Nasal gene expression in T2-low asthma

<bold>Introduction:</bold> T2-low asthma is characterized by the absence of T2 inflammation and resistance to inhaled corticosteroids with unknown molecular mechanisms and limited treatment options. Our prior work demonstrated altered nasal brush transcriptome in asthma, reflecting disease-relevant biology. This study aims to explore nasal gene expression related to T2-low asthma in ATLANTIS. <bold>Methods:</bold> We compared nasal RNA-seq data from 82 T2-low and 63 T2-high (male 24% and 46%; FEV1 %pred 89 and 80; BMI: 26 and 26 respectively) asthma patients to 57 healthy controls. T2-low asthma was defined as blood eosinophils (BE) < 0.15*109/L; FeNO < 25 ppb and T2-high as BE > 0.3*109/L; FeNO > 25 ppb. The remaining 194 patients were classified as undetermined and not included in the current analysis. <bold>Results:</bold> T2-low asthma patients were more often female and allergic and had more small airway disease (RV/TLC, %pred: 98 vs 89, p = 0.01) compared to controls. Although strong gene expression differences were found in T2-high asthma, T2-low asthma showed no genome-wide differentially expressed genes compared to healthy controls. Using CIBERSORTx cellular deconvolution, we found higher predicted club cell proportions in T2-low asthma compared to controls (median [IQR]: 0.03 [0, 0.12] vs 0 [0, 0.04], FDR = 0.017). Weighted Gene Coexpression Network Analysis identified two gene modules linked to T2-low asthma, involved in T-cell immunity and ribosomal RNA biology, with the HLA-DPB1 and RPL23 being the hub genes. <bold>Conclusion:</bold> Although we did not detect genome-wide significant gene expression differences in T2-low asthma, we did observe higher club cell proportions and suggestive evidence of T-cell mediated immune responses, possibly contributing to T2-low asthma pathogenesis.