Elevated MMP ‐9 Is Associated With Accelerated Lung Function Decline and COPD Development: A Prospective Cohort Study and Mendelian Randomisation Analysis

ABSTRACT Background and Objective The imbalance in proteases/antiproteases caused by inflammation contributes to COPD, and matrix metalloproteinase‐9 (MMP‐9) may play an important role. Therefore, we aimed to investigate the associations of MMP‐9 with respiratory health outcomes. Methods This study was conducted in two parts. Firstly, we performed a prospective cohort study to investigate the association of circulating MMP‐9 and respiratory health outcomes. Participants completed a questionnaire, spirometry, and chest CT, and provided blood samples at baseline. Follow‐up visits were conducted annually. Study outcomes were the development of spirometry‐defined COPD, lung function decline, and exacerbations. Secondly, we performed a two‐sample Mendelian randomisation (MR) study to evaluate the causal effect between genetically predicted MMP‐9 expression and lung function. Results Overall, 1328 participants were included in the baseline analysis, and 1034 (78%) completed the 2‐year follow‐up. Higher plasma MMP‐9 at baseline was associated with chronic respiratory symptoms, severe emphysema, and air trapping. During the 2‐year follow‐up, each SD increase in plasma MMP‐9 was associated with accelerated decline in pre‐bronchodilator FEV 1 (adjusted difference = 6.4 [95% CI: 0.7–12.1] mL/year) and FVC (adjusted difference = 18.0 [95% CI: 7.6–28.5] mL/year), and a higher exacerbation incidence. In participants with normal spirometry at baseline, higher plasma MMP‐9 was associated with progression to spirometry‐defined COPD (adjusted OR = 1.93, 95% CI: 1.05–3.57). A MR study demonstrated similar results toward negative associations of genetically predicted MMP‐9 expression with FEV 1 and FVC. Conclusion The longitudinal cohort and MR study provide evidence that MMP‐9 might play a causative role in lung function decline and spirometry‐defined COPD development. image