genotype identifies glucocorticoid responsiveness in severe asthma.

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. 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 (1245A) allele limits conversion, whereas the adrenal permissive (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 (FEVPP). (1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEVPP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined ( = 318). Validation was performed in a second cohort (SARP I&II; = 184). DHEA-sulfate is associated with FEVPP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEVPP compared with noGC patients (54.3% vs. 75.1%; < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEVPP difference in GC vs. noGC patients (73.4% vs. 78.9%; = 0.39). Results were independently confirmed: FEVPP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 ( < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 ( = 0.92). The adrenal restrictive (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.