@article{583f10713d3741e1a7592baaf8bb311e,
title = "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.",
keywords = "Androgens, Glucocorticoids, HSD3B1, Inflammation, Steroids",
author = "Joe Zein and Benjamin Gaston and Peter Bazeley and DeBoer, {Mark D.} and Igo, {Robert P.} and Bleecker, {Eugene R.} and Deborah Meyers and Suzy Comhair and Marozkina, {Nadzeya V.} and Calvin Cotton and Mona Patel and Mohammad Alyamani and Weiling Xu and Busse, {William W.} and Calhoun, {William J.} and Victor Ortega and Hawkins, {Gregory A.} and Mario Castro and Chung, {Kian Fan} and Fahy, {John V.} and Fitzpatrick, {Anne M.} and Elliot Israel and Jarjour, {Nizar N.} and Bruce Levy and Mauger, {David T.} and Moore, {Wendy C.} and Patricia Noel and Peters, {Stephen P.} and Teague, {W. Gerald} and Wenzel, {Sally E.} and Erzurum, {Serpil C.} and Nima Sharifi",
note = "Funding Information: ACKNOWLEDGMENTS. We thank the patients and their families for their participation in the Severe Asthma Research Program; the site-based study coordinators and regulatory personnel for enrolling participants, the Data Safety and Monitoring Board for program oversight, and National Institute of Health/National Heart, Lung, and Blood Institute project officers and staff who administered the protocol. 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{\textquoteright}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). We also thank the Harrington Discovery Institute of University Hospitals, Cleveland, for grant support. Funding Information: Severe Asthma Research Programs (SARP) are comprehensive networks sponsored by the National Institutes of Health/ National Heart, Lung, and Blood Institute that aimed to characterize and understand the pathobiology of severe asthma. Here, we determined FEV1PP in the SARP III cohort for patients with asthma treated with (GC) and without (noGC) daily oral GCs. Confirmatory studies were performed in patients with severe asthma from the SARP I&II study. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = jan,
day = "28",
doi = "10.1073/pnas.1918819117",
language = "English (US)",
volume = "117",
pages = "2187--2193",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "4",
}