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

Authors

Bo Zeng, Chaoqun Zhou, Li Li, Yongbo Zhu

Published in

International journal of chronic obstructive pulmonary disease. Volume 21. Pages 635367. Epub Oct 01, 2026.

Abstract

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.
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.
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.
MRI-defined obesity axes provided genetic evidence supporting potential causal associations with airway diseases through inflammatory mediation pathways.

PMID:
42836120
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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