Melbourne School of Population and Global Health - Theses
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ItemThe impact of household risk factors and their interactions with antioxidative stress genes on respiratory health( 2019)Background: Asthma affects people of all ages and is associated with a substantial impact on both the individual and the community, yet there are few effective strategies to prevent its development or persistence. This is because the aetiology of asthma and factors influencing its progression or remission are currently poorly understood. Asthma primarily affects lung function. Progressive lung function decline associated with asthma is well-recognised but has not been commonly investigated as an outcome in asthma studies. Knowledge on the critical factors influencing maximal development of lung function in childhood is scarce. The development of asthma and allergic diseases is very complex and believed to be influenced by multiple genetic and environmental factors that may influence asthma risk from pre-conception through to adult life. A range of strategies modifying environmental exposures have been trialled to potentially reduce the risk of asthma, with many studies finding no evidence of substantial benefit, or only limited benefit, from the interventions. Additionally, although some genes are associated with increased asthma risk, the associations are small and only explain a small percentage of the large asthma burden. There is evidence of some gene-environmental interactions, but these relationships are varied and complex and have not yet been fully investigated or understood. Elucidating the interactions between environmental risk factors and genetic factors and their associations with respiratory outcomes in both childhood and adulthood may help identify asthma prevention strategies. The main aim of my PhD work was to investigate one group of gene-environment interactions; the relationship between oxidative exposures and antioxidant genes on asthma and lung function. Specifically, I investigated the associations between various household environmental oxidant exposures and respiratory outcomes from childhood to middle age and examined whether those associations were modified by Glutathione s-Transferase (GST) genes, which are known buffers of oxidative stress. Methods: I used a range of methods to address my research aims, including a systematic literature review and data analyses of two longitudinal cohort studies: the Melbourne Atopy Cohort study (MACS), and the Tasmanian Longitudinal Health Study (TAHS). MACS began as a randomised controlled trial investigating the effects of infant formulas at weaning and, has subsequently become a prospective birth cohort. Initially, 620 pregnant women were recruited between 1990 and 1994. The MACS children have now been followed up to 18 years of age. The TAHS is a population-based study of respiratory disease spanning from childhood to adulthood. The study began in 1968, recruiting 8,583 Tasmanian school children born in 1961 (approx. 98.8% of the Tasmanian population for 1961 births). Extensive follow-ups of initial participants were conducted in 2002 and 2012, respectively, when participants were in their 40s and 50s. Both the MACS and the TAHS collected a substantial amount of exposure and outcome data at multiple ages over the lifespan through questionnaires and clinical testing, providing a great opportunity to address questions concerning gene-environment interactions and respiratory health outcomes. I investigated the following oxidative exposures: early life tobacco smoke, early life paracetamol, heating and cooking facilities, mould, long term and current active and passive tobacco smoke. Previous evidence suggests that these common home environmental exposures are associated with increased oxidative stress, and therefore, their impacts are likely to be modified by GST genes. So, in conjunction with these exposures, I investigated potential interactions with GST gene polymorphisms at two significant developmental stages: during lung function growth in childhood and adolescence, and during lung function decline in middle age. Research Gaps: Firstly, I systematically reviewed the current evidence on interactions between indoor air pollution and GST genes in association with allergies, asthma and lung function (Aim 1: Chapter 3). I then conducted a study to examine the interactions between early life tobacco smoke exposure and GST genes on asthma and lung function in childhood and adolescence using Melbourne Atopy Cohort Study (MACS) data (Aim 2: Chapter 5). Another study on the potential interactions between paracetamol use before 2 years of age and GST genes in association with asthma and lung function in later life was performed using MACS data (Aim 3: Chapter 6). In this study, I adjusted for early life exposure to respiratory infections, an important confounding factor which has not been adjusted for by many previous studies. Finally, I conducted a study using data from the TAHS to investigate similar associations in middle-age (Aim 4: Chapter 7). In this analysis, I identified seven longitudinal exposure profiles using Latent Class Analysis (LCA) methods with common household air exposures including heating and cooking types, mould exposure, passive and active smoking. I then determined the associations between these risk profiles and respiratory outcomes, and whether these profiles were modified by GST genes. Linear and logistic regression were used to investigate these associations. Results: Aim 1. My systematic review of the relationship between indoor air pollution, GST genes and asthma identified 22 eligible studies, with 15 finding some evidence of gene-environment interactions. Overall, carriers of GSTM1/T1 null and GSTP1 Val105 genotypes exposed to indoor air pollution, were more susceptible to developing asthma and reduced lung function. However, these findings were more consistent in studies of children compared to studies of adults (Chapter 3). Aim 2. I found evidence that early life tobacco smoke exposure was associated with an increased risk of asthma, reduced lung function growth between 12 and 18 years, and reduced lung function at 18 years, with girls appearing to be more susceptible than boys (master research program). I also found an interaction between early life tobacco smoke exposure and GST genotypes on lung function at both 12 and 18 years. Carriers of GST null mutations and GSTP1 Ile/Ile alleles were more susceptible to tobacco smoke in early life, and these associations were not found in carriers of other GST genotypes (Chapter 5). Aim 3. I found some evidence that early life paracetamol use may be associated with impaired lung function and increased risk of asthma in adolescence after adjustment for the frequency of early life respiratory tract infections. Interaction analysis suggested that these associations were only for carriers of GSTM1 null and GSTP1 Ile/Ile genotypes, I did not find evidence for carriers of other GST genotypes (Chapter 6). Aim 4. I found that the exposure profiles of “Wood heating”, “All gas”, “Wood heating/smoking” and “Wood heating/gas cooking” were associated with persistent asthma and greater lung function decline by age 53 years. Carriers of GSTP1 Ile/Ile genotypes had a greater risk of asthma at age 53 years with exposure to “All gas” and “Wood heating/smoking” compared to a reference group (reverse cycle air conditioning, electric cooking and no smoking). Carriers of GSTM1 null and GSTP1 Ile/Ile genotypes had a greater risk of accelerated lung function decline when exposed to “Wood & gas heating/gas cooking/smoking” and “Wood heating/gas cooking” compared this reference group. These associations were not observed in carriers of other genotypes (Chapter 7). Conclusions: My work identified several household risk factors associated with the progression of asthma, limited maximal lung function development in childhood, or accelerated lung function decline in adulthood. Additionally, this work provides evidence on interactions between household exposures and GST polymorphisms and has contributed significantly to our understanding of gene-environment interactions in relation to respiratory health. These findings highlight the importance of considering potential gene-environment interactions in studies that investigate exposures associated with lung oxidative stress. These findings have the potential to inform guidelines and preventive strategies, especially for people who are at increased risk.