Genetic Epidemiology of COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是美国第四大死因，也是唯一频率稳步增加的主要死因。该提案将建立一个种族多样性队列，该队列足够大，并适当设计用于COPD的全基因组关联分析。共招募10，500例受试者，包括对照吸烟者和COPD严重程度全范围（GOLD 1 - 4期）的受试者。该队列将用于横断面分析，尽管长期纵向随访将是未来的目标。本研究的主要重点是全基因组关联分析，以确定决定COPD易感性的遗传风险因素以及COPD相关性。 表型COPD病例的详细表型分析，包括肺气肿和气道疾病的胸部CT扫描评估，将允许识别COPD综合征异质组分的遗传决定因素。待研究的假设是：1）使用计算机断层扫描以及临床和生理测量对COPD受试者进行精确的表型表征，将提供能够将广泛的COPD综合征分解为临床显著亚型的数据。2)全基因组关联研究将确定COPD易感性的遗传决定因素，从而深入了解临床相关的COPD亚型。3)不同的遗传决定因素影响肺气肿和气道疾病的发展。全基因组关联分析将包括四个阶段，以确定COPD易感基因使用病例对照设计。具体目标是：（1）建立队列。在两个种族组（非西班牙裔白人和非裔美国人）中识别COPD病例和对照队列并进行表型分析，以进行遗传和自然史研究。(2)全基因组关联研究。在I期研究中，将在每个种族组的COPD病例对照样本中检测全基因组单核苷酸多态性（SNP）与COPD和COPD相关表型的相关性。在第二阶段，每个种族群体中排名最高的6,000个SNP将在独立样本的第二轮关联分析中进行验证和测试。在第3阶段，将分析每个种族组中排名最高的50个SNP周围的基因组区域，以鉴定产生确认的关联信号的基因/区域。在第4阶段，将在整个研究人群中进行最终易感基因鉴定，并在波士顿早发性COPD研究和国际COPD遗传学网络中进行外部验证。(3)将使用影像学、生理学和临床数据（包括CT肺气肿和气道表型、功能损害程度和COPD严重程度）对COPD亚型进行流行病学表征。最后，将检测来自Aim 2的已鉴定COPD基因中的SNP与这些COPD亚型的关联。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the only leading cause of death that is steadily increasing in frequency. This proposal will establish a racially diverse cohort that is sufficiently large and appropriately designed for genome-wide association analysis of COPD. A total of 10,500 subjects will be recruited, including control smokers and subjects across the full range of COPD severity (GOLD Stages 1 through 4). This cohort will be used for cross-sectional analysis, although long-term longitudinal follow-up will be a future goal. The primary focus of the study will be genome-wide association analysis to identify the genetic risk factors that determine susceptibility for COPD and COPD related phenotypes. Detailed phenotyping of COPD cases, including chest CT scan assessment of emphysema and airway disease, will allow identification of genetic determinants for the heterogeneous components of the COPD syndrome. The hypotheses to be studied are: 1) Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, will provide data that will enable the broad COPD syndrome to be decomposed into clinically significant subtypes. 2) Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes. 3) Distinct genetic determinants influence the development of emphysema and airway disease. The genome-wide association analysis will involve four phases to identify COPD susceptibility genes using a case-control design. The Specific Aims are (1) Cohort Building. Identify and phenotype COPD case and control cohorts in two racial groups (non-Hispanic whites and African Americans) for genetic and natural history studies. (2) Genome-wide Association Study. In Phase 1, a genome-wide panel of single nucleotide polymorphisms (SNPs) will be tested for association with COPD and COPD-related phenotypes in COPD case-control samples within each racial group. In Phase 2, the top-ranked 6,000 SNPs in each racial group will be validated and tested in a second round of association analysis in independent samples. In Phase 3, the genomic regions around the top-ranked 50 SNPs in each racial group will be analyzed to identify genes/regions yielding confirmed association signals. In Phase 4, final susceptibility gene identification will be performed in the entire study population, with external validation in the Boston Early-Onset COPD Study and International COPD Genetics Network. (3) Epidemiologic characterization of subtypes of COPD using the radiologic, physiologic, and clinical data including CT emphysema and airway phenotypes, degree of functional impairment, and severity of COPD, will be performed. Finally, SNPs in the identified COPD genes from Aim 2 will be tested for association with these COPD subtypes.