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 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 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.

中文翻译：

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HSD3B1基因型可识别严重哮喘中的糖皮质激素反应性。

病因不明，哮喘对糖皮质激素治疗的抵抗力是主要的健康问题。糖皮质激素抑制肾上腺雄激素的产生。但是，雄激素对哮喘有潜在的益处。HSD3B1编码3β-羟基类固醇脱氢酶-1（3β-HSD1），催化从肾上腺脱氢表雄酮（DHEA）到强效雄激素的外周转化，并具有种系错义编码多态性。肾上腺限制性HSD3B1（1245A）等位基因限制了转化，而肾上腺容许性HSD3B1（1245C）等位基因则将DHEA代谢增加为有效的雄激素。在严重哮喘研究计划（SARP）III队列中，我们确定了DHEA-硫酸盐与1秒钟内预测的强制呼气量百分比（FEV1PP）之间的关联。评估了HSD3B1（1245）基因型，并确定每日（口服）糖皮质激素治疗（GC）和不口服（NOGC）患者的肾上腺限制性和肾上腺容许性等位基因与FEV1PP之间的相关性（n = 318）。在第二个队列中进行验证（SARP I＆II； n = 184）。DHEA-硫酸盐与FEV1PP有关，并通过GC处理被抑制。纯肾上腺限制性基因型的GC患者FEV1PP低于noGC患者（54.3％vs. 75.1％； P <0.001）。在具有纯合子肾上腺容许基因型的患者中，GC与noGC患者之间没有FEV1PP差异（73.4％对78.9％； P = 0.39）。结果独立确认：GC与noGC的纯合子肾上腺限制性基因型的FEV1PP为49.8 vs. 63.4（P <0.001），而纯合子肾上腺容许基因型的FEV1PP为66.7 vs. 67.7（P = 0.92）。肾上腺限制性HSD3B1（1245）基因型与GC耐药性相关。这种作用似乎是由GC抑制3β-HSD1底物引起的。我们的结果提示了预测GC耐药性和药物干预的机会。