The exploration of immunological landscape and drug targets in chronic rhinosinusitis with nasal polyps.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory disorder characterized by nasal obstruction and polyp formation. Despite its prevalence, the complex pathogenesis of CRSwNP remains not fully understood, hindering the development of effective treatments. This study aims to delineate the immunological landscape of CRSwNP by integrating single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) approaches. Methods: We conducted a systematic MR analysis using summary statistics from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data. The identified genes were further scrutinized through scRNA-seq analysis of CRSwNP tissues to assess cell-specific expression patterns. Pathway enrichment and protein-protein interaction (PPI) network analyses were performed to explore the biological mechanisms underlying CRSwNP. Results: The MR analysis identified several genes, including HLA-DRB1, HLA-DQA1, and HLA-DQB1, as significantly associated with CRSwNP. The scRNA-seq analysis validated these findings, revealing cell-specific enrichment in basal cells. Notably, these genes were found to be involved in immune cell recruitment and the reshaping of the immune microenvironment. Furthermore, the study highlighted the role of genes like TCF7L1, KANSL1-AS1, and POLR2J3, which showed contrasting expression patterns and potential regulatory roles in CRSwNP. Conclusion: This integrative study provides novel insights into the molecular and cellular underpinnings of CRSwNP. The identified genes and their role in immunopathogenesis offer potential therapeutic targets and highlight the importance of cell-specific gene expression in disease mechanisms. The combination of MR with scRNA-seq represents a powerful approach to elucidate complex traits and may pave the way for precision medicine in CRSwNP management.