Abstract
BACKGROUND: Despite significant advances in understanding the epigenetic landscape of chronic rhinosinusitis (CRS), the specific microRNAs (miRNAs) with a causal role in CRS pathogenesis remain unclear. OBJECTIVE: This study aims to identify miRNAs that causally contribute to CRS and to elucidate their clinical relevance and underlying molecular mechanisms. METHODS: We employed Mendelian randomization (MR) analysis, leveraging mirQTLs as exposure variables and two independent CRS datasets as outcomes, to identify miRNAs causally linked to CRS. Robustness of the findings was ensured through multiple sensitivity analyses. The expression levels of identified CRS-associated miRNAs were validated using qRT-PCR, and their diagnostic potential was assessed through ROC curve analysis. Target genes and potential pathways regulated by the causal miRNAs were predicted via MiRNet and enrichment analyses, followed by experimental validation using western blotting and immunohistochemistry. RESULTS: MiR-130a-3p and miR-196b-5p were significantly associated with an increased risk of CRS, while miR-339-3p was associated with a decreased risk. These associations were confirmed by qRT-PCR, and no evidence of pleiotropy or heterogeneity was observed. ROC analysis revealed diagnostic potential for these miRNAs in CRS. Enrichment and experimental analyses suggested that the MAPK and PI3K-AKT pathways are predominantly activated by the target genes of the positively and negatively associated miRNAs, respectively. CONCLUSIONS: MiR-130a-3p and miR-196b-5p are positively associated with CRS risk, whereas miR-339-3p is protective. These miRNAs represent promising diagnostic biomarkers and therapeutic targets for CRS. The MAPK and PI3K-AKT pathways likely mediate the effects of these causal miRNAs, offering further insight into the molecular mechanisms underlying CRS.