjects, but not in non-diabetic subjects.