Genetically Predicted Use of Common Analgesics and Risk of Chronic Obstructive Pulmonary Disease: A Bidirectional...

Observational studies suggest a link between common analgesic use and chronic obstructive pulmonary disease (COPD), but causality is unclear. This study aimed to investigate the bidirectional causal relationship between the genetically predicted use of paracetamol, aspirin, and ibuprofen, and COPD risk using a two-sample Mendelian randomization (MR) approach.

We performed a bidirectional MR study using summary statistics from large-scale genome-wide association studies (GWAS). Genetic instruments for paracetamol, aspirin, and ibuprofen use were from the UK Biobank (N=457,547). COPD summary statistics were from the FinnGen consortium (24,138 cases, 409,070 controls). The primary analysis used the inverse-variance weighted (IVW) method. We conducted extensive sensitivity analyses (MR-Egger, weighted median, weighted mode, MR-PRESSO) to assess pleiotropy and heterogeneity.

Genetically predicted paracetamol use was significantly associated with an increased risk of COPD (IVW OR: 6.00, 95% CI: 2.43-14.82, P < 0.001). Conversely, genetically predicted aspirin use was associated with a decreased risk of COPD (IVW OR: 0.19, 95% CI: 0.05-0.71, P = 0.014). Genetically predicted ibuprofen use showed no significant association with COPD risk (IVW OR: 0.47, 95% CI: 0.06-3.82, P = 0.483). In the reverse analysis, genetic liability to COPD was not causally associated with the use of any of the three analgesics (P > 0.05). Sensitivity analyses supported the robustness of these findings, showing no significant directional pleiotropy or heterogeneity for the primary results.

This MR study provides genetic evidence supporting a causal relationship between paracetamol use and an increased risk of COPD, and between aspirin use and a decreased risk. These findings suggest that the choice of analgesic may have important implications for COPD risk, warranting further clinical investigation.