Melbourne School of Population and Global Health - Theses
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ItemRisk factors for and outcomes of lung function deficits throughout the lifespan( 2019)Good lung function is essential for general health and longevity. The lungs are responsible for providing oxygen to meet the metabolic demands of the body and expelling waste products of cellular respiration. They also play a critical role in maintaining acid-base balance. Impaired lung function imposes significant health issues. Chronic obstructive pulmonary disease (COPD) in late adulthood is responsible for the largest burden. Across the life course, lung function passes through different phases (development, growth, plateau, and decline). Lung function is influenced by multiple risk factors that act at different periods, which together form a complex web contributing to lifetime risk. Understanding how particular risk factors influence each phase as well as the lifetime trajectory of lung function and the consequences of these impairments is critical for evidence-based strategies to promote lung health and prevent lung diseases. However, such understanding is limited. Specifically, some major gaps in this literature include: how reduced lung development and growth in early life influence the risk of COPD and its phenotypes in later life; how multiple early life factors interact and predict long-term lung function deficits and COPD; how adult life factors interact with genetic and early life factors to influence lung function decline; and what are the determinants and consequences of different lifetime lung function trajectories. In this thesis, I aim to investigate risk factors for, and outcomes of, lung function deficits throughout the life course, using data from the Tasmanian Longitudinal Health Study (TAHS). My specific objectives are (1) to investigate the association between childhood lung function and asthma-COPD phenotypes in middle age, (2) to identify childhood respiratory risk factor profiles that influence lung function and COPD development in middle age and to examine the causal pathways involving potential mediators and effect modifiers, (3) to establish trajectories of lung function from childhood to the sixth decade and to investigate the association between identified lung function trajectories and both early life determinants and subsequent COPD risk, and (4) to investigate how interactions between major adverse exposures in adulthood, early life respiratory risk factors and potential genetic factors may influence lung function decline in middle age. In chapter 4, I present my findings that lower lung function at age seven years predicted higher risk of COPD and asthma-COPD overlap syndrome (ACOS) in middle age, independent of personal smoking. In particular, I found that being in the lowest quartile of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) at age seven years was associated with a 5.8 fold and 9.8 fold increase in the risk of COPD and ACOS, respectively. In chapter 5, I present my results identifying six distinct profiles of childhood respiratory risk factors. These risk profiles were associated with differing risks of reduced lung function and COPD in middle age. Among four risk profiles associated with increased risk of lung function deficits and COPD in middle age, the “frequent asthma, bronchitis, allergy” profile was found to be the most “at risk” group. The associations between this profile and COPD and reduced lung function were largely mediated through adult active asthma (62.5% for COPD), with some mediation through reduced childhood lung function (26.5% for COPD). I also found that the association between the “frequent asthma, bronchitis, allergy” profile and middle-aged lung function was aggravated by personal smoking. In chapter 6, I present my results identifying six distinct trajectories of FEV1 from the first to the sixth decade of life, using group-based trajectory modelling. I found that three “unfavourable” trajectories were associated with an increased risk of COPD and collectively contributed 75% of the COPD burden at the sixth decade. Two of the six trajectories were novel and contradict the long-held paradigm that lung function established in childhood tracks through life. I also found that childhood factors including childhood asthma, bronchitis, pneumonia, hayfever, eczema, parental asthma and maternal smoking during childhood predicted membership of the three unfavourable trajectories. In chapter 7, I report my findings that current smoking, current adult asthma, occupational exposures, and living close to major roads were associated with accelerated decline in post-bronchodilator FEV1 and FEV1/FVC, suggesting a predisposition to subsequent airflow obstruction; while body mass index (BMI) gain and incident obesity were associated with both FEV1 and FVC decline, suggesting a predisposition to restrictive lung deficits. Notably, I observed interactions between childhood factors and personal smoking and occupational exposure to vapors/gases/dusts/fumes (VGDF). In particular, accelerated lung function decline associated with current smoking and occupational VGDF was accentuated for those with low childhood lung function, a glutathione-S-transferase M1 (GSTM1) null genotype, or exposure to maternal smoking. Overall, my thesis findings have advanced the current knowledge of the influence of lifetime risk factors on lung function deficits across the life course and their consequences. My findings provide a basis for developing tools that clinicians could use to predict/assess long-term lung health for a child based on his/her exposure patterns. They also provide further impetus for close clinical monitoring of children with impaired lung function. From the public health perspective, my findings suggest that preventing impaired lung function from early life, avoiding unfavourable lifetime lung function trajectories, and promoting favourable lung function trajectories would reduce the burden of lung function impairment, particularly in relation to COPD. My findings also highlight the need for an integrated and comprehensive “life course” preventive strategy, taking into account genetic and lifetime environmental risk factors, and their interactions.
