Genetic and Epigenetic Associations with Pre-COPD Lung Function Trajectories

Rationale: Understanding 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. Methods: Blood 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. Results: Subjects 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. Conclusions: High risk trajectories that progress to COPD exhibited genetic and epigenetic associations at epithelial and histocompatibility genes as well as accelerated epigenetic ageing.