THE GENETIC EPIDEMIOLOGY OF ASTHMA IN COSTA RICA

这项建议旨在研究影响少数群体(西班牙裔)哮喘发病的遗传因素。为此，我们将集中关注居住在哥斯达黎加中央山谷的、遗传上与世隔绝、哮喘发病率高的拉美裔人口。为了确定该人群中可能包含哮喘遗传决定因素和相关表型的基因组区域，我们将利用一项独特的研究设计，收集15个哮喘大家系(600个个体)和300个无关哮喘儿童及其父母(900个个体)的表型和基因数据。我们将对这些大型家系进行基因组筛查，并将对哮喘与七种与哮喘相关的中间表型进行连锁分析，包括呼吸道反应性、FEV1、支气管扩张剂反应性、对常见空气变应原的皮试反应性、血清总IgE和过敏原特异性IgE以及外周血嗜酸细胞计数。还将在亲子三人组中进行基因组筛查，并重建祖先单倍型，以确定影响哮喘相关表型的区域。在显示扩大的哮喘家系和/或哮喘相关表型的连锁和无关哮喘受试者的显著连锁不平衡的候选区域内，将通过测试与位置候选基因内的单核苷酸多态的遗传关联来进行精细定位。通过在基因隔离的人群中利用独特的大样本研究设计，我们应该能够解决一个重要但研究不足的问题：基因对拉美裔哮喘表型表达的影响。因此，这项建议将极大地有助于我们理解拉美裔美国人中一个重大公共卫生问题的发病机制：支气管哮喘。

This proposal seeks to examine the genetic factors that influence the development of asthma in a minority group at high risk for the disease (Hispanics). To this end, we will concentrate on a genetically isolated Hispanic population with high asthma prevalence living in the Central Valley of Costa Rica. To identify regions of the genome likely to contain genetic determinants of asthma and associated phenotypes in this population, we will utilize a unique study design that entails collection of phenotypic and genotypic data on 15 large pedigrees multiplex for asthma (600 individuals) and 300 unrelated asthmatic children and their parents (900 individuals). We will conduct a genome screen on these large pedigrees, and we will perform linkage analysis of asthma and seven intermediate phenotypes related to asthma including airway responsiveness; FEV 1; bronchodilator responsiveness; skin test reactivity to common aeroallergens; serum total and allergen-specific IgE; and peripheral blood eosinophil count. A genome screen will also be conducted in the parent-child trios, and ancestral haplotypes will be reconstructed to identify regions influencing asthma- associated phenotypes. Within candidate regions demonstrating both linkage in extended pedigrees to asthma and/or asthma-related phenotypes and significant linkage disequilibrium within the unrelated asthmatic subjects, fine mapping will be performed by testing for genetic association to single nucleotide polymorphisrns within positional candidate genes. By utilizing a unique study design with a large sample size in a genetically isolated population, we should be able to address an important but insufficiently studied problem: the genetic influences on the expression of the asthma phenotype in Hispanics. Thus, this proposal will greatly contribute to our understanding of the pathogenesis of a significant public health problem among Hispanic Americans: bronchial asthma.