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 FEV₁ (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 FEV₁ 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.