13 results on '"Eugene Bleecker"'
Search Results
2. Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program
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Xiaowei Hu, Dandi Qiao, Wonji Kim, Matthew Moll, Pallavi P. Balte, Leslie A. Lange, Traci M. Bartz, Rajesh Kumar, Xingnan Li, Bing Yu, Brian E. Cade, Cecelia A. Laurie, Tamar Sofer, Ingo Ruczinski, Deborah A. Nickerson, Donna M. Muzny, Ginger A. Metcalf, Harshavardhan Doddapaneni, Stacy Gabriel, Namrata Gupta, Shannon Dugan-Perez, L. Adrienne Cupples, Laura R. Loehr, Deepti Jain, Jerome I. Rotter, James G. Wilson, Bruce M. Psaty, Myriam Fornage, Alanna C. Morrison, Ramachandran S. Vasan, George Washko, Stephen S. Rich, George T. O’Connor, Eugene Bleecker, Robert C. Kaplan, Ravi Kalhan, Susan Redline, Sina A. Gharib, Deborah Meyers, Victor Ortega, Josée Dupuis, Stephanie J. London, Tuuli Lappalainen, Elizabeth C. Oelsner, Edwin K. Silverman, R. Graham Barr, Timothy A. Thornton, Heather E. Wheeler, Michael H. Cho, Hae Kyung Im, and Ani Manichaikul
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Pulmonary Disease, Chronic Obstructive ,Risk Factors ,Genetics ,Humans ,National Heart, Lung, and Blood Institute (U.S.) ,Transcriptome ,Lung ,Article ,United States ,Genetics (clinical) - Abstract
While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV(1)] and its ratio to forced vital capacity [FEV(1)/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV(1) and FEV(1)/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08–1.43] for PTRS versus 1.10 [0.96–1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p
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- 2022
3. Novel Privacy Considerations for Large Scale Proteomics
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Andrew C. Hill, Elizabeth M. Litkowski, Ani Manichaikul, Bing Yu, Betty A. Gorbet, Leslie Lange, Katherine A. Pratte, Katerina J. Kechris, Matthew DeCamp, Marilyn Coors, Victor E. Ortega, Stephen S. Rich, Jerome I. Rotter, Robert E. Gerzsten, Clary B. Clish, Jeffrey Curtis, Xiaowei Hu, Debby Ngo, Wanda K. O'Neal, Deborah Meyers, Eugene Bleecker, Brian D. Hobbs, Michael H. Cho, Farnoush Banaei-Kashani, Claire Guo, and Russell Bowler
- Abstract
Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to match proteomes to genomes for 2,812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We were able to correctly match 90%-95% of proteomes to their correct genome and for 95%-99% we could match the proteome to the 1% most likely genome. The accuracy of matching in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. When serial proteomes are available, the matching algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1,000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable.
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- 2022
4. DNA Sequencing Analysis of Cystic Fibrosis Transmembrane Regulator Gene Identifies Cystic Fibrosis-Associated Variants in the Severe Asthma Research Program
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Manuel E. Izquierdo, Chad R. Marion, Wendy Moore, Karen Raraigh, Jennifer Taylor-Cousar L, Gary Cutting, E. Ampleford, Gregory A. Hawkins, Joe Zein, Mario Castro, Loren C. Denlinger, Serpil Erzurum, John Fahy, Elliot Israel, Nizar Jarjour, David Mauger, Bruce D. Levy, Sally Wenzel, Prescott Woodruff, Eugene Bleecker, Deborah A. Meyers, and Victor E. Ortega
- Abstract
Background: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods: We analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare CFTR variants (frequencyCFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.
