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

Camilla J Kobylecki,Shoaib Afzal,Børge G Nordestgaard

doi:10.1016/j.ebiom.2015.11.026

Camilla J Kobylecki, Shoaib Afzal + Show 1 more

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https://doi.org/10.1016/j.ebiom.2015.11.026

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Journal: eBioMedicine	Publication Date: Nov 14, 2015
Citations: 21	License type: cc-by

Affiliation: Gentofte Hospital, Copenhagen University Hospital

Abstract

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.

Highlights

Cardiovascular disease is the leading cause of morbidity and mortality in individuals with diabetes, with a 2–4 fold higher risk of cardiovascular disease and up to 3 fold higher risk of mortality compared to those without diabetes (Fox et al, 2004; Preis et al, 2009)
The frequency of diabetes did not differ between rs1799895 (R213G) heterozygotes and non-carriers, nor did any baseline characteristics (Table 1); as previously shown plasma extracellular superoxide dismutase was 9-fold higher in heterozygotes compared to non-carriers in the Copenhagen City Heart Study (CCHS) (Juul et al, 2004)
In this study of 95,857 white individuals from the Danish general population, including 4498 with diabetes, risk of cardiovascular disease and heart failure was higher in R213G heterozygotes versus noncarriers in diabetic subjects, but not in non-diabetic subjects

Summary

Introduction

Cardiovascular disease is the leading cause of morbidity and mortality in individuals with diabetes, with a 2–4 fold higher risk of cardiovascular disease and up to 3 fold higher risk of mortality compared to those without diabetes (Fox et al, 2004; Preis et al, 2009). 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. 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). 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 b 0.001). Interpretation: Risk of cardiovascular disease and heart failure was higher in R213G heterozygotes versus noncarriers in diabetic subjects, but not in non-diabetic subjects

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