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Impact of gene-environment interactions within inflammatory and oxidative stress pathways on the development of chronic obstructive lung disease (COPD)

Curjuric, Ivan. Impact of gene-environment interactions within inflammatory and oxidative stress pathways on the development of chronic obstructive lung disease (COPD). 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10183

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Abstract

Introduction
Chronic obstructive lung disease (COPD) has major impact on global morbidity, mortality and health care costs. The global initiative for obstructive lung disease (GOLD) defines COPD as ratio of forced expiratory volume in the 1st second over totally exhaled lung volume (FEV1/FVC) <0.7 after airway dilatation. The largest COPD risk factor is still tobacco smoking. Recent evidence points to effects of occupational exposures, environmental tobacco smoke and ambient air pollution. Two major etiological pathways are proposed: first, an imbalance of proteases and antiproteases leading to destruction of lung tissue, second, an oxidant/antioxidant imbalance favoring oxidative stress. Genes from both systems were associated with COPD or lung function, but inconsistently. Environmental exposure effects depend on individual susceptibility to oxidative stress, determined by functional capacity of involved enzymes and variation in respective genes. Identifying susceptibility factors thus requires studying gene-environment interaction. Ambient air pollution might be an important COPD risk factor due to its oxidizing effects and omnipresence.
The thesis aimed to estimate COPD burden in Switzerland from epidemiological data. The role of ambient air pollution in COPD causation was studied regarding interactions with oxidative stress candidate genes. The impact of air pollution was compared to tobacco smoke regarding involved genes and pathways mediating exposure effects.
Methods
The thesis was based on data from the Swiss Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA), a population based cohort started in 1991 with a first follow-up in 2002. Participants answered detailed health questionnaires on life style habits, occupational exposures, and preexisting disease. Lung function was measured in both examinations without airway dilatation but with standardized protocols and strict quality criteria. Individual air pollution exposure estimates were available for particulate matter of median diameter less than 10 micrometer (PM10) from a Gaussian dispersion model using Swiss emission data from years 1990 and 2000. DNA of over 6000 persons was available for candidate gene studies. Genome wide data was obtained on 1457 persons in the framework of the international GABRIEL consortium on asthma.
Results
COPD incidence was 14.2 cases/1000 person years (PY), an estimate at the higher range of comparable studies and only partly explainable by differing age, smoking or follow-up time. 20.9% of baseline, mostly mild obstructive cases did not persist. Obstruction progression or persistence in moderate-severe stages during follow-up was associated with health service use and dyspnea at follow-up. Non-persistence, suggestive of hidden asthma, was marginally associated with health service use. Pre-bronchodilation spirometry had prognostic value in predicting future adverse health events despite misclassification for hidden asthma.
Variants in glutathione S-tranferase class P1 and heme-oxygenase 1, genes belonging to the body’s first line defense against oxidative stress, significantly modified the effect of reduced PM10 exposure on lung function decline, with strongest effects observed on FEF25-75 decline. Benefits from air pollution reductions were not equally distributed across the population, but according to differing endogenous capacity to cope with oxidative stress.
Regarding lung function decline, ambient PM10 and tobacco smoke exposure interacted with different genes from a large set of 152 oxidative stress genes comprising 12679 single nucleotide polymorphisms. Interaction effects in strongest SNPs of nominally interacting genes (p<0.05) were larger for tobacco smoke than PM10, but the percentage explained outcome variability was comparable for both exposures on the population level.
Discussion
COPD incidence is comparably high in Switzerland, but possibly overestimated by hidden asthma. Ambient air pollution contributes to COPD causation via interactions with oxidative stress defense genes modulating lung function decline. Benefits from clean air are not equally distributed among society, but determined by individual genetic make-up. Genes and molecular pathways activated by air pollution and tobacco smoke differ, possibly due to different levels of oxidative stress. The impact of air pollution at population level might be comparable to tobacco smoke regarding explained variability in lung function decline.
The findings underline the importance of oxidative stress in shaping lung function decline, and thus COPD risk. From a Public Health and prevention view, thought is warranted about recommending antioxidant administration by fruit, vegetable or supplement enriched diet to susceptible population groups in periods of high pollution. The role of air pollution in COPD causation needs greater attention in Public Health policy and research. Current limitations could be overcome by a new, large national cohort.
Advisors:Probst-Hensch, Nicole
Committee Members:Tanner, Marcel and Vollenweider, Peter
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology > Genetic Epidemiology of Non-Communicable Diseases (Probst-Hensch)
03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin > Genetic Epidemiology of Non-Communicable Diseases (Probst-Hensch)
Item Type:Thesis
Thesis no:10183
Bibsysno:Link to catalogue
Number of Pages:178 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:51
Deposited On:03 Dec 2012 13:30

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