RATIONALEUnderstanding the pathobiology of life-course lung function trajectories that progress to COPD, especially with a rapidly declining phenotype, can inform preventive interventions. Genetic and environmental interactions may contribute to these high-risk trajectories through epigenetic variation Objectives: A pilot to broadly characterise genetic and epigenetic contributions to high-risk trajectories in middle-aged people.METHODSBlood genome-wide genetic and epigenetic markers were profiled in 160 donors at 45 years of age from the Tasmanian Longitudinal Health Study (TAHS). High-risk subjects were selected from three previously published lifetime FEV1 trajectories that together accounted for 75% of COPD prevalence at age 53 years, and were matched to persistently high trajectory controls. Differentially methylated regions and epigenetic age acceleration differences between the groups were examined. The impact of co-morbidities and genetic variants on the observed epigenetic associations were investigated.RESULTSSubjects from the high risk FEV1 trajectories exhibited 55 novel regions of epigenetic divergence (FDR < 0.05) at genes related to cellular adhesion and epithelial biology. Current asthma or COPD co-morbidities partially explained these changes. Allelic variation at Major Histocompatibility Complex (MHC) and other loci was associated with epigenetic changes and linked to lung specific gene expression signatures and COPD/lung function traits in GWAS. Epigenetic age acceleration was independently associated with high-risk trajectories, which was most pronounced in the rapid decline one.CONCLUSIONSHigh risk trajectories that progress to COPD exhibited genetic and epigenetic associations at epithelial and histocompatibility genes as well as accelerated epigenetic ageing.

Background: Landscape fires affect millions of individuals globally and are becoming increasingly prevalent and intense. Increased respiratory and cardiac-associated hospital admissions occur during landscape fire events. A greater understanding of how landscape fire smoke (LFS) affects cardiorespiratory disease is required to identify prevention and treatment strategies. We developed a unique system to assess different exposure levels of LFS from specific geographical locations on cardiorespiratory health. Methods: LFS particulates are generated from geo-specific fuel sources using a customised combustion chamber following which the fine fraction (<10µm) is collected by percolation. 8 week old female Balb/C mice are intranasally instilled with physiologically representative high (100µg/m3, 24 hour equiv.) and moderate (25µg/m3, 24 hour equiv.) concentrations of LFS particulates daily for 3 (acute) and 14 (chronic) days. The effects of LFS exposure on lung function and key immunological and pathological responses in the airways and heart were assessed. Results: Inhalation of particulates from LFS results in a decrease in gas diffusion, increased airways hyperresponsiveness and promotes severe, steroid-insensitive disease in an experimental model of asthma. LFS exposure suppresses immune responses in the lungs and perturbs the expression of key antioxidant genes and markers of cardiovascular disease in heart tissue. Conclusion: We have developed a novel platform of LFS exposure to investigate the mechanisms that underpin how LFS affects respiratory and cardiovascular physiology in vulnerable groups, particularly those with asthma and pregnant women and their offspring infants. Grant Support: MRFF