ESPEYB17 8. Adrenals New Hope (3 abstracts)
8.12. HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma
Zein J , Gaston B , Bazeley P , DeBoer MD , Igo RP Jr , 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
To read the full abstract: Proc Natl Acad Sci U S A. 2020; 117(4): 2187–2193. PMID: 31932420.
Since their discovery ~70 years ago, glucocorticoids (GC) have been widely used to elicit a systemic anti-inflammatory response, and currently play a major role in the treatment of asthma and other inflammatory diseases (1). However, unresponsiveness to GC in some individuals is a major limitation in the treatment of asthma, and the mechanisms underlying this clinical entity are not fully elucidated (1). Indeed, severe asthma is generally defined as asthma that remains symptomatic despite high-dose inhaled GC and/or systemic GC therapy. GCs inhibit production of adrenal androgens, which may have potential benefits in asthma. The enzyme 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1) catalyzes the peripheral conversion of adrenal dehydroepiandrosterone (DHEA) to more potent androgens. At a missense polymorphism in its gene HSD3B1, the 1245A restrictive allele limits DHEA metabolism to potent androgens, whereas the 1245C permissive allele increases conversion. The 1245A restrictive genotype is associated with GC resistance, and this effect appears to be driven by GC suppression of 3β-HSD1 substrate (2). In population studies, animal models and cell culture experiments, androgens are associated with several benefits in asthma, however, the role of GC-induced androgen suppression in the pathophysiology of severe, GC-resistant asthma in humans is not established (3, 4).
In this retrospective cohort study (n =318), Zein et al. tested the hypothesis that the restrictive HSD3B1 allele that limits DHEA-S conversion to potent androgens impairs pulmonary function specifically when GC treatment suppresses adrenal DHEA-S production, limiting substrate availability for 3β-HSD1 and possibly providing a mechanistic explanation for GC-resistant severe asthma. In the Severe Asthma Research Program (SARP) III cohort, they tested the association between DHEA-S and percentage predicted forced expiratory volume in 1 s (FEV1PP). DHEA-S levels were positively associated with FEV1PP, and these levels were suppressed on those with GC treatment. Among homozygotes for the HSD3B1 (1245A) restrictive genotype, GC patients had lower FEV1PP than noGC patients (54.3% vs. 75.1%; P< 0.001). Among homozygotes for the HSD3B1 (1245C) permissive genotype, there was no difference in FEV1PP between GC vs. noGC patients (73.4% vs. 78.9%; P =0.39). The adrenal restrictive HSD3B1(1245C) genotype was associated with GC resistance and this effect appeared to be driven by GC suppression of 3β-HSD1 substrate.
These data suggest the possibility that HSD3B1 genotype is predictive of which patients might benefit from systemic GC therapy and, for those who are resistant, who might benefit from androgen replacement in severe asthma. Furthermore, this study provides evidence that implicate an androgen synthesis variant in GC-resistance in asthma. In addition, it demonstrates an adverse consequence of adrenal androgen suppression with GC therapy, showing a positive relationship between circulating adrenal DHEA-S levels and lung function. These data, although limited by the inclusion only of Caucasian patients, provide a potential mechanism for the gender and pubertal maturation differences observed in asthma or other inflammatory diseases (5, 6).
References:
1. Barnes PJ, Adcock IM, Glucocorticoid resistance in inflammatory diseases. Lancet 2009; 373; 1905–1917.
2. Sabharwal N, Sharifi N. HSD3B1 genotypes conferring adrenal-restrictive and adrenal-permissive phenotypes in prostate cancer and beyond. Endocrinology. 2019; 160(9): 2180–2188.1. Hazeldine J, Arlt W, Lord JM. Dehydroepiandrosterone as a regulator of immune cell function. J. Steroid Biochem. Mol. Biol. 2010; 120(2–3): 127–36.
3. Marozkina N, Zein J, DeBoer MD, Logan L, Veri L, Ross K, Gaston B. Dehydroepiandrosterone supplementation may benefit women with asthma who have low androgen levels: A pilot study. Pulm. Ther. 2019; 5(2): 213–220.
4. Teague WG, Phillips BR, Fahy JV, Wenzel SE, Fitzpatrick AM, Moore WC, Hastie AT, Bleecker ER, Meyers DA, Peters SP, Castro M, Coverstone AM, Bacharier LB, Ly NP, Peters MC, Denlinger LC, Ramratnam S, Sorkness RL, Gaston BM, Erzurum SC, Comhair SAA, Myers RE, Zein J, DeBoer MD, Irani AM, Israel E, Levy B, Cardet JC, Phipatanakul W, Gaffin JM, Holguin F, Fajt ML, Aujla SJ, Mauger DT, Jarjour NN. Baseline features of the severe asthma research program (SARP III) cohort: Differences with age. J. Allergy Clin. Immunol. Pract. 2018; 6(2): 545–554.e4.
5. Becklake MR, Kauffmann F. Gender differences in airway behaviour over the human life span. 1999; 54(12): 1119–38.
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