Melbourne School of Population and Global Health - Theses
Permanent URI for this collection
Search Results
1 - 3 of 3
-
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.
-
ItemHow do socio-economic characteristics influence the effect of disability acquisition on mental health? An analysis of effect modification and mediation( 2019)Background People with disabilities in Australia experience poorer mental health than people without disability. However, the mechanisms by which disability leads to poor mental health are inadequately understood. This PhD thesis aims to form a better understanding of how people’s socio-economic circumstances influence the effect of disability acquisition on mental health. Elucidating the causal mechanisms underpinning this relationship will inform the development of effective public health and social policies to improve the mental health of people with disabilities. Methods I used data from the Household, Income and Labour Dynamics in Australia Survey – a large nationally representative longitudinal dataset – to quantify the effect of disability on mental health and to examine the socio-economic mechanisms leading from disability acquisition to poor mental health. I identified adults who acquired a disability during their participation in the survey and used data both before and after they acquired the disability to estimate the causal effect of disability on mental health. Firstly, I conducted analyses of effect modification, examining a wide range of different socio-economic factors to determine whether they influenced the magnitude of the effect of disability acquisition on mental health, using inverse probability weighting and fixed effects models to better control for confounding. Secondly, I conducted causal mediation analyses to further examine the socio-economic mechanisms leading from disability to poor mental health, using sequential mediation analysis to examine a broad range of socio-economic characteristics and an interventional mediation approach to quantify indirect effects operating through two distinct socio-economic characteristics: employment and income. Finally, I examined the indirect effect mediated by employment in greater detail, further decomposing the natural indirect effect through employment to estimate the proportion attributable to interaction, mediation and their joint effects. Results There is a clinically significant and large effect of disability acquisition on mental health. The analyses of effect modification provided evidence that the magnitude of the effect differed according to people’s socio-economic characteristics, with greater effects observed for more disadvantaged groups. The mediation analyses provided additional evidence that socio-economic characteristics contribute to the effect of disability acquisition on mental health. A third of the effect was found to be mediated by material socio-economic factors such as employment, income, wealth, financial hardship and housing characteristics, and a further investigation of the indirect effect through employment and income highlighted employment (but not income) as an important contributing factor, explaining 11% of the effect alone. Finally, further decomposition of the indirect effect through employment suggested that the mediated effect was due to interaction between disability and employment, rather than pure mediation. Conclusion The findings of this thesis highlight the importance of the social determinants of health in generating mental health inequalities. Interventions should prioritise addressing the social determinants of health to improve the mental health of people with disabilities and reduce disability-related mental health inequalities. Furthermore, the evidence that employment is a key mediator of the effect of disability acquisition on mental health indicates that policy strategies are needed to target the causes of low employment rates for people with disabilities.
-
ItemNatural history and consequences of food sensitisation: results from two birth cohort studies( 2016)The prevalence of allergic diseases is increasing worldwide, particularly in Australia and other “westernised” countries. More recently, evidence suggests a second wave of the “allergy epidemic”, with an increase in the prevalence of food allergies. Despite intense research in this area, there are numerous questions concerning the potential risk factors for the development of allergic diseases. It has been shown that sensitisation to aeroallergens is strongly associated with allergy progression. However the associations between food sensitisation and the development of allergic conditions remain unclear. Therefore, my doctoral work has investigated the natural history of food sensitisation from infancy up to adolescence in an allergy high-risk cohort. I have also investigated the associations between early life food sensitisation and subsequent probable food allergy, asthma, allergic rhinitis and lung function during later childhood and adolescence. Data from an Australian allergy high-risk cohort (Melbourne Atopy Cohort Study (MACS)), and a German population-based cohort (Influence of Life-style related factors on the development of the Immune System and Allergies in East and West Germany PLUS the influence of traffic emissions and genetics (LISAplus)), were used to address the aims of this thesis. MACS recruited 620 infants with a family history of allergic disease prior to birth. The infants were followed from birth up to 18 years and skin prick test (SPT) was conducted at 6, 12 and 24 months, 12 and 18 years. LISAplus recruited 3,097 neonates from four German cities: Munich, Leipzig, Wesel and Bad Honnef. The participants were followed from birth up to 15 years and serum specific IgE was measured at age 2, 6, 10 and 15 years. In both cohorts, multiple surveys, that assessed the occurrence of allergic disease, were distributed throughout the follow-up period. Using these data along with sensitisation data, this thesis has contributed knowledge to address the following issues: Natural History of food sensitisation from infancy up to 18 years A better understanding of the natural history of food sensitisation provides insight, from a public health perspective, to appreciate the likely subsequent burden of food allergy and other allergic diseases over the life course. Longitudinal data on the natural history of food sensitisation beyond early childhood are scarce. Using MACS data, the prevalence of food sensitisation was found to be highest in infancy and declined after the age of 12 months. In the first two years of life, egg white was the most common food sensitisation followed by peanut and cow’s milk while peanut was the most prevalent food allergen at 18 years. Boys with eczema had the highest prevalences of egg and milk sensitisation throughout the follow-ups. A small proportion of children developed late onset food sensitisation (after the age of 2 years) which was unlikely to be clinically relevant. Consequences of early life food sensitisation Longitudinal birth cohort studies with prospective collection of data are the most appropriate design to evaluate the temporal association between early life food sensitisation and development of probable food allergy, asthma, allergic rhinitis and lung function during later childhood and adolescence. An association between food sensitisation at 12 months and the presence of adolescent food sensitisation and probable food allergy was noted in MACS, with sensitisation to more than one food allergen being the strongest predictor. I also demonstrated that early life sensitisation to food without concurrent aeroallergen sensitisation was associated with increased risk of asthma and allergic rhinitis during later childhood (i.e. 10-12 years) in both the MACS and LISAplus studies. Stronger associations were observed for co-sensitisation to both food and aeroallergen. However, only co-sensitisation to both food and aeroallergens in early life was found to be associated with asthma and allergic rhinitis at 18 years in MACS. These findings support the concept of an “atopic march”, in which early life food sensitisation progresses to later asthma and allergic rhinitis. Moreover, I have demonstrated evidence that sensitisation to food allergens only at 6 or 12 months in MACS was associated with reduced FEV1 in adolescence. Most of the observed effect was a direct association, although early life asthma but not aeroallergen sensitisation mediated these associations in part. However, these associations need to be confirmed in population-based studies as sensitisation was not assessed in the first year of life in the LISAplus study. In conclusion, the results I present in this thesis increase our knowledge of the relationship between food sensitisation and allergic disease. Additionally, they suggest that further efforts to prevent the development of food sensitisation, and hence the progression from food sensitisation to food allergy, asthma, allergic rhinitis and lung function impairment should be explored.