<i>HSD3B1</i> 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. <i>HSD3B1</i> 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 <i>HSD3B1</i>(1245A) allele limits conversion, whereas the adrenal permissive <i>HSD3B1</i>(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). <i>HSD3B1</i>(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 (<i>n</i> = 318). Validation was performed in a second cohort (SARP I&II; <i>n</i> = 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%; <i>P</i> < 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%; <i>P</i> = 0.39). Results were independently confirmed: FEV₁PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (<i>P</i> < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (<i>P</i> = 0.92). The adrenal restrictive <i>HSD3B1</i>(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.