Browsing by Author "Chung, Kian Fan"

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    Benefits of Airway Androgen Receptor Expression in Human Asthma
    (American Thoracic Society, 2021) Zein, Joe G.; McManus, Jeffrey M.; Sharifi, Nima; Erzurum, Serpil C.; Marozkina, Nadzeya; Lahm, Timothy; Giddings, Olivia; Davis, Michael D.; DeBoer, Mark D.; Comhair, Suzy A.; Bazeley, Peter; Kim, Hyun Jo; Busse, William; Calhoun, William; Castro, Mario; Chung, Kian Fan; Fahy, John V.; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce D.; Mauger, David T.; Moore, Wendy C.; Ortega, Victor E.; Peters, Michael; Bleecker, Eugene R.; Meyers, Deborah A.; Zhao, Yi; Wenzel, Sally E.; Gaston, Benjamin; Biostatistics, School of Public Health
    Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways. Objectives: To measure whether AR and its ligands are associated with human asthma outcomes. Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men. Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.
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    HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma
    (National Academy of Sciences, 2020-01-28) Zein, Joe; Gaston, Benjamin; Bazeley, Peter; DeBoer, Mark D.; Igo, Robert P., Jr; Bleecker, Eugene R.; Meyers, Deborah; Comhair, Suzy; Marozkina, Nadzeya V.; Cotton, Calvin; Patel, Mona; Alyamani, Mohammad; Xu, Weiling; Busse, William W.; Calhoun, William J.; Ortega, Victor; Hawkins, Gregory A.; Castro, Mario; Chung, Kian Fan; Fahy, John V.; Fitzpatrick, Anne M.; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce; Mauger, David T.; Moore, Wendy C.; Noel, Patricia; Peters, Stephen P.; Teague, W. Gerald; Wenzel, Sally E.; Erzurum, Serpil C.; Sharifi, Nima; Medicine, School of Medicine
    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.