Integrative Analysis of Plasma Proteome and Genome Reveals Novel Drug Targets for Chronic Rhinosinusitis and Nasal Polyps.

BACKGROUND

Chronic rhinosinusitis (CRS) and nasal polyps (NP) are chronic inflammatory conditions with unsatisfactory treatment outcomes due to frequent recurrence of refractory disease. Identifying new therapeutic targets is essential.

METHODS

We conducted a proteome-wide Mendelian randomization (MR) analysis by integrating genome-wide association study genomic data of CRS/NP with cis-proteomic quantitative trait locus data to identify plasma proteins associated with CRS/NP risk. We validated the main findings using the Steiger test, Bayesian colocalisation, summary-data-based MR, and proteome-wide association studies. Single-cell expression analysis, enrichment analysis, protein-protein interaction networks, and drug availability assessments were performed to elucidate the functional pathways of the proteins and explore their potential as therapeutic targets for CRS/NP.

RESULTS

We identified nine proteins associated with the risk of NP and four proteins associated with the risk of CRS through proteome-wide MR analysis. Among these, three proteins (IL2RB, IL7R, and POR) associated with NP demonstrated the highest level of evidence and were prioritized. The protein-coding genes were primarily expressed in early secretory cells, tuft cells, ionocyte cells, basal cells, and secretory cells. These genes play significant roles in regulating the adaptive immune response and cytokine-cytokine receptor interaction. Four proteins (IL2RB, IL7R, POR, and TNFSF11) interacted with known drug targets for NP.

CONCLUSIONS

Our study prioritizes IL2RB and IL7R as key mediators of CRS/NP pathogenesis via immune dysregulation. Their interactions with existing biologics underscore translational potential, offering mechanistic insights and actionable targets for biotherapy development. Clinical trial number: Not applicable.