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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056371-04
Application #
6184090
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1997-07-10
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$660,282
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Hong, Xiumei; Tsai, Hui-Ju; Liu, Xin et al. (2008) A large-scale genome-wide linkage analysis to map loci linked to stature in Chinese population. J Clin Endocrinol Metab 93:4511-8
Palmer, Lyle J; Celedon, Juan C; Weiss, Scott T et al. (2002) Ascaris lumbricoides infection is associated with increased risk of childhood asthma and atopy in rural China. Am J Respir Crit Care Med 165:1489-93
Niu, Tianhua; Qin, Zhaohui S; Xu, Xiping et al. (2002) Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am J Hum Genet 70:157-69
Wang, Z; Chen, C; Niu, T et al. (2001) Association of asthma with beta(2)-adrenergic receptor gene polymorphism and cigarette smoking. Am J Respir Crit Care Med 163:1404-9
Betensky, R A; Hudson, J I; Jones, C A et al. (2001) A computationally simple test of homogeneity of odds ratios for twin data. Genet Epidemiol 20:228-38
Xu, X; Niu, T; Chen, C et al. (2001) Association of airway responsiveness with asthma and persistent wheeze in a Chinese population. Chest 119:691-700
Venners, S A; Wang, X; Chen, C et al. (2001) Exposure-response relationship between paternal smoking and children's pulmonary function. Am J Respir Crit Care Med 164:973-6
Xu, X; Fang, Z; Wang, B et al. (2001) A genomewide search for quantitative-trait loci underlying asthma. Am J Hum Genet 69:1271-7
Celedon, J C; Silverman, E K; Weiss, S T et al. (2000) Application of an algorithm for the diagnosis of asthma in Chinese families: limitations and alternatives for the phenotypic assessment of asthma in family-based genetic studies. Am J Respir Crit Care Med 162:1679-84
Niu, T; Rogus, J J; Chen, C et al. (2000) Familial aggregation of bronchodilator response: a community-based study. Am J Respir Crit Care Med 162:1833-7

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