The Genetic Epidemiology of Asthma in Costa Rica

描述（由申请人提供）：西班牙裔美国人的显著多样性是鉴别该族群哮喘易感基因的主要障碍。本研究旨在确定哥斯达黎加中央谷地高哮喘患病率的西班牙裔人群的哮喘易感基因。在R01 HL66289的支持下，自2001年以来，我们收集了中央山谷2504个个体的表型和基因型数据（8个哮喘儿童大谱系中的671个成员，611个哮喘儿童及其父母[1833个个体]）。在哮喘儿童大家庭的成员中，我们进行了哮喘及其中间表型的全基因组连锁分析，包括气道反应性和血清总IgE。我们确定了两个符合全基因组标准的位点，它们与哥斯达黎加人哮喘的两种关键中间表型有显著联系：气道反应性（所有受试者）和血清总IgE（男性）。我们目前正在对600对父母-儿童三人组进行哮喘和12q24染色体气道反应性的精细映射关联研究的初始阶段，这些三人组先前为本提案的父母资助而招募。根据我们迄今为止的发现，我们假设染色体12q24上的一个基因影响哥斯达黎加人的哮喘和气道反应性，而chr上的一个基因。20p12对哥斯达黎加男性血清总IgE的影响为了验证这一假设，我们将对900名接受父母资助的个体（300名患有哮喘的男孩及其父母）进行基因分型并检测染色体20p12中连锁不平衡（LD）标记的单核苷酸多态性（snp）与血清总IgE之间的关系。我们将招募600名哮喘患儿及其父母（1800人）。然后，我们将在这个新的队列中对染色体12q24和20p12的snp与哮喘和/或其中间表型（气道反应性和血清总IgE）之间的关联进行基因分型和测试，以复制我们最初的精细定位关联研究，并确定哮喘和/或其中间表型的候选基因。然后，我们将对24名哥斯达黎加哮喘儿童的15个候选基因进行测序。最后，我们将在3,600个人（1,200名患有哮喘的儿童及其父母）中进行基因分型和测试，以确定这些基因中的snp和单倍型与哮喘和/或其中间表型之间的关联。

DESCRIPTION (provided by applicant): The marked diversity of U.S. Hispanics is a major barrier for identification of asthma-susceptibility genes in this ethnic group. This proposal seeks to identify asthma-susceptibility genes in a genetically isolated Hispanic population with high prevalence of asthma in the Central Valley of Costa Rica. With support from R01 HL66289, we have collected phenotypic and genotypic data in 2,504 individuals in the Central Valley (671 members of 8 large pedigrees of children with asthma, and 611 children with asthma and their parents [1,833 individuals]) since 2001. Among members of large families of children with asthma, we conducted genome-wide linkage analyses of asthma and its intermediate phenotypes, including airway responsiveness and total serum IgE. We identified two loci meeting genome-wide criteria for significant linkage to two critical intermediate phenotypes of asthma in Costa Ricans: airway responsiveness (in all subjects) and total serum IgE (in males). We are currently conducting the initial phase of fine-mapping association studies of asthma and airway responsiveness on chromosome 12q24 in 600 parent-child trios previously recruited for the parent grant for this proposal. On the basis of our findings to date, we hypothesize that a gene(s) on chromosome 12q24 influences asthma and airway responsiveness in Costa Ricans, and that a gene(s) on chr. 20p12 influences total serum IgE in male Costa Ricans. To test this hypothesis, we will genotype and test for association between linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) in chromosome 20p12 and total serum IgE in 900 individuals (300 boys with asthma and their parents) recruited for the parent grant. We will recruit 600 children with asthma and their parents (1,800 individuals). We will then genotype and test for association between SNPs in chromosomes 12q24 and 20p12 and asthma and/or its intermediate phenotypes (airway responsiveness and total serum IgE) in this new cohort for replication of our initial fine-mapping association studies, and identification of candidate genes for asthma and/or its intermediate phenotypes. We will then sequence 15 candidate genes in 24 Costa Rican children with asthma. Finally, we will genotype and test for association between SNPs and haplotypes in these genes and asthma and/or its intermediate phenotypes in 3,600 individuals (1,200 children with asthma and their parents) recruited for the parent grant and for the current application.