<i>HSD3B1</i> genotype identifies glucocorticoid responsiveness in severe asthma
Joe Zein, Benjamin Gaston, Peter Bazeley, Mark D. DeBoer, Robert P. Igo, Eugene R. Bleecker, Deborah A. Meyers, Suzy Comhair, Nadzeya Marozkina, Calvin U. Cotton, Mona Patel, Mohammad Alyamani, Weiling Xu, William W. Busse, William J. Calhoun, Victor E. Ortega, Gregory A. Hawkins, Mario Castro, Kian Fan Chung, John V. Fahy, Anne M. Fitzpatrick, Elliot Israel, Nizar N. Jarjour, Bruce D. Levy, David T. Mauger, Wendy C. Moore, Patricia Noël, Stephen P. Peters, W. Gerald Teague, Sally E. Wenzel, Serpil C. Erzurum, Nima Sharifi
Abstract
Significance Although resistance to glucocorticoids is a major clinical problem, the underlying mechanisms are unknown. It is known that glucocorticoid use can suppress adrenal androgen production. In population studies, animal models, and cell culture experiments, androgens are associated with several benefits in asthma, but neither androgen use in glucocorticoid-resistant asthma nor the genetic determinants of androgen responsiveness have been studied in humans. A missense-encoding variant in HSD3B1 is known to regulate conversion from adrenal precursors to potent androgens and clinical outcomes in prostate cancer. This is the first genetic evidence to our knowledge that implicates an androgen synthesis variant in resistance to glucocorticoids for asthma or any other inflammatory disease. Furthermore, this study demonstrates an adverse consequence of adrenal androgen suppression with glucocorticoid therapy.