Many of the factors associated with asthma risk in childhood are linked to lung function alterations in early adult life, which are related, in turn, to later asthma, COPD and even death. The objective of this project is to assess prospectively the role of early life events and their interaction with genetic variation in determining risk for the development of symptoms and lung function alterations associated with adult asthma and COPD. The project has 5 specific aims: 1. To determine the relation of early lung function, wheezing LRIs, atopy, and bronchial hyperresponsiveness (BHR) to lung function and respiratory symptoms up to age 28; 2. To determine whether being overweight is associated with persistence of asthma-like symptoms, peak flow variability and airflow limitation to age 28; and whether genetic and developmental factors that control levels of and responses to leptin explain these associations; 3. To establish airway immune biomarker panels that distinguish specific asthma subphenotypes with their distinct pathogenetic mechanisms of development, and to establish the impact of variants in the IL-4 receptor alpha chain, MMP-9 and IL-8 genes on airway biomarkers within subphenotypes; 4. To investigate alterations in airway structure as measured by high- resolution computerized tomography in relation to early wheezing phenotypes, continued symptoms, lung function, BHR, allergen sensitization and biomarkers of airway inflammation; and 5. To assess the roles of a) circulating levels of ligands of the epidermal growth factor receptor and related MMPs, and b) variations in the genes encoding for these proteins, as determinants of the risk for asthma, lung function and BHR. We will use a combination of modern imaging approaches, molecular epidemiology, physiological lung function measurements, non-invasive assessment of airway inflammation, targeted genotyping and standard epidemiologic techniques to assess comprehensively the respiratory health of participants in the Tucson Children's Respiratory Study, a nonselected population followed from birth to their mid-20s. As the only respiratory study of adults which exhaustively recorded events occurring in the first 6 years of life, this approach will provide a unique opportunity to assess prospectively the role of early life events in determining risk for adult asthma and COPD. Elucidating these relations will foster the development of new strategies for the prevention and treatment of asthma and, potentially, of airflow limitation in adult life. ? ? ?
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