Clinical and genetic predictors of MUC5AC expression in patients with asthma

Title: Clinical and genetic predictors of MUC5AC expression in patients with asthma <bold>Introduction:</bold> Patients with asthma frequently report productive cough. Mucus hypersecretion has been related to overexpression of the airway mucin MUC5AC. We sought to investigate clinical markers and genes that predict MUC5AC expression in patients with asthma. <bold>Methods:</bold> Bronchial bushings obtained from patients with asthma in the UPSTREAM (n=33) and RECONSTRUCT (n=21) studies were subjected to RNA sequencing. Clinical and paraclinical data, along with genes associated with MUC5AC expression were assessed using stepwise linear regression and quantitative contribution was calculated using squared semi-partial correlations. <bold>Results:</bold> The expression of MUC5AC was most strongly correlated with SPDEF expression (r=0.48, P<0.001) and was significantly higher in patients with FeNO ≥25 ppm compared with <25 ppm (P=0.001), whereas no difference was seen in patients with blood eosinophil counts ≥0.3x109/L compared with <0.3 x109/L (P=0.13) or sputum eosinophil differential counts ≥3% compared with <3% (P=0.32). In a stepwise linear regression model, prior exacerbations, higher FeNO and blood TSLP levels, and higher expression of EGFR and SPDEF significantly predicted higher levels of MUC5AC expression. Altogether, these variables explained 62% of the variance in MUC5AC expression, with SPDEF gene expression and FeNO being the strongest predictors explaining 29% and 13%, respectively. <bold>Conclusion:</bold> MUC5AC expression was predicted by exacerbations and epithelial activation involving IL-13 and TSLP, as well as EGRF and SPDEF, but not by eosinophilia. This indicates epithelial inflammation as the primary driver of mucus hypersecretion.