Abstract
To elucidate the bidirectional associations and mechanisms linking the increasingly prevalent conditions of asthma, gastroesophageal reflux disease (GERD), and osteoarthritis (OA), with a focus on exploring the mediating role of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in these associations. Employing a comprehensive two-sample, bidirectional Mendelian randomization (MR) framework, this study was designed to investigate the associations between asthma, GERD, and OA (including overall OA, hip OA [HOA] and knee OA [KOA]), incorporating a two-step MR approach to assess the mediating role of NSAIDs within these associations. The genetic foundations for asthma and overall OA were precisely obtained from the UK Biobank, complemented by an in-depth analysis of KOA and HOA through an extensive meta-analysis merging data from the UK Biobank with arcOGEN, enabled by the European Bioinformatics Institute (EBI). Genetic insights into GERD were derived from a comprehensive GWAS dataset also hosted by EBI. Our analysis applied a broad array of statistical techniques, including Inverse Variance Weighted (IVW), MR-Egger, Weighted Mode, Weighted Median, and MR-PRESSO methods, coupled with the False Discovery Rate (FDR) procedure, to rigorously minimize false-positive risks. Bidirectional MR analysis reveals mutual increased risks between asthma and GERD (asthma to GERD OR = 1.55, 95% CI = 1.20–2.01, P < .001; GERD to asthma OR = 1.04, 95% CI = 1.03–1.04, P < .001), and associations with OA (asthma to overall OA OR = 1.03, 95% CI = 1.01–1.05, P = .01; asthma to KOA OR = 1.67, 95% CI = 1.20–2.32, P < .01; overall OA to asthma OR = 1.12, 95% CI = 1.03–1.21, P = .01; KOA to asthma OR = 1.0034, 95% CI = 1.0001–1.0069, P = .03). No significant associations were found between asthma and HOA. GERD is associated with an increased risk for OA (OR = 1.03, 95% CI = 1.03–1.04, P < .001 for overall OA; OR = 1.72, 95% CI = 1.59–1.86, P < .001 for KOA; OR = 1.32, 95% CI = 1.20–1.45, P < .001 for HOA) and vice versa for OA subtypes increasing the risk of GERD (overall OA OR = 5.32, 95% CI = 2.74–10.36, P < .001; KOA OR = 1.12, 95% CI = 1.09–1.16, P < .001; HOA OR = 1.05, 95% CI = 1.02–1.07, P < .001). NSAIDs exhibit a protective effect against asthma in OA patients (β=-0.40, 95% CI=-0.60 to -0.20, P < .001), but their impact on the progression from OA to GERD is marked by variability, as indicated by the wide CI (β = 0.68, 95% CI=-0.32 to 1.68, P < .001).Bidirectional associations were found between asthma and OA subtypes (excluding HOA) and between asthma and GERD. GERD's linkage to increased OA risk underscores mutual bidirectionality with OA subtypes. While NSAIDs show potential in mitigating OA to asthma progression, their impact on the OA to GERD trajectory remains uncertain.