Key genes associated with the comorbidity of allergic rhinitis and chronic rhinosinusitis with nasal polyps: Identification, experimental validation, and an observational study using transcriptomic profiling and Mendelian randomization analysis in hu

Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) frequently coexists with allergic rhinitis (AR). However, the underlying connection between these 2 conditions remains poorly understood. This study aimed to identify and validate key comorbidity genes associated with both AR and CRSwNP, providing novel therapeutic targets and strategies. Transcriptomic data related to AR and CRSwNP were analyzed. Key comorbidity genes were 1st identified through differential expression analysis in the GSE19190 and GSE136825 datasets, Mendelian randomization studies for AR and CRSwNP, and gene expression analysis in AR-related datasets (GSE19190, GSE46171), and CRSwNP-related datasets (GSE136825, GSE179265). Subsequent functional enrichment, immune infiltration, and drug prediction analyses were conducted based on these key comorbidity genes to explore potential therapeutic targets and mechanisms behind the AR-CRSwNP overlap. Reverse transcription quantitative polymerase chain reaction was performed to validate gene expression in clinical samples. Additionally, single-sample gene set enrichment analysis was carried out for CRSwNP. Two key comorbidity genes, CD109 and CPA3, were identified as critical for AR and CRSwNP, with elevated expression in both conditions. Reverse transcription quantitative polymerase chain reaction confirmed a significant increase in CD109 expression in CRSwNP + AR samples (P = .01). Functional enrichment analysis revealed that genes linked to AR were primarily associated with "asthma" and "hematopoietic cell lineage," while CRSwNP-related genes were enriched in "cell cycle" and "allograft rejection." This study found that significant differences in immune cell infiltration were observed. In the AR group, both CD109 and CPA3 showed the strongest positive correlation with CD56 bright natural killer cells. In the CRSwNP group, CPA3 had the strongest positive correlation with activated B cells, while CD109 was positively correlated with memory CD8 T cells. CRSwNP samples exhibited higher pyroptosis-related gene scores. Furthermore, drug prediction analyses identified 5 potential drugs for CPA3 and 12 for CD109, presenting new treatment avenues for both conditions. CD109 and CPA3 were identified as key comorbidity genes in AR and CRSwNP, with their expression validated in clinical samples. Genes related to pyroptosis may also play a significant role in CRSwNP. These findings provide a theoretical foundation for the development of targeted therapies for AR and CRSwNP.