GENETIC EPIDEMIOLOGY OF RSV BRONCHIOLITIS AND ASTHMA

这项建议旨在为首席调查员(PI)提供一个机会，在由高资质赞助商和联合调查员组成的咨询委员会的监督下，获得设计和进行遗传流行病学研究的知识和技能。这一K23奖项与PI在儿科、危重护理、结果研究、临床流行病学和医学信息学方面的背景相结合，为发展专注于复杂炎症性肺部疾病遗传流行病学研究的以患者为中心的成功的独立研究事业提供了极大的潜力。这项建议的总体科学目标是确定以前健康的婴儿中由呼吸道合胞病毒(RSV)引起的严重毛细支气管炎与儿童哮喘后来发展之间的遗传联系。采用前瞻性队列设计，我们建议跟踪1990年至2000年期间在波士顿儿童医院因确诊为呼吸道合胞病毒毛细支气管炎而住院的大量患者，当他们达到3至13岁时，以识别那些持续或新发的喘息者。使用面试者管理的问卷，我们将评估哮喘和特应性疾病的诊断和症状，以及亲生父母和指标儿童的环境暴露。父母将在2到5年的时间里每三个月接受一次调查，以评估他们的孩子喘息的持续性。问卷调查结果将被纳入多元Logistic回归模型，以预测婴儿期RSV毛细支气管炎后儿童哮喘的发展。将从父母和索引儿童身上抽取血液进行DNA分析，以测试一氧化氮合酶基因等位基因分布的传递不平衡。我们假设遗传机制赋予婴儿期RSV毛细支气管炎后持续喘息的易感性，并且这种易感性在调节一氧化氮合酶的基因中被发现。这项建议对美国600多万儿童哮喘患者的护理至关重要。确定与儿童哮喘发病相关的基因可能导致有针对性的干预措施，旨在预防和治疗这种以每年5%的速度增长的疾病。

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.