Biomarkers of ageing and lung function trajectory: a multi-omics study in a UK birth cohort

BACKGROUND: Accelerated biological ageing and cellular senescence are pathogenically implicated in COPD and may represent therapeutic targets. Adverse early-life lung function trajectories offer opportunities to prevent COPD but their relationship with epigenetic and proteomic ageing biomarkers remains unexplored. We investigated using conventional epidemiological and Mendelian randomisation (MR) methods. METHODS: Outcomes were the two lowest of five FEV 1 trajectories (Persistently Low and Below Average) previously identified using latent profile analysis (ages 8-30) in the Avon Longitudinal Study of Parents and Children. Exposures included nine measures of blood-derived epigenetic age acceleration (EAA) and thirteen senescence-associated plasma proteins (ages 7-9). We used logistic regression to estimate odds of lower trajectory membership by exposure and bidirectional one-sample MR to investigate causation. RESULTS: Higher plasma CXCL10 (OR 1.29 per SD; 95% CI 1.03, 1.57), IL6 (OR 1.29; 1.03, 1.57) and IL33 (OR 1.23; 1.04, 1.44) were associated with Persistently Low lung function trajectory, with little evidence for associations between EAA and lower trajectories. MR provided little evidence that genetically predicted plasma proteins influenced risk of lower trajectories, but lower genetically proxied childhood FEV1 predicted higher plasma CXCL10 at ages 9 (β -0.34; -0.65, -0.03) and 24 (β -0.38; -0.67, -0.08). INTERPRETATION: Childhood plasma CXCL10, IL6 and IL33, but not EAA, predict low lung function trajectory into early adulthood. Lower childhood lung function may causally relate to persistently increased plasma CXCL10. Future research should investigate IL33 as a potential therapeutic target in low lung function trajectory and persistent systemic inflammation as a mechanism for associated multimorbidity.