This application proposes to continue the participation of investigators at the University of Wisconsin in an interactive network of six centers in the U.S. (the Asthma Clinical Research Network or ACRN ) in conducing studies of novel therapeutic approaches to asthma and in disseminating findings to the practicing community. The need for such a network was suggested by epidemiological data showing increases in the mortality, morbidity, prevalence, and costs of asthma, by clinical and basic research studies showing that asthma is linked to inflammation in the airways, and by the accelerating rate of development of potentially highly effective, but also potentially costly treatments for asthma. Defining the place of these new therapies was seen as requiring collaborative, multi-center studies examining large numbers of subjects reflecting the diversity of the U.S. population. In its first 5 years, the ACRN established an interactive infrastructure to meet this need and has added a research site at Harlem Hospital in New York, which serves a predominantly minority population. The ACRN completed and published trials of the effects of regular use of a beta-agonist in subjects with mild asthma ( BAGS ) and of the efficacy of the anti-inflammatory agent, colchicine, as an alternate to an inhaled corticosteriod in moderate asthma. It is now conducting two additional trials comparing these effects of a long-acting beta-agonist, an inhaled corticosteriod, and the combination of the two in altering clinical and physiologic outcomes, and airway inflammation in moderate or severe asthma. A fifth study, establishing doses of different inhaled corticosteriods with equivalent effects on cortisol secretion, is about to be started. The trials completed have been presented at the ATS, ACCP, and AAAAI, as have been nearly a dozen ancillary studies designed to improve the performance of clinical research. Of these studies, three have so far been published in peer-reviewed journals. The ACRN has also reported, and is submitting for publication, the results of a subgroup analysis of subjects in the BAGS study showing that subjects with different genotypes for the beta-adrenergic receptor are differently affected by regular use of albuterol. This application specifically proposes continued participation of the University of Wisconsin Asthma Clinical Research group in the multicentered, collaborative trials of the ACRN. The studies proposed include a comparison of the clinical efficacy of doses of different inhaled corticosteriods with equal systemic effects (as estimated from the study described above), a prospective study of the effects of regular use of an inhaled beta-agonist in subjects stratified by genotype for the beta-adrenergic receptor, a study analyzing the efficacy of a leukotriene pathway antagonist in enabling reduction or elimination of inhaled corticosteriod therapy in subjects with mild or moderate persistent asthma, and other studies illustrated briefly in this application, but modified or replaced by the ACRN Steering Committee in response to new information or the release of new forms of therapy.
| Wang, Y; Tong, C; Wang, Z et al. (2015) Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma. Pharmacogenomics J 15:422-9 |
| Dunn, Ryan M; Lehman, Erik; Chinchilli, Vernon M et al. (2015) Impact of Age and Sex on Response to Asthma Therapy. Am J Respir Crit Care Med 192:551-8 |
| Brehm, John M; Ramratnam, Sima K; Tse, Sze Man et al. (2015) Stress and Bronchodilator Response in Children with Asthma. Am J Respir Crit Care Med 192:47-56 |
| Israel, Elliot; Lasky-Su, Jessica; Markezich, Amy et al. (2015) Genome-wide association study of short-acting ?2-agonists. A novel genome-wide significant locus on chromosome 2 near ASB3. Am J Respir Crit Care Med 191:530-7 |
| Lambert, Allison; Drummond, M Bradley; Wei, Christine et al. (2015) Diagnostic accuracy of FEV1/forced vital capacity ratio z scores in asthmatic patients. J Allergy Clin Immunol 136:649-653.e4 |
| Duan, Q L; Lasky-Su, J; Himes, B E et al. (2014) A genome-wide association study of bronchodilator response in asthmatics. Pharmacogenomics J 14:41-7 |
| Szefler, Stanley J; Chinchilli, Vernon M; Israel, Elliot et al. (2012) Key observations from the NHLBI Asthma Clinical Research Network. Thorax 67:450-5 |
| Tantisira, Kelan G; Damask, Amy; Szefler, Stanley J et al. (2012) Genome-wide association identifies the T gene as a novel asthma pharmacogenetic locus. Am J Respir Crit Care Med 185:1286-91 |
| Tantisira, Kelan G; Lasky-Su, Jessica; Harada, Michishige et al. (2011) Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 365:1173-83 |
| Wechsler, Michael E; Castro, Mario; Lehman, Erik et al. (2011) Impact of race on asthma treatment failures in the asthma clinical research network. Am J Respir Crit Care Med 184:1247-53 |
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