Genetic Epidemiology of COPD

慢性阻塞性肺病的遗传流行病学

• 批准号: 7502748
• 负责人: Edwin K Silverman
• 金额: $ 89.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502748
• 关键词: African American; Boston; Cause of Death; Chest; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Data; Cross-Sectional Studies; Data; Development; Disease; Disease susceptibility; Doctor of Medicine; Frequencies; Future; Genes; Genetic; Genetic Determinism; Genome; Genomics; Goals; Gold; International; Lung diseases; Measures; Natural History; Not Hispanic or Latino; Phase; Phenotype; Physiological; Population Study; Predisposition; Principal Investigator; Pulmonary Emphysema; Race; Range; Recruitment Activity; Sampling; Severities; Severity of illness; Signal Transduction; Single Nucleotide Polymorphism; Smoker; Staging; Susceptibility Gene; Syndrome; Testing; United States; Validation; X-Ray Computed Tomography; case control; clinically relevant; clinically significant; cohort; design; disorder subtype; early onset; follow-up; functional disability; genetic epidemiology; genetic risk factor; genome wide association study; insight

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.

描述（由申请人提供）：慢性阻塞性肺病 (COPD) 是美国第四大死因，也是唯一一个发病率稳步增加的主要原因。该提案将建立一个足够大且适当设计的种族多样化队列，用于慢性阻塞性肺病的全基因组关联分析。总共将招募 10,500 名受试者，包括对照组吸烟者和所有 COPD 严重程度（GOLD 第 1 至 4 阶段）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。该研究的主要重点是全基因组关联分析，以确定决定慢性阻塞性肺病易感性的遗传风险因素以及慢性阻塞性肺病相关疾病 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，将有助于识别 COPD 综合征异质成分的遗传决定因素。要研究的假设是： 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，将提供数据，使广泛的 COPD 综合征能够分解为 有临床意义的亚型。 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涉及四个阶段，以使用病例对照设计来识别 COPD 易感基因。具体目标是 (1) 队列建设。对两个种族群体（非西班牙裔白人和非裔美国人）中的慢性阻塞性肺病病例和对照队列进行识别和表型分析，以进行遗传和自然史研究。 (2)全基因组关联研究。在第一阶段，将测试全基因组单核苷酸多态性 (SNP) 组与每个种族群体内 COPD 病例对照样本中 COPD 和 COPD 相关表型的关联。在第二阶段，每个种族组中排名最高的 6,000 个 SNP 将在独立样本的第二轮关联分析中得到验证和测试。在第 3 阶段，排名靠前的基因组区域 将分析每个种族组中的 50 个 SNP，以识别产生已确认关联信号的基因/区域。在第四阶段，最终的易感基因鉴定将在整个研究人群中进行，并在波士顿早发性慢性阻塞性肺病研究和国际慢性阻塞性肺病遗传学网络中进行外部验证。 (3)流行病学 将使用放射学、生理学和临床数据（包括 CT 肺气肿和气道表型、功能损伤程度和 COPD 严重程度）对 COPD 亚型进行表征。最后，将测试 Aim 2 中确定的 COPD 基因中的 S​​NP 与这些 COPD 亚型的关联。