The Genetic Epidemiology of COPD in Costa Rica

描述(申请人提供)：这项申请将研究影响拉美裔慢性阻塞性肺疾病(COPD)发展的遗传因素，拉美裔是该疾病的高风险少数群体。为此，我们将集中关注居住在哥斯达黎加中央山谷的基因隔离的慢性阻塞性肺病高患病率的西班牙裔人口。为了确定该人群中可能包含COPD相关表型遗传决定因素的基因组区域，我们将利用一项研究设计，收集30个患有中到重度COPD先证者的大家庭的表型和基因数据，这些大家庭有多个个体受到吸烟相关气流障碍的影响，包括来自哥斯达黎加中央山谷创始人群体后裔的900个个体。我们将使用短串联重复序列(STR)标记对这些大型家系进行基因组扫描，并对六种与COPD相关的表型进行连锁分析：慢性支气管炎；气流阻塞；FEV1；FEV1/FVC；支气管扩张剂反应性；以及血清总IgE。在基因组扫描中显示与COPD相关表型相关的基因组区域内，我们将对窄间距STR标记进行分型，并测试这些标记与COPD相关表型之间的关联。在选定的基因组区域内，我们将测试候选基因中的单核苷酸多态(SNPs)与COPD相关表型之间的关联。通过在基因隔离的人群中利用基于家庭的大样本研究设计，我们应该能够解决一个重要但尚未研究的问题：基因对拉美裔COPD表型表达的影响。这一应用将极大地帮助我们了解COPD的一般发病机制，特别是拉美裔美国人的发病机制。

DESCRIPTION (provided by applicant): This application will examine the genetic factors that influence the development of chronic obstructive pulmonary disease (COPD) in Hispanics, a minority group at high risk for the disease. To this end, we will concentrate on a genetically isolated Hispanic population with a high prevalence of COPD living in the Central Valley of Costa Rica. To identify regions of the genome likely to contain genetic determinants of COPD-related phenotypes in this population, we will utilize a study design that entails collection of phenotypic and genotypic data on 30 large families of probands with moderate to severe COPD that have multiple individuals affected with smoking-related airflow obstruction, comprising 900 individuals from descendants of the Costa Rican Central Valley founder population. We will conduct a genome scan on these large pedigrees using short-tandem repeat (STR) markers and perform linkage analysis of six COPDrelated phenotypes: chronic bronchitis; airflow obstruction; FEV1; FEV1/FVC; bronchodilator responsiveness; and total serum IgE. Within genomic regions demonstrating linkage to COPD-related phenotypes in the genome scan, we will genotype narrowly spaced STR markers and test for linkage between these markers and COPD-related phenotypes. Within selected genomic regions, we will then test for association between single nucleotide polymorphisms (SNPs) in candidate genes and COPD-related phenotypes. By utilizing a family-based study design with a large sample size in a genetically isolated population, we should be able to address an important yet unstudied problem: the genetic influences on the expression of the COPD phenotype in Hispanics. This application will greatly contribute to our understanding of the pathogenesis of COPD in general, and among Hispanics in particular.