Pharmacogenetic Effects on Clusters of Lung Function Decline

<bold>Rationale:</bold> Studies have suggested pneumoprotective effects of respiratory and cardiovascular drugs, but this may be limited to therapy responders. <bold>Aim:</bold> To investigate whether effects of LABA, ICS, statin, or beta1-blocker (BB)-use on lung function trajectories differ based on genetic variation. <bold>Methods:</bold> Within the Rotterdam Study, a population-based cohort study of adults aged ≥45 years, drug exposure was quantified from pharmacy records. Propensity-score matching and multinomial logistic regression was performed to model drug-effects on lung function trajectory clusters (previously identified based on FEV₁ and FVC patterns). Models were additionally stratified by genetic variation in each drug target. <bold>Results:</bold> Among 3,784 individuals, 2,975 (78.6%) were classified as normal lung function decliners, 432 (11.4%) as rapid decliners, and 377 (10.0%) as improvers. Full exposure to LABA increased the odds of being an improver (OR=1.95 [95%CI: 1.15-3.29]) and was modified by genetic variation in beta2-receptor (8.23 [1.26-53.9] in <italic>ADRB2</italic> variant group vs. 1.44 [0.36-5.69] in wildtype). ICS-use increased the odds of being an improver (1.95 [1.15-3.29]), but showed no significant association when stratified by genetic risk (<italic>NR3C1</italic>). Statin-use increased the odds of being an improver (1.45 [1.23-1.72]), consistently over <italic>HMGCR</italic> variant groups. BB-use showed a higher odds of being an improver (4.14 [1.51-11.30]) and borderline with being a rapid decliner (2.43 [0.99-5.95]) in the <italic>ADRB1</italic> variant group. <bold>Conclusions:</bold> Our study suggests that ICS, LABA, BB and statin-use favorably affect lung function trajectories in adults, while BB-use may also associate with rapid decline. Genotype-specific effects were observed for LABA and BB-use.