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 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.

Inheritance of a common androgen synthesis variant allele is associated with female COVID susceptibility in UK Biobank

“…It was recently shown in a large, randomized trial that treatment with the glucocorticoid dexamethasone strongly reduced mortality in COVID patients on ventilation but not in patients receiving no respiratory support 33 . Taken together with the findings we report here and our previous finding that HSD3B1 genotype affects response to glucocorticoid treatment in asthma with the adrenal-permissive 1245C allele associated with reduced airway inflammation 11 , this raises the question of whether HSD3B1 genotype could affect response to dexamethasone in COVID patients. The differential effects of dexamethasone in patients who were or were not receiving respiratory support also highlights how the results of steroid-induced immune suppression could be context-dependent: immune suppression could make it harder to ward off an initial infection, but could be beneficial in a patient with an advanced infection and out-of-control inflammatory response.…”

“…The enzyme 3β-hydroxysteroid dehydrogenase isotype 1 (3βHSD1) catalyzes a critical and rate-limiting step in the pathway to production in peripheral tissues of the potent androgens testosterone and dihydrotestosterone (DHT) from adrenally produced precursors dehydroepiandrosterone (DHEA) and its sulfated form DHEA-S 10 . The adrenal-permissive form of the gene for 3βHSD1, HSD3B1(1245C), that was originally linked to faster prostate cancer progression in the face of androgen deprivation therapy (i.e., medical castration) because of adrenally derived androgen synthesis [16][17][18][19][20][21] , has more recently been shown to also affect the response to oral glucocorticoid treatment in patients with severe asthma 11 . The 1245C, or adrenal-permissive allele, encodes a form of the enzyme that is resistant to ubiquitination and degradation, thus leading to increased production of potent androgens from adrenal precursors.…”

“…By contrast, the 1245A, or adrenal-restrictive allele, encodes a more rapidly degraded form of the enzyme, leading to less production of potent androgens 22 . A side effect of glucocorticoid treatment is suppression of circulating DHEA and DHEA-S levels 11 . Active androgens (i.e., potent agonists of the androgen receptor) testosterone and DHT are thought to downregulate immune/inflammatory responses 9 .…”

“…Here we show an association between inheritance of the common adrenal-permissive missense-encoding variant HSD3B1 (1245C), that enables androgen synthesis from adrenal precursors 10 , and susceptibility to COVID. The adrenal-permissive HSD3B1(1245C) has previously been linked to suppression of inflammation in severe asthma 11 . In analysis of COVID test results from the UK Biobank, we show that in older (≥ 70 years of age) subjects, the adrenal-permissive variant is associated with a greater chance of being COVID-positive.…”

Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2

“…harbors an AR-responsive enhancer that is induced by male gonadal hormones in prostate tissue (Wang et al, 2007), raising the possibility of a similar mode of regulation in the respiratory system. Furthermore, certain pulmonary disease process outcomes, including asthma, are sex steroid associated (Zein et al, 2020). Therefore, we sought to investigate whether male sex was associated with higher expression of TMPRSS2 or AR in human lung.…”