Browsing by Author "Bleecker, Eugene R."
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Item 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 HealthRationale: 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.Item CCL5 is a Potential Bridge Between Type-1 and Type-2 Inflammation in Asthma(Elsevier, 2023) Gauthier, Marc; Kale, Sagar Laxman; Oriss, Timothy B.; Gorry, Michael; Ramonell, Richard P.; Dalton, Kathryn; Ray, Prabir; Fahy, John V.; Seibold, Max A.; Castro, Mario; Jarjour, Nizar; Gaston, Benjamin; Bleecker, Eugene R.; Meyers, Deborah A.; Moore, Wendy; Hastie, Annette T.; Israel, Elliot; Levy, Bruce D.; Mauger, David; Erzurum, Serpil; Comhair, Suzy A.; Wenzel, Sally E.; Ray, Anuradha; Pediatrics, School of MedicineBackground: Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation. Methods: CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model. Results: Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation. Conclusion: CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.Item Comparison of whole genome sequencing and targeted sequencing for mitochondrial DNA(Elsevier, 2021) Chen, Ruoying; Aldred, Micheala A.; Xu, Weiling; Zein, Joe; Bazeley, Peter; Comhai, Suzy A. A.; Meyers, Deborah A.; Bleecker, Eugene R.; Liu, Chunyu; Erzurum, Serpil C.; Hu, Bo; NHLBI Severe Asthma Research Program (SARP); Medicine, School of MedicineMitochondrial dysfunction has emerged to be associated with a broad spectrum of diseases, and there is an increasing demand for accurate detection of mitochondrial DNA (mtDNA) variants. Whole genome sequencing (WGS) has been the dominant sequencing approach to identify genetic variants in recent decades, but most studies focus on variants on the nuclear genome. Whole genome sequencing is also costly and time consuming. Sequencing specifically targeted for mtDNA is commonly used in the diagnostic settings and has lower costs. However, there is a lack of pairwise comparisons between these two sequencing approaches for calling mtDNA variants on a population basis. In this study, we compared WGS and mtDNA-targeted sequencing (targeted-seq) in analyzing mitochondrial DNA from 1499 participants recruited into the Severe Asthma Research Program (SARP). Our study reveals that targeted-sequencing and WGS have comparable capacity to determine genotypes and to call haplogroups and homoplasmies on mtDNA. However, there exists a large variability in calling heteroplasmies, especially for low-frequency heteroplasmies, which indicates that investigators should be cautious about heteroplasmies acquired from different sequencing methods. Further research is highly desired to improve variant detection methods for mitochondrial DNA.Item Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways(Elsevier, 2020) Li, Xingnan; Christenson, Stephanie A.; Modena, Brian; Li, Huashi; Busse, William W.; Castro, Mario; Denlinger, Loren C.; Erzurum, Serpil C.; Fahy, John V.; Gaston, Benjamin; Hastie, Annette T.; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce D.; Moore, Wendy C.; Woodruff, Prescott G.; Kaminski, Naftali; Wenzel, Sally E.; Bleecker, Eugene R.; Meyers, Deborah A.; Pediatrics, School of MedicineBackground The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium. Objectives We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program. Methods Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed. Results Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10−9 < P < 1.8 × 10−4). Higher expression levels of GSDMB correlated with asthma and greater number of exacerbations (P < .05). Expression levels of GSDMB correlated with genes involved in IFN signaling, MHC class I antigen presentation, and immune system pathways (false-discovery rate–adjusted P < .05). rs1031458 and rs3902920 in GSDMB colocalized with IFN regulatory factor binding sites and associated with GSDMB expression, asthma severity, and asthma exacerbations (P < .05). Conclusions By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity.Item 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 MedicineAsthma 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.Item Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations(medRxiv, 2023-12-05) Xu, Weiling; Hong, Yun Soo; Hu, Bo; Comhair, Suzy A. A.; Janocha, Allison J.; Zein, Joe G.; Chen, Ruoying; Meyers, Deborah A.; Mauger, David T.; Ortega, Victor E.; Bleecker, Eugene R.; Castro, Mario; Denlinger, Loren C.; Fahy, John V.; Israel, Elliot; Levy, Bruce D.; Jarjour, Nizar N.; Moore, Wendy C.; Wenzel, Sally E.; Gaston, Benjamin; Liu, Chunyu; Arking, Dan E.; Erzurum, Serpil C.; National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) and TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Pediatrics, School of MedicineRationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation. Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations. Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations. Measures and main results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007). Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.Item PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment(Elsevier, 2021) Israel, Elliot; Denlinger, Loren C.; Bacharier, Leonard B.; LaVange, Lisa M.; Moore, Wendy C.; Peters, Michael C.; Georas, Steve N.; Wright, Rosalind J.; Mauger, David T.; Noel, Patricia; Akuthota, Praveen; Bach, Julia; Bleecker, Eugene R.; Cardet, Juan Carlos; Carr, Tara F.; Castro, Mario; Cinelli, Angeles; Comhair, Suzy A.A.; Covar, Ronina A.; Alexander, Laura Crotty; DiMango, Emily A.; Erzurum, Serpil C.; Fahy, John V.; Fajt, Merritt L.; Gaston, Benjamin M.; Hoffman, Eric A.; Holguin, Fernando; Jackson, Daniel J.; Jain, Sonia; Jarjour, Nizar N.; Ji, Yuan; Kenyon, Nicholas J.; Kosorok, Michael R.; Kraft, Monica; Krishnan, Jerry A.; Kumar, Rajesh; Liu, Andrew H.; Liu, Mark C.; Ly, Ngoc P.; Marquis, M. Alison; Martinez, Fernando D.; Moy, James N.; O’Neal, Wanda K.; Ortega, Victor E.; Peden, David B.; Phipatanakul, Wanda; Ross, Kristie; Smith, Lewis J.; Szefler, Stanley J.; Teague, W. Gerald; Tulchinsky, Abigail F.; Vijayanand, Pandurangan; Wechsler, Michael E.; Wenzel, Sally E.; White, Steven R.; Zeki, Amir A.; Ivanova, Anastasia; Pediatrics, School of MedicineSevere asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.Item Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma(American Thoracic Society, 2021) Denlinger, Loren C.; Phillips, Brenda R.; Sorkness, Ronald L.; Bleecker, Eugene R.; Castro, Mario; DeBoer, Mark D.; Fitzpatrick, Anne M.; Hastie, Annette T.; Gaffin, Jonathan M.; Moore, Wendy C.; Peters, Michael C.; Peters, Stephen P.; Phipatanakul, Wanda; Cardet, Juan Carlos; Erzurum, Serpil C.; Fahy, John V.; Fajt, Merritt L.; Gaston, Benjamin; Levy, Bruce D.; Meyers, Deborah A.; Ross, Kristie; Teague, W. Gerald; Wenzel, Sally E.; Woodruff, Prescott G.; Zein, Joe; Jarjour, Nizar N.; Mauger, David T.; Israel, Elliot; Pediatrics, School of MedicineRationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function. Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline. Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant’s post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5–2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline. Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3–1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index. Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.Item Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk(American Physiological Society, 2022) Wang, Zeneng; Xu, Weiling; Comhair, Suzy A. A.; Fu, Xiaoming; Shao, Zhili; Bearden, Rebecca; Zein, Joe G.; Bleecker, Eugene R.; Castro, Mario; Denlinger, Loren C.; Fahy, John V.; Israel, Elliot; Levy, Bruce D.; Jarjour, Nizar N.; Moore, Wendy C.; Wenzel, Sally E.; Mauger, David T.; Gaston, Benjamin; Hazen, Stanley L.; Erzurum, Serpil C.; Pediatrics, School of MedicineAsthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe (n = 253) and nonsevere (n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood (r2 = 0.038) or sputum eosinophils (r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.Item Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk(American Physiological Society, 2022-11) Wang, Zeneng; Xu, Weiling; Comhair, Suzy A. A.; Fu, Xiaoming; Shao, Zhili; Bearden, Rebecca; Zein, Joe G.; Bleecker, Eugene R.; Castro, Mario; Denlinger, Loren C.; Fahy, John V.; Israel, Elliot; Levy, Bruce D.; Jarjour, Nizar N.; Moore, Wendy C.; Wenzel, Sally E.; Mauger, David T.; Gaston, Benjamin; Hazen, Stanley L.; Erzurum, Serpil C.; Pediatrics, School of MedicineAsthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe (n = 253) and nonsevere (n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood (r2 = 0.038) or sputum eosinophils (r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.