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- 2022
5. Novel Privacy Considerations for Large Scale Proteomics
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Andrew C. Hill, Elizabeth M. Litkowski, Ani Manichaikul, Leslie Lange, Katherine A. Pratte, Katerina J. Kechris, Matthew DeCamp, Marilyn Coors, Victor E. Ortega, Stephen S. Rich, Jerome I. Rotter, Robert E. Gerzsten, Clary B. Clish, Jeffery Curtis, Xiaowei Hu, Debby Ngo, Wanda K O’Neal, Deborah Meyers, Eugene Bleecker, Brian D. Hobbs, Michael H. Cho, Farnoush Banaeikashani, and Russell P. Bowler
- Abstract
IntroductionPrivacy protection is a core principle of genomic research but needs further refinement for high-throughput proteomic platforms.MethodsWe identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS) and then calculated genotype probabilities by protein level for each protein-genotype combination (training). Using the most significant 100 proteins, we applied a naïve Bayesian approach to match proteomes to genomes for 2,812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA) with SomaScan 1.3K proteomes and also 2,646 COPDGene subjects with SomaScan 5K proteomes (testing). We tested whether subtracting mean genotype effect for each pQTL SNP would obscure genetic identity.ResultsIn the four testing cohorts, we were able to correctly match 90%-95% their proteomes to their correct genome and for 95%-99% we could match the proteome to the 1% most likely genome. With larger profiling (SomaScan 5K), correct identification was > 99%. The accuracy of matching in subjects with African ancestry was lower (∼60%) unless training included diverse subjects. Mean genotype effect adjustment reduced identification accuracy nearly to random guess.ConclusionLarge proteomic datasets (> 1,000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered deidentified. These findings suggest that large scale proteomic data be given privacy protections of genomic data, or that bioinformatic transformations (such as adjustment for genotype effect) should be applied to obfuscate identity.
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- 2022
6. Estimated Ventricular Size, Asthma Severity, and Exacerbations
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Samuel Y. Ash, Gonzalo Vegas Sanchez-Ferrero, Mark L. Schiebler, Farbod N. Rahaghi, Ashish Rai, Carolyn E. Come, James C. Ross, Alysha G. Colon, Juan Carlos Cardet, Eugene R. Bleecker, Mario Castro, John V. Fahy, Sean B. Fain, Benjamin M. Gaston, Eric A. Hoffman, Nizar N. Jarjour, Jason K. Lempel, David T. Mauger, Matthew C. Tattersall, Sally E. Wenzel, Bruce D. Levy, George R. Washko, Elliot Israel, Raul San Jose Estepar, Bruce Levy, George Washko, Manuela Cernadas, Wanda Phipatanakul, Sally Wenzel, Merritt Fajt, Benjamin Gaston, James Chmiel, W. Gerald Teague, Anne-Marie Irani, Serpil Erzurum, Sumita Khatri, Suzy Comhair, Raed Dweik, Kristie Ross, Ross Myers, Wendy Moore, Deborah Meyers, Eugene Bleecker, Stephen Peters, Annette Hastie, Victor Ortega, Greg Hawkins, Xingan Li, Anne Fitzpatrick, Nazar Jarjour, Loren Denlinger, Sean Fain, Ronald Sorkness, Leonard Bacharier, David Gierada, Kenneth Schechtman, Jason Woods, John Fahy, Prescott Woodruff, Ngoc Ly, and David Mauger
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Pulmonary and Respiratory Medicine ,COPD ,medicine.medical_specialty ,Aorta ,Exacerbation ,business.industry ,Critical Care and Intensive Care Medicine ,medicine.disease ,Cystic fibrosis ,respiratory tract diseases ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,medicine.artery ,Internal medicine ,Cohort ,Pulmonary artery ,medicine ,Cardiology ,030212 general & internal medicine ,Respiratory system ,Cardiology and Cardiovascular Medicine ,business ,Asthma - Abstract
Background Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size. Methods We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression. Results Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m2 smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m2 smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations. Conclusions In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations. Trial Registry ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov
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- 2020
7. Clinical and molecular implications of RGS2 promoter genetic variation in severe asthma
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Juan Carlos Cardet, Donghwa Kim, Eugene Bleecker, Thomas Casale, Elliot Israel, David Mauger, Deborah Meyers, Yaping Tu, Stephen Liggett, and Victor Ortega
