Genetic and cross-species single-cell analyses prioritize CD83 in antigen-presenting cells as a candidate therapeutic target in asthma.

Background: Asthma remains a heterogeneous inflammatory airway disease, and current therapies, including biologics, benefit only selected patient subsets. We aimed to identify genetically supported therapeutic targets with clear mechanistic and translational relevance in asthma. Methods: We integrated cis-eQTL and cis-pQTL instruments for 585 druggable genes with asthma genome-wide association data from FinnGen, EBI, and UK Biobank, comprising more than 1.1 million participants in total, using Mendelian randomization, colocalization, and SMR/HEIDI analyses. We then combined cell-type-specific single-cell eQTL Mendelian randomization with lung single-cell RNA sequencing from a house dust mite mouse model and public human and cynomolgus monkey single-cell datasets to define the cellular context of the prioritized signal. Phenome-wide association analysis and Connectivity Map screening were used to assess target specificity and nominate candidate compounds. Results: CD83 emerged as the most consistently supported candidate across the genetic prioritization pipeline. Higher genetically predicted CD83 expression showed a consistent risk-increasing association across independent cohorts, and protein-level analyses together with colocalization provided convergent support for CD83 as the prioritized gene at this locus. Mechanistically, integrating cell-type-specific human genetics with cross-species single-cell transcriptomics localized the signal to antigen-presenting cells, particularly memory B cells and dendritic cells. Across human, mouse, and monkey datasets, CD83-positive antigen-presenting cells were consistently enriched for MHCII antigen-presentation and T-cell activation programs following allergen challenge. Phenome-wide analyses did not identify major genome-wide significant associations outside the asthma signal, and signature-reversal analysis highlighted hydroxyfasudil and prunetin as candidate compounds for further evaluation. Conclusions: These findings prioritize CD83 in antigen-presenting cells as a genetically supported candidate therapeutic target in asthma. More broadly, they provide a translational framework linking human causal genetics to cell-specific mechanism and therapeutic nomination, and support direct CD83 perturbation studies in airway inflammation.