HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

Joe Zein; Benjamin Gaston; Peter Bazeley; Mark D. DeBoer; Robert P. Igo; 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

doi:10.1073/pnas.1918819117

HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

Joe Zein, Benjamin Gaston, Peter Bazeley, Mark D. DeBoer, Robert P. Igo, 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. FahyAnne 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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2187-2193
Number of pages	7
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	4
DOIs	https://doi.org/10.1073/pnas.1918819117
State	Published - Jan 28 2020

Keywords

Androgens
Glucocorticoids
HSD3B1
Inflammation
Steroids

ASJC Scopus subject areas

General

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10.1073/pnas.1918819117

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Zein, J., Gaston, B., Bazeley, P., DeBoer, M. D., Igo, R. P., Bleecker, E. R., Meyers, D., Comhair, S., Marozkina, N. V., Cotton, C., Patel, M., Alyamani, M., Xu, W., Busse, W. W., Calhoun, W. J., Ortega, V., Hawkins, G. A., Castro, M., Chung, K. F., ... Sharifi, N. (2020). HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma. Proceedings of the National Academy of Sciences of the United States of America, 117(4), 2187-2193. https://doi.org/10.1073/pnas.1918819117

Zein, J, Gaston, B, Bazeley, P, DeBoer, MD, Igo, RP, Bleecker, ER, Meyers, D, Comhair, S, Marozkina, NV, Cotton, C, Patel, M, Alyamani, M, Xu, W, Busse, WW, Calhoun, WJ, Ortega, V, Hawkins, GA, Castro, M, Chung, KF, Fahy, JV, Fitzpatrick, AM, Israel, E, Jarjour, NN, Levy, B, Mauger, DT, Moore, WC, Noel, P, Peters, SP, Teague, WG, Wenzel, SE, Erzurum, SC & Sharifi, N 2020, 'HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 4, pp. 2187-2193. https://doi.org/10.1073/pnas.1918819117

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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",

year = "2020",

month = jan,

day = "28",

doi = "10.1073/pnas.1918819117",

language = "English (US)",

volume = "117",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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T1 - HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

AU - Zein, Joe

AU - Gaston, Benjamin

AU - Bazeley, Peter

AU - DeBoer, Mark D.

AU - Igo, Robert P.

AU - Bleecker, Eugene R.

AU - Meyers, Deborah

AU - Comhair, Suzy

AU - Marozkina, Nadzeya V.

AU - Cotton, Calvin

AU - Patel, Mona

AU - Alyamani, Mohammad

AU - Xu, Weiling

AU - Busse, William W.

AU - Calhoun, William J.

AU - Ortega, Victor

AU - Hawkins, Gregory A.

AU - Castro, Mario

AU - Chung, Kian Fan

AU - Fahy, John V.

AU - Fitzpatrick, Anne M.

AU - Israel, Elliot

AU - Jarjour, Nizar N.

AU - Levy, Bruce

AU - Mauger, David T.

AU - Moore, Wendy C.

AU - Noel, Patricia

AU - Peters, Stephen P.

AU - Teague, W. Gerald

AU - Wenzel, Sally E.

AU - Erzurum, Serpil C.

AU - Sharifi, Nima

PY - 2020/1/28

Y1 - 2020/1/28

N2 - 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.

AB - 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.

KW - Androgens

KW - Glucocorticoids

KW - HSD3B1

KW - Inflammation

KW - Steroids

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JF - Proceedings of the National Academy of Sciences of the United States of America

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HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

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