[Mendelian randomization analysis integrating genomics and proteomics reveals cytochrome P450 oxidoreductase as a potential target for the treatment of chronic rhinosinusitis with nasal polyps].

Objective: To explore potential therapeutic targets for chronic rhinosinusitis with nasal polyps (CRSwNP) through Mendelian randomization (MR) analysis integrating genomics and proteomics. Methods: Potential therapeutic targets were identified at the gene expression and protein levels using MR, summary-data-based Mendelian randomization (SMR), and colocalization analysis. Cis-eQTLs from the eQTLGen database and cis-pQTLs from the deCODE database were used as instrumental variables to validate targets at the gene expression and protein levels, respectively. Genetic data for CRSwNP were obtained from the FinnGen database and the IEU database. Thirty patients with CRSwNP and 30 patients with nasal septal deviation as the control group who were treated at the Second Affiliated Hospital of Harbin Medical University from September 2024 to September 2025 were enrolled in the study to detect the expression levels of target genes in the peripheral blood and nasal polyp tissue of CRSwNP patients, including 33 males and 27 females, aged 22 to 59 years old. In vitro experiments were conducted using the human RPMI 2650 cell line to preliminarily explore the potential mechanisms of action of the target genes. GraphPad Prism 9.0 was used for statistical analysis. Results: MR analysis revealed a significant negative association between cytochrome P450 oxidoreductase (POR) and CRSwNP risk (discovery cohort: OR=0.87, P=1.47×10-5; replication cohort: OR=0.82, P=1.09×10-7); cis-pQTL-MR analysis further supported this association (OR=0.77, P=4.12×10-4). POR protein expression was downregulated in both peripheral blood and polyp tissue from CRSwNP patients (P<0.01 for all comparisons). In vitro experiments suggested that POR may inhibit activation of the NF-κB pathway. Conclusion: Mult-omics MR analysis suggests that POR is a potential therapeutic target for CRSwNP, and it may influence the inflammatory microenvironment by regulating the NF-κB pathway.