Benefits of Airway Androgen Receptor Expression in Human Asthma
Joe Zein, Jeffrey M. McManus, Nima Sharifi, Serpil C. Erzurum, Nadzeya Marozkina, Timothy Lahm, Olivia Giddings, Michael D. Davis, Mark D. DeBoer, Suzy Comhair, Peter Bazeley, Hyun Jo Kim, William W. Busse, William J. Calhoun, Mario Castro, Kian Fan Chung, John V. Fahy, Elliot Israel, Nizar N. Jarjour, Bruce D. Levy, David T. Mauger, Wendy C. Moore, Victor E. Ortega, Michael C. Peters, Eugene R. Bleecker, Deborah A. Meyers, Yi Zhao, Sally E. Wenzel, Benjamin Gaston
Abstract
Abstract Rationale Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways. Objectives To measure whether AR and its ligands are associated with human asthma outcomes. Methods We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (Fe NO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey). Measurements and Main Results In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R 2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R 2 = 0.056, P = 0.016) and was negatively associated with Fe NO (R 2 = 0.178, P = 9.8 × 10−6) and NOS2 (nitric oxide synthase gene) expression (R 2 = 0.281, P = 1.2 × 10−10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men. Conclusions Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower Fe NO in human asthma. The role of androgens should be considered in asthma management.