Increased Cardiovascular Morbidity and Mortality in Type 2 Diabetes Is Associated With the Glutathione S Transferase Theta–Null Genotype

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Abstract
Glutathione S-transferases (GSTs) modulate oxidative stress, and variation in GST genes has been associated with cardiovascular disease risk. We prospectively determined smoking-related cardiovascular morbidity by GST genotype in a large cohort of individuals with type 2 diabetes using a population-based diabetes research database (DARTS). We performed a cohort study of 2015 individuals with type 2 diabetes. Individuals were genotyped for the Ile105Val variant of GSTP1 and the deleted variants of GSTT1 and GSTM1. Clinical characteristics, smoking status, and incidence of subsequent cardiovascular events were obtained by examining the DARTS databases. Variation in the GSTP1 and GSTM1 genes was not associated with smoking-related risk of death or cardiovascular events. There was an increase in the rate of cardiovascular events in smokers lacking the GSTT1 gene compared with smokers with the GSTT1 gene intact (hazard ratio [HR], 1.96; P=0.001). This excess of cardiovascular events was due to both strokes (HR, 2.7; P=0.008) and myocardial infarctions (HR, 1.9; P=0.006). The rate of death as a result of a cardiovascular event was even more markedly increased in the GSTT1-null smokers (HR, 2.7; P=0.001), with a 2-fold increase in myocardial infarction fatality ratio. These effects translated into an increase in overall death and a decrease in age at death. We also found that the GSTT1- genotype was associated with progression of both diabetic retinopathy and nephropathy (P=0.005 and P=0.01, respectively), although we found little evidence for an interaction with smoking. Genetic absence of the GSTT1 enzyme is an independent and powerful predictor of premature vascular morbidity and death in individuals with type 2 diabetes.