Biological pathways linking lung function impairment to incident COPD: a prospective cohort study

Lung function impairment, including obstructive spirometry and preserved ratio impaired spirometry (PRISm), represents high-risk spirometric phenotypes for chronic obstructive pulmonary disease (COPD), yet the underlying biological pathways remain unclear. We analyzed 346,666 UK Biobank participants using pre-bronchodilator spirometry and classified lung function as normal, PRISm, or obstructive spirometry. Obstructive spirometry was treated as a distinct spirometric phenotype rather than a clinical diagnosis of COPD. 59 blood biomarkers and 251 metabolites were evaluated as potential mediators, and incident COPD was identified using the UK Biobank integrated ‘first occurrence’ fields. Linear regression and multivariable Cox models were applied. Lower FEV₁% and FVC% predicted, as well as PRISm and obstructive spirometry, were associated with increased COPD risk. Significant interactions were observed with smoking status and asthma status for PRISm, and with BMI, smoking status, and asthma for obstructive spirometry. Mediation analyses suggested modest contributions of inflammatory and lipid-related pathways, with combined mediation proportions of 4.25 and 2.60% for PRISm and 1.71 and 1.34% for obstructive spirometry, respectively. Additional statistical mediators were observed across hematological, hepatic, renal, endocrine, glycemic, bone mineral, amino acid, and ketone body domains. These findings identify circulating biomarkers associated with high-risk spirometric phenotypes and subsequent COPD risk, warranting further longitudinal and experimental investigation.