HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

• Type of Material: Article
• Authors: Joe Zein, Cleveland Clinic; Benjamin Gaston, Indiana University; Peter Bazeley, Cleveland Clinic; Mark D. DeBoer, University of Virginia; Robert P. Igo, Jr., Case Western Reserve University; Eugene R. Bleecker, University of Arizona; Deborah Meyers, University of Arizona; Suzy Comhair, Cleveland Clinic; Nadzeya V. Marozkina, Case Western Reserve University; Calvin Cotton, Case Western Reserve University; Mona Patel, Cleveland Clinic; Mohammad Alyamani, Cleveland Clinic; Weiling Xu, Cleveland Clinic; William W. Busse, University of Wisconsin; William J. Calhoun, University of Texas Medical Branch; Victor Ortega, Wake Forest University; Gregory A. Hawkins, Wake Forest University; Mario Castro, University of Kansas; Kian Fan Chung, Imperial College London; John V. Fahy, University of California San Francisco; Anne Fitzpatrick, Emory University; Elliot Israel, Harvard University; Nizar N. Jarjour, University of Wisconsin; Bruce Levy, Harvard University; David T. Mauger, Pennsylvania State University; Wendy C. Moore, Wake Forest University; Patricia Noel, NHLBI; Stephen P. Peters, Wake Forest University; W. Gerald Teague, University of Virginia; Sally E. Wenzel, University of Pittsburgh; Serpil C. Erzurum, Cleveland Clinic; Nima Sharifi, Cleveland Clinic
• Language: English
• Date: 2020-01-28
• Publisher: United States National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2020 the Author(s). Published by PNAS.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1918819117
• Title of Journal or Parent Work: PNAS
• Volume: 117
• Issue: 4
• Start Page: 2187
• End Page: 2193
• Grant/Funding Information: We also thank the Harrington Discovery Institute of University Hospitals, Cleveland, for grant support.; Supported by a grant from the National Heart, Lung, and Blood Institute Severe Asthma Research Program (U10 HL109250, P01 HL128192, and P01 HL101871 to Rainbow Babies and Children’s Hospital Virginia-Cleveland Consortium, and RO1 HL69170, U10 HL109250, K08 HL133381, P01 HL103453, P01 HL081064, R01CA172382, R01CA190289, R01 CA236780, and a grant from the Prostate Cancer Foundation to the Cleveland Clinic).
• Keywords: steroids; Pulmonary function; Resistance; HSD3B1; Testosterone; androgens; Lung function; inflammation; Multidisciplinary Sciences; Science & Technology; Association; National heart; glucocorticoids; Science & Technology - Other Topics; Androgen deprivation therapy; Phenotype; Features; Dehydroepiandrosterone
• Research Categories: Biology, Genetics; Health Sciences, Epidemiology; Biology, Biostatistics; Health Sciences, Public Health

Abstract

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.