Objective To systematically identify potential pathological molecular and therapeutic targets for type 2 airway inflammatory diseases using Mendelian randomization (MR) and co-localization analysis.

Methods This study analyzed 4,302 druggable plasma proteins as exposure factors and performed transcriptional MR analysis using their cis-expression quantitative trait loci (cis-eQTL) as instrumental variables. Disease outcome datasets from the UK Biobank and Finnish Cohortwere used for discovery and replication validation, respectively. For proteins successfully validated, cis-protein quantitative trait loci (cis-pQTL) were further used for protein-level MR analysis. By combining co-localization analysis, reverse MR analysis, and mediation analysis, we investigated the association of these plasma proteins with allergic rhinitis (AR), asthma (AS), and nasal polyps (NP).

Results cis-eQTL MR analysis of 2528 proteins identified 10 proteins associated with AR (TLR10, ERBB3, PNMT, etc.), 7 associated with AS (ERBB3, SLC40A1, PRKCQ, etc.), and 3 associated with NP (IL18RAP, AXL, ERBB3). cis-pQTL MR analysis showed that IL18RAP was associated with lower NP disease risk, while ERBB3 was associated with lower risks of AR, AS, and NP. Co-localization analysis supported the association between ERBB3 and AR (pp.H4 = 0.910). Mediation analysis revealed that the associations between ERBB3 and AR/AS were mediated by eosinophils, with mediation effects accounting for 12.51% and 17.64% of the observed associations, respectively.

Conclusion This study identified unique and shared molecular targets for type 2 airway inflammatory diseases, with ERBB3 potentially serving as a shared protective factor and biomarker for AR, AS, and NP.