Abstract 1425: Polymorphisms of Glutamate-cysteine Ligase Modifier Subunit and Catalytic Subunit Genes Increase the Susceptibility of Smokers to Myocardial Infarction and Coronary Endothelial Vasomotor Dysfunction
Glutathione, tripeptide thiols, is a major and naturally occurring anti-oxidant that protects cells from oxidative injury. We have previously reported that polymorphisms of modifier subunit (GCLM) and catalytic subunit (GCLC) genes of glutamate-cysteine ligase, a rate-limiting enzyme for glutathione synthesis, are associated with reduction in synthesis and plasma levels of glutathione. Smoking is known to be a major oxidant stress risk factor for cardiovascular diseases. This study assessed our hypothesis that polymorphisms of GCLM and GCLC genes may increase the susceptibility of smokers to myocardial infarction (MI) and impairment of coronary endothelial vasomotor function.
Methods: This study included 1012 consecutive patients who underwent coronary angiography for chest pain in our hospital (204 MI patients, 808 non-MI patients). Epicardial diameter response of the left anterior descending coronary artery to intracoronary infusion of acetylcholine (ACh, 50 and 100 μg/min) was measured by quantitative coronary angiography in a subset of 188 consecutive patients with angiographically normal coronary arteries.
Results: Smokers with a polymorphism of the GCLM or GCLC gene had the strongest impairment of ACh-induced coronary dilation (% change in coronary diameter from baseline at 50 μg/min of ACh, −15 ± 3% and −14 ± 2%, respectively), followed by smokers without polymorphisms (−7 ± 2%) and nonsmokers with a polymorphism of the GCLM or GCLC gene (−5 ± 2% and −4 ± 2%). The dilator response to nitrate was similar among the groups of patients. In smokers (n = 234), frequency of MI was higher in patients with a polymorphism of the GCLM or GCLC gene than in those without polymorphisms (43.8 % and 47.2 % vs. 31.8 %, respectively, p < 0.01 in each). Polymorphism of the GCLM or GCLC gene was a strong risk factor for MI in smokers, in multiple logistic regression analysis using traditional risk factors as covariates (ORs, 4.2 and 3.8; 95% CI, 1.9 – 5.0 and 1.8 – 4.5, respectively, p < 0.01 in each). In nonsmokers (n = 778), a polymorphism was not a significant risk factor for MI in the multivariate analysis.
Conclusion: Polymorphisms of the GCLM or GCLC gene may increase the susceptibility of smokers to MI and impairment of coronary endothelial vasomotor function.