期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 4, 页码 2187-2193出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1918819117
关键词
steroids; glucocorticoids; inflammation; androgens; HSD3B1
资金
- National Heart, Lung, and Blood Institute Severe Asthma Research Program [U10 HL109250, P01 HL128192, P01 HL101871, RO1 HL69170, K08 HL133381, P01 HL103453, P01 HL081064, R01CA172382, R01CA190289, R01 CA236780]
- National Heart, Lung, and Blood Institute Severe Asthma Research Program (Prostate Cancer Foundation)
- Harrington Discovery Institute of University Hospitals, Cleveland
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 beta-hydroxysteroid dehydrogenase-1 (3 beta-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD38/(1245A) allele limits conversion, whereas the adrenal permissive HSD38/(12450 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 3 beta-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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