Genetic susceptibility to asbestos and tobacco smoke related non-malignant pleuropulmonary changes
Year: 2013
Type: dissertation
Study design: Observational Study
Abstract: Both tobacco smoke and asbestos fibers enter the body mainly by inhalation. In the lungs, they may evoke oxidative stress, alter the protease-antiprotease balance, induce innate and adaptive immune responses, and create persistent inflammation leading eventually to lung injury. The type and severity of lung injury induced by foreign compounds varies greatly between individuals, even with similar exposure history. These differences are believed to originate from the complex interplay between genetic, epigenetic, environmental, and life course factors. In this thesis, the roles of several genes encoding proteins involved in xenobiotic metabolism (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1, and NAT2), protease-antiprotease balance (MMP1, MMP9, MMP12, SERPINE2, and TIMP2), innate immunity (NLRP3 and CARD8), and inflammation (TNF, TGFB1, and GC) were studied in the development of asbestos and tobacco smoke exposure related nonmalignant pleural and pulmonary changes, peripheral obstruction, and impairment of pulmonary diffusing capacity in two clinically and radiologically examined cohorts of Finnish construction workers. The results indicate that polymorphisms of xenobiotic metabolizing genes are potential modifiers of the risk of developing pleural and pulmonary changes related to asbestos and tobacco smoke exposures. The most convincing evidence came from GSTT1; the deletion of this gene was significantly associated with several types of changes in the whole study population and in both of the study cohorts separately. In addition, certain genotype in GSTM3 gene was associated with lowered pulmonary function. Furthermore, gene polymorphisms in metalloproteinase MMP9, metalloproteinase inhibitor TIMP2, and inflammatory cytokines TNF and TGFB1 were associated with different emphysema subtypes and/or lung function. Together with the finding that certain genotypes of the serine protease inhibitor gene SERPINE2 predispose to panlobular emphysema, they imply that polymorphisms of genes involved in protease-antiprotease balance likely contribute to the development of pulmonary emphysema and bronchial obstruction, and different molecular mechanisms may explain the development of different emphysema subtypes. The present results also indicate that genetic variation in innate immunity related genes might have an important role in coping with asbestos exposure. One finding supporting this view was the association between interstitial lung fibrosis and polymorphism of NLRP3, an essential component of the NLRP3 inflammasome complex. Polymorphism in another member of the complex, CARD8, was associated with the greatest thickness of pleural plaques. In conclusion, the results of this thesis work show that genetic variation is an important modifier of the risks for developing non-malignant lung diseases related to external exposures. The present findings may also help to clarify the molecular mechanisms behind these diseases, expediting their prevention and the development of more efficient therapies.
Source: Työväentutkimus Vuosikirja
Author: Mari Kukkonen
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2136495645