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Immunology ,Immunology and Allergy - Published
- 2022
8. Imaging-based clusters in former smokers of the COPD cohort associate with clinical characteristics: the SubPopulations and intermediate outcome measures in COPD study (SPIROMICS)
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Babak Haghighi, Sanghun Choi, Jiwoong Choi, Eric A. Hoffman, Alejandro P. Comellas, John D. Newell, Chang Hyun Lee, R. Graham Barr, Eugene Bleecker, Christopher B. Cooper, David Couper, Mei Lan Han, Nadia N. Hansel, Richard E. Kanner, Ella A. Kazerooni, Eric A. C. Kleerup, Fernando J. Martinez, Wanda O’Neal, Robert Paine, Stephen I. Rennard, Benjamin M. Smith, Prescott G. Woodruff, and Ching-Long Lin
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Male ,medicine.medical_specialty ,Asymptomatic ,030218 nuclear medicine & medical imaging ,Cohort Studies ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,Imaging, Three-Dimensional ,0302 clinical medicine ,Forced Expiratory Volume ,Internal medicine ,Outcome Assessment, Health Care ,Imaging-based cluster analysis ,Humans ,COPD ,Medicine ,Expiration ,Aged ,Emphysema ,lcsh:RC705-779 ,Lung ,business.industry ,Research ,Smoking ,Functional small airway disease ,lcsh:Diseases of the respiratory system ,Middle Aged ,respiratory system ,Former Smoker ,medicine.disease ,respiratory tract diseases ,Cross-Sectional Studies ,medicine.anatomical_structure ,030228 respiratory system ,Cohort ,Cardiology ,Breathing ,Female ,medicine.symptom ,Tomography, X-Ray Computed ,Former smokers ,business ,Airway - Abstract
Background Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping. Methods An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration. Results We derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema. Conclusions QCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes. Electronic supplementary material The online version of this article (10.1186/s12931-019-1121-z) contains supplementary material, which is available to authorized users.
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- 2019
9. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial
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Gary T Ferguson, J Mark FitzGerald, Eugene R Bleecker, Michel Laviolette, David Bernstein, Craig LaForce, Lyndon Mansfield, Peter Barker, Yanping Wu, Maria Jison, Mitchell Goldman, Guy Chouinard, Maryam Rostami, Jean Oosthuizen, Bonavuth Pek, Deepen Patel, Pierre-Alain Houle, Sohail Khattak, Patrick Killorn, Claus Keller, Isabelle Schenkenberger, Stefan Zielen, Sabine Ballenberger, Martin Hoffmann, Joachim Kirschner, Márta Papp, Teréz Kecskés, Magdolna Póczi, Lajos Molnár, Éva Radeczky, Judit Schlezák, Ewa Springer, Violetta Balicka, Jadwiga Kaczmarek, Danuta Madra-Rogacka, Ewa Pisarczyk-Bogacka, Malgorzata Zurowska-Gebala, Maciej Marczak, Piotr Napora, Witold Pomiecko, Erika Pribulova, Svetlana Kurthova, Maria Drugdova, Denisa Kavkova, Luboslava Frajtova, Alexander Golubov, Dagmar Paulinyova, Daniela Hasicova, Miriam Michalickova, Miguel Trevino, Charles Campbell, Andrew Wachtel, Eugene Bleecker, Selwyn Spangenthal, Edward Kerwin, Paul Ratner, Samir Arora, Gregory Feldman, Benedict Okwara, Humberto Cruz, Lawrence Sher, Andrew Pedinoff, and Clinton Corder
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Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Injections, Subcutaneous ,Population ,Placebo ,Antibodies, Monoclonal, Humanized ,Severity of Illness Index ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,Forced Expiratory Volume ,Severity of illness ,medicine ,Clinical endpoint ,Humans ,030212 general & internal medicine ,Anti-Asthmatic Agents ,Pulmonary Eosinophilia ,education ,Asthma ,Aged ,education.field_of_study ,Biological Products ,Intention-to-treat analysis ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,Benralizumab ,medicine.disease ,Bronchodilator Agents ,030228 respiratory system ,chemistry ,Chronic Disease ,Disease Progression ,Female ,business - Abstract