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ItemImpact of traffic related air pollution on asthma, allergic diseases and lung function( 2016)Traffic related air pollution (TRAP), the most common type of air pollution in urban areas, has been hypothesised to increase the risk of asthma and allergic diseases. However, epidemiological studies investigating the associations of TRAP exposure and these outcomes have found inconsistent results. These inconsistencies can be partially explained by genetic variations associated with regulating oxidative stress. Therefore, the aim of my doctoral work is to investigate the effects of TRAP exposure on asthma, allergic diseases and lung function while examining these effects are modified by Glutathione S-Transferase (GST) polymorphisms. Polymorphisms of GST genes which are associated with regulating oxidative stress pathways are of special interest because of the biological mechanisms which play an important role in modulating inflammatory responses triggered by reactive oxygen species. In Chapter 2, a critical review of the literature revealed that there are major knowledge gaps in the effects of TRAP exposure on asthma, allergic diseases and lung function, and their interactions with GST polymorphisms. Hence, the specific research aims of the present thesis were to: (i) systematically synthesise the evidence for the association between early life TRAP exposure and the risk of asthma, hay fever and allergic sensitisation during childhood and adolescence, (ii) investigate the relationship between TRAP exposure during first year of life and asthma and hay fever to late adolescence, (iii) investigate the relationship between current annual TRAP exposure and current asthma in middle aged adults and asthma, allergic sensitisation and lung function, (iv) investigate the association of the effect of TRAP exposure over five years in adults and outcomes of asthma and lung function, and to examine if GST gene polymorphisms modify the associations in aims ii, iii and iv. In Chapter 3, my systematic review and meta-analyses of birth cohort studies found that: long term exposure to particulate matter less than 2.5 µm in diameter (PM2.5) or black carbon from birth associated with asthma incidence in childhood, and early life exposure to PM2.5, black carbon or nitrogen dioxide (NO2) exposure were associated with a trend of increased risk of asthma incidence throughout childhood. In Chapter 4, my work in the Melbourne atopy cohort study (MACS), a birth cohort of children with family history of allergic diseases showed that, early life TRAP exposure defined as the cumulative length of major roads within 150 metres of each participant’s residence during the first year of life associated with increased risk of asthma and wheeze at the age of 12 years in carriers of Glutathione S-Transferase theta1 (GSTT1) null genotype. In Chapters 6 and 7, I used two proxies for TRAP: (i) mean annual NO2 exposure, estimated for current residential addresses using a validated land use regression model or (ii) living less than 200 metres from a major road. In Chapter 6, I found that current mean annual exposure to NO2 was associated with increased risk of aero-allergen sensitisation. In addition, current mean annual NO2 and living less than 200 metres from a major road were associated with increased risk of wheeze. In this group of middle age adults, living less than 200 metres from a major road was associated with lower levels of pre- and post-BD FEV1. Carriers of the GSTT1 null genotype had an increased risk of asthma and allergic outcomes when exposed to TRAP compared to GSTT1 non null genotype. In Chapter 7, I found that exposure to higher levels of NO2 over five years was associated with increased risk of asthma. Furthermore, over a five year period, living less than 200 metres from a major road was associated with asthma, wheeze and lower levels of FEV1, FVC and FEV1/FVC. Increased risk of asthma and wheeze associated with living less than 200 metres from a major road over five years was more marked in carriers of the GSTT1 null genotype. Overall, the present thesis has contributed significantly to the current knowledge of TRAP exposure, asthma, allergic diseases and lung function. Consistently, GSTT1 null genotype carriers exposed to TRAP showed an increased risk of these outcomes. The overarching goal being to establish an integrated strategy to improve air quality especially in urban areas, which will benefit the community and reduce the burden of asthma, allergic diseases and poor lung function. An integrated plan can be adopted in controlling TRAP in urban areas including; providing efficient public transport network, use of clean fuel in vehicles, reducing house densities near major roads and vehicles should be monitored regularly for emissions. In setting future air quality guidelines high-risk groups should take into account including genetically susceptible populations and standards should consider lower levels of air pollution which can cause potential adverse health outcomes in these vulnerable subgroups.