Airway responsiveness and lung function, endpoints with a strong genetic basis, are central to the obstructive airway diseases (asthma and COPD). In contrast, the dissection of the underlying genes will require unique sample resources, accurate and comprehensive phenotyping, and an efficient study design. To address to this three-pronged challenge, a genomic screen is proposed that brings together a large, homogenous, mostly untreated sample from Anhui, China, a wealth of expertise in asthma phenotypes, and a potent study design based on extreme discordant sib pairs. Since this approach utilizes an extant asthmatic family population, no support for data collection will be required. The primary focus of the application will be two intermediate phenotypes related to asthma and COPD: airway responsiveness (characterized by increased responsiveness to histamine methacholine or other nonspecific agonists and measured by the slope of the dose response relationship) and FEV1. Since both traits are continuous, the appropriate study design is one that considers only siblings with extremely discordant phenotypes. For many studies, this strategy is not feasible due to the thousands of families that must be phenotyped to identify a sample of such siblings. The plan is to utilize the organization of a well-established network in China to collect 150 extreme discordant sib pairs of each intermediate phenotype. For airway responsiveness, the estimated power from this sample, equivalent to roughly 600 concordant sib pairs, is intended to surpass the power of all existing studies, including the U.S. Collaborative Study on Asthma. Further, with similar power, this will be the first study to test for linkage to FEV1. Moreover, to further augment power, potential phenotypic heterogeneity will be reduced by stratifying the analyses by total and specific serum IgE levels, skin test reactivity, peripheral blood eosinophilia, respiratory symptoms, age, gender, bronchodilator response, and cigarette smoking.
Showing the most recent 10 out of 13 publications