Summary Background Benralizumab is a humanised, anti-interleukin 5 receptor α monoclonal antibody that directly and rapidly depletes eosinophils, reduces asthma exacerbations, and improves lung function for patients with severe eosinophilic asthma. The objective of this trial was to assess the safety and efficacy of benralizumab for patients with mild to moderate, persistent asthma. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients aged 18–75 years, weighing at least 40 kg, and with a postbronchodilator reversibility in forced expiratory volume in 1 s (FEV 1 ) of at least 12% at screening, from 52 clinical research centres in six countries. Patients must have been receiving either low- to medium-dosage inhaled corticosteroids (ICS) or low-dosage ICS plus long-acting β 2 agonist fixed-combination therapy at screening, had a morning prebronchodilator FEV 1 of more than 50% to 90% predicted at screening, and had one or more of the following symptoms within the 7 days before randomisation: a daytime or night-time asthma symptom score of at least 1 for at least 2 days, rescue short-acting β 2 agonist use for at least 2 days, or night-time awakenings due to asthma for at least one night. We converted patients' ICS treatments to 180 μg or 200 μg budesonide dry powder inhaler twice daily for the entire duration of the study using the approved dosages in the patients' respective countries and randomly allocated them (1:1; stratified by blood eosinophil count [ vs ≥300 cells per μL] and region [USA vs the rest of the world]) with an interactive web-based voice response system to receive subcutaneous placebo or benralizumab 30 mg injections every 4 weeks for 12 weeks. All patients and investigators involved in patient treatment or clinical assessment and those assessing outcomes were masked to treatment allocation. The primary endpoint was change from baseline prebronchodilator FEV 1 at week 12. Efficacy analyses used an intention to treat approach. This trial is registered with ClinicalTrials.gov, number NCT02322775. Findings Between Feb 2, 2015, and April 24, 2015, we enrolled 351 patients, with 211 (60%) randomly assigned (105 [50%] to placebo and 106 [50%] to benralizumab). Benralizumab resulted in an 80 mL (95% CI 0–150; p=0·04) greater improvement (least-squares mean difference) in prebronchodilator FEV 1 after 12 weeks than did placebo (placebo group: 2246 mL [SD 768] at baseline vs 2261 mL [796] at week 12, change from baseline of 0 mL; benralizumab group: 2248 mL [606] vs 2310 mL [670], 70 mL). 44 (42%) patients in the benralizumab group had adverse events compared with 49 (47%) in the placebo group. The most common adverse events for both groups were nasopharyngitis (eight [8%] patients in each group) and upper respiratory tract infections (five [5%] patients in each group). Serious adverse events occurred in two (2%) patients each in the benralizumab (pancytopenia and a suicide attempt, both considered unrelated to treatment) and placebo (cervix carcinoma and colon adenoma) groups. Interpretation This study suggests that active and modifiable disease processes might be ongoing in patients with mild to moderate, persistent asthma receiving ICS. Although the lung function improvement observed does not warrant use of benralizumab in this population because it did not reach the minimum clinically important difference of 10%, further studies to assess this finding should be considered. Funding AstraZeneca.
- Published
- 2016
10. Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial
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Michael E, Wechsler, Susan J, Kunselman, Vernon M, Chinchilli, Eugene, Bleecker, Homer A, Boushey, William J, Calhoun, Bill T, Ameredes, Mario, Castro, Timothy J, Craig, Loren, Denlinger, John V, Fahy, Nizar, Jarjour, Shamsah, Kazani, Sophia, Kim, Monica, Kraft, Stephen C, Lazarus, Robert F, Lemanske, Amy, Markezich, Richard J, Martin, Perdita, Permaul, Stephen P, Peters, Joe, Ramsdell, Christine A, Sorkness, E Rand, Sutherland, Stanley J, Szefler, Michael J, Walter, Stephen I, Wasserman, Elliot, Israel, and Cheryl, Wilmoth
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Adult ,Male ,Agonist ,medicine.medical_specialty ,Genotype ,medicine.drug_class ,Peak Expiratory Flow Rate ,Placebo ,Gastroenterology ,Double-Blind Method ,Internal medicine ,Administration, Inhalation ,medicine ,Humans ,Albuterol ,Glucocorticoids ,Salmeterol Xinafoate ,Asthma ,Cross-Over Studies ,Polymorphism, Genetic ,Intention-to-treat analysis ,business.industry ,Beclomethasone ,General Medicine ,Adrenergic beta-Agonists ,Middle Aged ,medicine.disease ,Crossover study ,respiratory tract diseases ,Treatment Outcome ,Anesthesia ,Corticosteroid ,Female ,Methacholine ,Receptors, Adrenergic, beta-2 ,Salmeterol ,business ,medicine.drug - Abstract
Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid.In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967.After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures.In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine.National Institutes of Health.
