HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.

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.

• Authors: Joe Zein, Benjamin Gaston, Peter Bazeley, Mark D DeBoer, Robert P Igo Jr, Eugene R Bleecker, Deborah Meyers, Suzy Comhair, Nadzeya V Marozkina, Calvin Cotton, Mona Patel, Mohammad Alyamani, Weiling Xu, William W Busse, William J Calhoun, Victor Ortega, Gregory A Hawkins, Mario Castro, Kian Fan Chung, John V Fahy, Anne M Fitzpatrick, Elliot Israel, Nizar N Jarjour, Bruce Levy, David T Mauger, Wendy C Moore, Patricia Noel, Stephen P Peters, W Gerald Teague, Sally E Wenzel, Serpil C Erzurum, Nima Sharifi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 4 Pg. 2187-2193 (01 28 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 31932420 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• 3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase
• Androgens
• Glucocorticoids
• Multienzyme Complexes
• Progesterone Reductase
• Steroid Isomerases

Topics

• Adult
• Aged
• Alleles
• Androgens (metabolism)
• Asthma (drug therapy, enzymology, genetics, metabolism)
• Cohort Studies
• Drug Resistance
• Female
• Genotype
• Glucocorticoids (administration & dosage)
• Humans
• Male
• Middle Aged
• Multienzyme Complexes (genetics, metabolism)
• Progesterone Reductase (genetics, metabolism)
• Steroid Isomerases (genetics, metabolism)
• Young Adult