HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma

Le résumé fourni par la source

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).

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