- Published
- 2009
11. Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS)
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David, Couper, Lisa M, LaVange, MeiLan, Han, R Graham, Barr, Eugene, Bleecker, Eric A, Hoffman, Richard, Kanner, Eric, Kleerup, Fernando J, Martinez, Prescott G, Woodruff, Stephen, Rennard, and Fred A, Wright
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Adult ,Aged, 80 and over ,Male ,Disease Management ,Middle Aged ,Prognosis ,Article ,respiratory tract diseases ,Pulmonary Disease, Chronic Obstructive ,Spirometry ,Surveys and Questionnaires ,Humans ,Female ,Prospective Studies ,Tomography, X-Ray Computed ,Biomarkers ,Aged ,Follow-Up Studies - Abstract
SPIROMICS is a multi-center observational study of chronic obstructive pulmonary disease (COPD) designed to guide future development of therapies for COPD by 1) providing robust criteria for sub-classifying COPD participants into groups most likely to benefit from a given therapy during a clinical trial, thereby improving the chances of successful outcome; and 2) identifying biomarkers/phenotypes that can be used as intermediate outcomes to reliably predict clinical benefit during therapeutic trials, thus reducing costs. The goal is to enroll 3,200 participants in four strata: severe COPD, mild/moderate COPD, smokers without airflow obstruction and non-smoking controls. Participants undergo a baseline visit including morphometric measures, spirometry, six-minute walk, an inspiratory and expiratory chest CT, and a set of standardized questionnaires. Biospecimens, including plasma, serum, DNA, urine and induced sputum, are collected and stored. There are three annual follow-up examinations, with quarterly telephone calls to assess for exacerbations, hospitalizations and mortality. Bronchoscopy is being performed in a subset of participants and a subset of COPD patients will be assessed during exacerbations. Adjudication of exacerbations and mortality will be undertaken. SPIROMICS is designed so that sub-studies and ancillary studies testing additional hypotheses can be added.
- Published
- 2013
12. Characteristics of perimenstrual asthma and its relation to asthma severity and control: data from the Severe Asthma Research Program
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Chitra K, Rao, Charity G, Moore, Eugene, Bleecker, William W, Busse, William, Calhoun, Mario, Castro, Kian Fan, Chung, Serpil C, Erzurum, Elliot, Israel, Douglas, Curran-Everett, and Sally E, Wenzel
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Adult ,Adolescent ,Aspirin ,Vital Capacity ,Middle Aged ,Models, Biological ,Severity of Illness Index ,Asthma ,Menstruation ,Young Adult ,Phenotype ,Treatment Outcome ,Surveys and Questionnaires ,Prostaglandins ,Humans ,Female ,Anti-Asthmatic Agents ,Original Research - Abstract
Although perimenstrual asthma (PMA) has been associated with severe and difficult-to-control asthma, it remains poorly characterized and understood. The objectives of this study were to identify clinical, demographic, and inflammatory factors associated with PMA and to assess the association of PMA with asthma severity and control.Women with asthma recruited to the National Heart, Lung, and Blood Institute Severe Asthma Research Program who reported PMA symptoms on a screening questionnaire were analyzed in relation to basic demographics, clinical questionnaire data, immunoinflammatory markers, and physiologic parameters. Univariate comparisons between PMA and non-PMA groups were performed. A severity-adjusted model predicting PMA was created. Additional models addressed the role of PMA in asthma control.Self-identified PMA was reported in 17% of the subjects (n = 92) and associated with higher BMI, lower FVC % predicted, and higher gastroesophageal reflux disease rates. Fifty-two percent of the PMA group met criteria for severe asthma compared with 30% of the non-PMA group. In multivariable analyses controlling for severity, aspirin sensitivity and lower FVC % predicted were associated with the presence of PMA. Furthermore, after controlling for severity and confounders, PMA remained associated with more asthma symptoms and urgent health-care utilization.PMA is common in women with severe asthma and associated with poorly controlled disease. Aspirin sensitivity and lower FVC % predicted are associated with PMA after adjusting for multiple factors, suggesting that alterations in prostaglandins may contribute to this phenotype.
- Published
- 2013
13. Airways reactivity and functional deterioration in relatives of COPD patients
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E. James Britt, Bernice Cohen, Harold Menkes, Eugene Bleecker, Solbert Permutt, Richard Rosenthal, and Philip Norman
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Pulmonary and Respiratory Medicine ,Adult ,Male ,Forced Expiratory Volume ,Vital Capacity ,Humans ,Methacholine Compounds ,Family ,Lung Diseases, Obstructive ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine - Published
- 1980
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