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HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.

Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195. Herman Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202. Department of Pediatrics, University of Virginia, Charlottesville, VA 22904. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106. Department of Medicine, University of Arizona Health Sciences, Tucson, AZ 85721. Department of Pediatrics, Rainbow Babies and Children's Hospital, and Case Western Reserve University, Cleveland, OH 44106. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706. Department of Medicine, University of Texas Medical Branch, TX 77555. Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27587. Department of Medicine, University of Kansas School of Medicine, Kansas City, KS 66160. The National Heart & Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom. Department of Pediatrics, San Francisco School of Medicine, University of California, San Francisco, CA 94143. Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322. Department of Medicine, Harvard Medical School, Boston, MA 02115. Center for Biostatistics and Epidemiology, Pennsylvania State University School of Medicine, Hershey, PA 16802. Severe Asthma Research Program (SARP), National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892. University of Pittsburgh Asthma Institute, University of Pittsburgh Medical Center-University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; sharifn@ccf.org.

Proceedings of the National Academy of Sciences of the United States of America. 2020;(4):2187-2193
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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.

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Publication Type : Clinical Trial

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MeSH terms : Glucocorticoids