This proposal is designed to provide an opportunity for the Principal Investigator (PI) to gain knowledge and skills in designing and conducting genetic epidemiology research under the supervision of an advisory committee comprised of highly qualified sponsors and co-investigators. This K23 award in combination with the PI's background in pediatrics, critical care, outcomes research, clinical epidemiology and medical informatics, provides excellent potential for development of a successful independent research career focused on patient-oriented research in the genetic epidemiology of complex inflammatory lung diseases. The overall scientific goal of this proposal is to determine the genetic association between severe bronchiolitis in previously healthy infants caused by respiratory syncytial virus (RSV) and the later development of childhood asthma. Using a prospective cohort design, we propose to follow the large population of patients who were hospitalized for confirmed RSV bronchiolitis during infancy at Children's Hospital, Boston from 1990 to 2000 when they reach 3 to 13 years of age to identify those with persistent or new onset wheezing. Using an interviewer-administered questionnaire, we will assess asthma and atopy diagnoses and symptoms and environmental exposures in both biological parents and the index child. Parents will be surveyed every three months over a 2 to 5 year period to assess the persistence of wheezing in their child. Questionnaire findings will be incorporated into a multiple logistic regression model to predict the development of childhood asthma after RSV bronchiolitis in infancy. Blood will be drawn from both parents and the index child for DNA analysis to test for transmission disequilibrium in the distribution of alleles of nitric oxide synthase genes. We hypothesize that genetic mechanisms confer susceptibility to persistent wheezing after RSV bronchiolitis in infancy and that this susceptibility is found in genes regulating nitric oxide synthase. This proposal is vital to the care of the greater than 6 million childhood asthmatics in the United States. Identifying the genes associated with the onset of childhood asthma could lead to targeted interventions aimed at prevention and treatment of this disorder that is increasing at a rate of 5 percent per year.
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