HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

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, 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

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: HSD3B1; androgens; glucocorticoids; inflammation; steroids.

Conflict of interest statement

Competing interest statement: Cleveland Clinic has applied for patents on HSD3B1.

Copyright © 2020 the Author(s). Published by PNAS.

Figures

Fig. 1.
Fig. 1.
DHEA-S concentration is associated with FEV1PP and suppressed with daily systemic GC use. (A) In subjects with asthma, FEV1PP correlates significantly with DHEA-S levels in both Caucasian men (blue circles; R2 = 0.15; P < 0.001) and women (open red circles; R2 = 0.03; P = 0.047). (B) Chronic daily GC use is associated with DHEA-S suppression in SARP III in men and women.
Fig. 2.
Fig. 2.
The adrenal restrictive HSD3B1(1245A) allele is specifically associated with poor pulmonary function in GC-treated patients with severe asthma. In Caucasian AA genotype patients with asthma enrolled in SARP III, baseline prebronchodilator FEV1PP (Pre-BD FEV1PP) (A) and postbronchodilator FEV1PP (Post-BD FEV1PP) (B) is lower for those in the GC vs. no GC treatment groups. In contrast, for the CC genotype, there is no difference between GC and no GC treatment groups. Lower Pre-BD FEV1PP (C) and Post-BD FEV1PP (D) for AA genotype patients receiving GC also occurs in Caucasian patients with severe asthma enrolled in SARP I&II. Error bars indicate SEs.
Fig. 3.
Fig. 3.
A model that explains physiologic effects of HSD3B1 inheritance on FEV1PP in patients with severe asthma. GC treatment suppresses adrenal DHEA, which may become a limiting substrate for 3β-HSD1, depending on HSD3B1 genotype. Adrenal permissive and adrenal restrictive alleles enable and limit metabolic flux through 3β-HSD1 and recovery of airflow.

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