Inflammation-Mediated Causal Effects of MRI-Defined Body-Composition Obesity Axes on Chronic Obstructive Pulmonary Disease, Asthma, and Allergic Rhinitis: A Mendelian Randomization Study

Background: Obesity is heterogeneous; conventional anthropometric measures combine fat distribution, ectopic fat deposition, and muscle volume, limiting refined causal inference for chronic airway diseases. We used four magnetic resonance imaging (MRI)-defined obesity axes to assess their causal effects on chronic obstructive pulmonary disease (COPD), asthma, and allergic rhinitis (AR), and to evaluate mediation by circulating inflammatory proteins. Methods: Genetic instruments were selected for four MRI-defined obesity axes. Two-sample Mendelian randomization (MR) used inverse-variance weighting as the primary method, with complementary sensitivity analyses and false discovery rate correction. Non-overlapping FinnGen outcome data were used for discovery, with replication in the Global Biobank Meta-analysis Initiative for COPD and asthma and the Million Veteran Program for AR, followed by meta-analysis. Two-step MR assessed inflammatory protein mediation. Results: Genetically predicted general obesity axis was associated with increased risks of COPD (OR = 1.125, 95% CI: 1.012– 1.250), asthma (OR = 1.533, 95% CI: 1.426– 1.647), and AR (OR = 1.624, 95% CI: 1.328– 1.987). The lower-body fat axis was associated with higher risks of COPD (OR = 1.192, 95% CI: 1.088– 1.306) and asthma (OR = 1.135, 95% CI: 1.052– 1.224). No causal evidence was observed for the other obesity axes. Replication and meta-analysis largely supported these findings, except for general obesity and AR, which showed borderline pooled evidence ( P = 0.055). Mediation analysis identified 17 candidate inflammatory pathways, of which 10 were significant. FLT3L mediated 18.17% of the effect of general obesity on COPD, and CXCL5 mediated 3.78% of its effect on asthma. CD40L receptor and LIFR mediated 5.59% and 12.65% of the lower-body fat–asthma effect, respectively, whereas CD40L receptor, CXCL10, IL-12B, OPG, and TNFRSF9 showed suppressive mediation in selected pathways. Conclusion: MRI-defined obesity axes provided genetic evidence supporting potential causal associations with airway diseases through inflammatory mediation pathways. Keywords: obesity axes, chronic obstructive pulmonary disease, asthma, allergic rhinitis, Mendelian randomization