Asthma, a chronic respiratory disease affecting over 20 million Americans and 300 million people worldwide, results from the complex interaction of multiple genetic and environmental factors. Many studies have searched for individual genetic variants that contribute to asthma susceptibility, but a thorough understanding of the genetic basis of asthma has not been achieved. Our main hypothesis is that the genetic architecture underlying asthma susceptibility can be better understood by considering multiple genes and incorporating multiple sources of genomic data, including human asthma and mouse airways hyperresponsiveness (AHR) data. This hypothesis will be addressed via specific aims in which we will: (1) identify genetic variants that predispose humans to asthma and modulate human AHR by mapping regions associated with AHR in inbred strains of mice to human genome-wide association data, (2) use gene expression data, known protein-protein interactions, and known functional pathways to enhance the search for asthma and AHR genetic variants in humans, and (3) integrate individual human genetic variants to create a multivariate predictive model of asthma. Novel variants identified by Specific Aims 1 and 2 will be validated by replication in independent human populations of asthmatics. The predictive model created in Specific Aim 3 will be validated through replication and prediction in independent human populations of asthmatics. By completing the specific aims, we hope to make progress towards the development of a comprehensive model of the genetics of asthma, particularly of asthma characterized by increased airways responsiveness.

Public Health Relevance

By completing this proposal, we hope to identify genetic variants that modulate asthma risk. Identifying such variants could provide biological insights that may eventually lead to a better understanding of asthma. Additionally, we will create a predictive model of asthma, which could potentially lead to the development of a clinical prognostic test of who is at risk for developing asthma.

Agency
National Institute of Health (NIH)
Type
Research Transition Award (R00)
Project #
5R00HL105663-04
Application #
8727091
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Tigno, Xenia
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Himes, Blanca E; Weitzman, Elissa R (2016) Innovations in health information technologies for chronic pulmonary diseases. Respir Res 17:38
Himes, Blanca E; Koziol-White, Cynthia; Johnson, Martin et al. (2015) Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma. PLoS One 10:e0134057
Sharma, Sunita; Zhou, Xiaobo; Thibault, Derek M et al. (2014) A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes. J Allergy Clin Immunol 134:1153-62
Himes, Blanca E; Jiang, Xiaofeng; Wagner, Peter et al. (2014) RNA-Seq transcriptome profiling identifies CRISPLD2 as a glucocorticoid responsive gene that modulates cytokine function in airway smooth muscle cells. PLoS One 9:e99625
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
Wu, Ann Chen; Himes, Blanca E; Lasky-Su, Jessica et al. (2014) Inhaled corticosteroid treatment modulates ZNF432 gene variant's effect on bronchodilator response in asthmatics. J Allergy Clin Immunol 133:723-8.e3
Bunyavanich, Supinda; Schadt, Eric E; Himes, Blanca E et al. (2014) Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis. BMC Med Genomics 7:48
Phillips, A J K; Robinson, P A; Klerman, E B (2013) Arousal state feedback as a potential physiological generator of the ultradian REM/NREM sleep cycle. J Theor Biol 319:75-87
Klerman, Elizabeth B; Wang, Wei; Duffy, Jeanne F et al. (2013) Survival analysis indicates that age-related decline in sleep continuity occurs exclusively during NREM sleep. Neurobiol Aging 34:309-18
Himes, Blanca E; Sheppard, Keith; Berndt, Annerose et al. (2013) Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene. PLoS One 8:e56179

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