CHILDHOOD ASTHMA: EARLY PREVENTION AND PHARMACOGENETICS

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Our group has recently demonstrated that early onset asthma (before age 3) is associated with more severe symptoms and more significant deficits in lung function (not readily reversible with bronchodilators) at age 11 than late onset asthma. In Project 1 of this application to the Pediatric Asthma Clinical Research Network, the potential role of inhaled corticosteroids in modifying the natural history of early onset asthma will be assessed. Children at high risk for asthma aged 24-47 months will be treated with either inhaled corticosteroids or placebo for a period of 18 months. The main outcome variables will be assessed during a one year observation period off trial drug immediately following the treatment phase. Number of symptom-free and controller-free days will be the main outcome variable. In addition, maximal flows obtained from partial expiratory flow volume loops and airway responses to cold dry air will also be compared in both treatment groups. These techniques have been successfully developed by our group for use in pre-school children. Genetic variants in the beta-adrenergic receptor gene have been described by Liggett et al, and we recently reported that one such polymorphism (glycine/arginine in residue 16) was strongly associated with response to albuterol in children. Project 2 will assess the influence of these genetic variants on response to standardized therapy among subjects with mild persistent and mild intermittent asthma. We expect to find that carriers of the Gly-16 variant of this gene will require more beta agonist and hence receive more control medication and require more inhaled corticosteroids than carriers of the Arg-16 variant. Our group is uniquely qualified to contribute to PACRN. We have a long experience in long-term clinical and epidemiological studies of childhood asthma, especially among infants and pre-schoolers. We have also established strong collaborative links with community health care providers especially those involved in the primary care of asthma among our Hispanic community in Tucson. Finally, we have a very active program in the genetics and pharmacogenetics of asthma that may prove very important for the long-term objectives of PACRN.