Accumulation of oxidative stress-related gene polymorphisms and the risk of coronary heart disease events in patients with type 2 diabetes - An 8-year prospective study

Objective: Oxidative stress, which is provoked in patients with diabetes, plays critical roles in the pathogenesis of coronary heart disease (CHD). We simultaneously determined 5 relatively common genetic variants related to oxidative stress and evaluated the combined effect on CHD. Methods: We enrolled 1977 Japanese type 2 diabetic subjects without history of CVD (males 66.1%, 59.5 +/- 10.0 years old), determined their genotypes regarding glutamate-cysteine ligase modifier subunit (GCLM) C-588T, manganese superoxide dismutase (SOD2) Vall6Ala, endothelial nitric oxide synthase (NOS3) G894T, NAD(P)H oxidase p22phox (CYBA) C242T, and myeloperoxidase (MPO) G-463A polymorphisms, and prospectively evaluated the association between these polymorphisms and CHD events. Results: The median follow-up period was 7.5 years and there were 85 new CHD events. The single association analysis revealed that there were no statistically significant associations between each polymorphism and the prevalence of CHD. Interestingly, the risk of CHD event was higher with the increase of the total number of 10 concomitant unfavorable "pro-oxidant alleles" in each subject (p for trend = 0.018, log-rank test). Especially, the carriers of >= 8 pro-oxidant alleles had a significantly increased risk as compared to the carriers of <8 pro-oxidant alleles, whether the other clinical variables were adjusted (HR 2.92 with 95%CI 1.50-5.67, p = 0.002) or not (HR 2.89 with 95%CI 1.49-5.59, p = 0.002). Conclusions: Accumulation of gene polymorphisms related to oxidative stress is likely associated with the development of CHD in patients with type 2 diabetes, suggesting that the combined information about these variants is useful to assess the risk of CHD. (C) 2014 Elsevier Ireland Ltd. All rights reserved.