Background-Glutathione S-transferases (GSTs) M1 and T1 detoxify products of oxidative stress and may protect against atherosclerosis and ischemic vascular disease (IVD). We tested the hypothesis that copy number variation (CNV) in GSTM1 and GSTT1 genes, known to be associated with stepwise decreases in catalytic activity, predict risk of IVD. Methods and Results-We included 23 059 Danes from 2 general population studies and 2 case-control studies, of whom 4930 had ischemic heart disease (IHD) and 2086 had ischemic cerebrovascular disease. A real-time polymerase chain reaction method genotyped for the exact number of GSTM1 and GSTT1 gene copies. We also performed meta-analyses, including our own and former studies, totaling 13 196 IHD cases and 33 228 controls. CNV in GSTM1 or GSTT1 or genotype combinations were not associated with an increased risk of IHD, myocardial infarction, ischemic cerebrovascular disease, ischemic stroke, or any ischemic vascular event in studies individually or combined or in the meta-analyses. Furthermore, genotypes did not interact with smoking on risk of disease end points. Finally, GST genotypes did not associate with markers of inflammation and oxidation or interact with smoking on markers of inflammation in the general population. In contrast, we observed the well-established association between CNV in GSTM1 and risk of bladder cancer. Conclusions-In studies including 6557 IVD cases and 16 502 controls and in meta-analyses of 13 196 cases and 33 228 controls, CNV in GSTM1 and GSTT1 genes did not associate with risk of IVD or with markers of inflammation. These observations were independent of smoking exposure. (Circ Cardiovasc Genet. 2011;4:418-428.)Key Words: atherosclerosis Ⅲ cardiovascular diseases Ⅲ genetics Ⅲ inflammation Ⅲ smoking M ultiple components in cigarette smoke, industrial chemicals, and air pollution can induce oxidative stress that leads to lipid peroxidation, inflammation, DNA damage, vascular dysfunction, and smooth muscle cell proliferation, which all contribute to atherosclerosis and, hence, ischemic vascular disease (IVD). 1,2 Thus, the study of genes encoding proteins involved in the detoxification of such components may be of major importance for the determination of interindividual susceptibility to IVD.
Editorial see p 339 Clinical Perspective on p 428Glutathione S-transferases (GSTs) are a superfamily of phase II drug-metabolizing enzymes catalyzing the conjugation of reduced glutathione with a variety of electrophilic compounds, including chemicals in cigarette smoke and air pollution, thereby protecting the cell against xenobiotics and oxidative stress. 3 Two genes from the GST family, GSTM1 and GSTT1, show copy number variation (CNV) from 0 to 2 gene copies per allele per gene. GSTM1*0/0 and GSTT1*0/0 are associated with loss of catalytic activity, 4,5 and a gene dosage effect between gene copy number and enzyme activity has been reported for both GSTM1 and GSTT1. 6 -8 The underlying hypothesis in epidemiological studies, therefore, is that CNV in GS...