Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes

Abstract

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes.Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (DL,CO) and specific diffusing capacity (expressed as DL,CO per unit of alveolar volume (VA)).The GSTT1 deletion polymorphism was associated with fibrotic changes (p50.003), and decreased DL,CO (p50.02) and DL,CO/VA (p50.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p50.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased DL,CO (OR 1.77, 95% CI 1.06-2.95) and DL,CO/VA (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques.Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

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

“…Interestingly, in our earlier study, we also found an association between GSTT1 deletion and severe type of fibrotic changes related to asbestos exposure [42]. This suggests that absence of GSTT1 enzyme activity might lead to increase in different kind of structural changes in the lungs, simultaneously or separately, depending on the type and duration of the exposures and their interaction with other inherited factors.…”

“…We have previously found an association between the GSTT1 deletion and low diffusing capacity for carbon monoxide (DL CO and DL CO /VA) among the current study population [42]. As lung tissue injury, which is characteristic to emphysema, influences negatively the gas exchange capacity, decreased diffusing capacity and emphysema often coexist.…”

Usefulness of Biomarkers in Work-Related Airway Disease

“…Associations between gene and exposure to silicosis have been also suggested as important for polymorphisms in gene for TNF-α and for the IL-1 receptor [83–85]. Fibrosis with the background of exposure to asbestos has been considered also as a result of oxidative stress [86] and linked with the GSTM1-null genotype responsible for reducing antioxidant function [87, 88]. A few gene–work environment interactions have been found in development of di-isocyanate-induced OA (DIIA), including HLA class II genes, genes associated with the response to Th2 cytokine and with antioxidant activity, or gene related to epithelial junctional integrity [89•].…”

Gene–Environment Interaction from International Cohorts: Impact on Development and Evolution of Occupational and Environmental Lung and Airway Disease

“…39 The GSTM1 null genotype (which reduces antioxidant activity) has been associated with the development of asbestos-induced lung disease in some studies but not in others. [40][41][42][43] In one study, the combination of a GSTM1 null with NAT2 slow-acetylator genotype had an additive effect in increasing the risk of developing both malignant and nonmalignant asbestos-induced lung disease. 43 Possible but variable associations between disease risk and polymorphisms in other genes involved in the response to oxidative stress, such as superoxide dismutase 2 (SOD2), GSTT1, GSTP1, and NLRP3, have also been suggested.…”

“…43 Possible but variable associations between disease risk and polymorphisms in other genes involved in the response to oxidative stress, such as superoxide dismutase 2 (SOD2), GSTT1, GSTP1, and NLRP3, have also been suggested. 41,42,[44][45][46] Gene-gene and other geneenvironment interactions (for instance, involving smoking) may also play a role in modifying the risk of asbestosis. 47 Gene-environment interactions in the case of silicosis have also been demonstrated.…”