Joe G Zein1,2, Jeffrey M McManus1, Nima Sharifi1, Serpil C Erzurum1,2, Nadzeya Marozkina3, Timothy Lahm4, Olivia Giddings5, Michael D Davis3, Mark D DeBoer6, Suzy A Comhair1,2, Peter Bazeley1,2, Hyun Jo Kim7, William Busse8, William Calhoun9, Mario Castro10, Kian Fan Chung11, John V Fahy10,12, Elliot Israel13, Nizar N Jarjour8, Bruce D Levy13, David T Mauger14, Wendy C Moore15, Victor E Ortega15, Michael Peters12, Eugene R Bleecker16, Deborah A Meyers16, Yi Zhao17, Sally E Wenzel18, Benjamin Gaston3. 1. Lerner Research Institute and. 2. Respiratory Institute, Cleveland Clinic, Cleveland, Ohio. 3. Department of Pediatrics. 4. Department of Medicine, and. 5. Department of Pediatrics and. 6. Department of Pediatrics, University of Virginia, Charlottesville, Virginia. 7. Department of Systems Biology and Bioinformatics, Case Western Reserve University, Cleveland, Ohio. 8. Department of Medicine, School of Medicine, University of Wisconsin, Madison, Wisconsin. 9. Department of Medicine, University of Texas Medical Branch, University of Texas, Galveston, Texas. 10. Division of Pulmonary, Critical Care, and Sleep Medicine, School of Medicine, University of Kansas, Kansas City, Kansas. 11. National Heart and Lung Institute, Imperial College London, London, United Kingdom. 12. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, California. 13. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts. 14. Center for Biostatistics and Epidemiology, School of Medicine, Pennsylvania State University, Hershey, Pennsylvania. 15. Section on Pulmonary, Critical Care, Allergic, and Immunologic Disease, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina. 16. Division of Genetics, Genomics, and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona; and. 17. Department of Biostatistics and Health Science Data, School of Medicine, Indiana University, Indianapolis, Indiana. 18. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
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 (FeNO) 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 (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 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 FeNO in human asthma. The role of androgens should be considered in asthma management.
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 (FeNO) 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 (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 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 FeNO in human asthma. The role of androgens should be considered in asthma management.
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