Genetic polymorphisms of xenobiotic-metabolizing enzymes influence the risk of pulmonary emphysema

Abstract

Pulmonary emphysema is a smoking-induced condition of the lung. Genetically determined differences in the activities of enzymes that metabolize oxidative agents are suspected to modify individual susceptibility to emphysema, as well as other smoking-related pulmonary disorders. We investigated whether polymorphisms in selected xenobiotic-metabolizing enzyme genes predispose to emphysematous changes and airflow limitation among Finnish Caucasian construction workers. PCR-based methods were used to analyze nine common polymorphisms in EPHX1, GSTM1, GSTM3, GSTP1, GSTT1, and NAT2 genes among 988 Finnish construction workers. The genotype data were compared with different emphysematous signs confirmed with high-resolution computed tomography and with forced vital capacity and forced expiratory volume in 1 s. For this, linear and logistic regression analyses, adjusted for the potential confounders, were used. The EPHX1 Tyr113His polymorphism was associated with emphysematous changes (P=0.007), including paraceptal (P=0.039), panlobular (P=0.013), and bullae (P=0.003) type changes. The GSTM3 promoter polymorphism was associated with forced expiratory volume in 1 s/forced vital capacity ratio (P=0.010), and the GSTT1 genotype with emphysematous signs (P=0.008), including paraceptal (P=0.015), panlobular (P=0.031), and bullae-type (P=0.045) changes. In further analysis, the GSTT1 deletion was found to pose a two-fold overall risk for having emphysematous changes (odds ratio: 2.01; 95% confidence interval: 1.33-3.03), and almost a four-fold risk for having severe emphysematous changes (odds ratio: 3.70; 95% confidence interval: 2.15-6.36). The results indicate a significant modifying role for GSTT1 gene polymorphism in the individual risk and severity of emphysematous changes.