Genetic Epidemiology of COPD

慢性阻塞性肺病的遗传流行病学

• 批准号: 8116583
• 负责人: Edwin K Silverman
• 金额: $ 241.89万
• 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/8116583
• 关键词: African American; Boston; Cause of Death; Chest; Chronic Obstructive Airway Disease; Clinical; Clinical Data; Cross-Sectional Studies; Data; Development; Disease; Disease susceptibility; Doctor of Medicine; Epidemiology; Frequencies; Future; Genes; Genetic; Genetic Determinism; Genomics; Goals; International; Measures; Natural History; Not Hispanic or Latino; Phase; Phenotype; Physiological; Population Study; Predisposition; Principal Investigator; Pulmonary Emphysema; Race; 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; genome-wide; 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）：慢性阻塞性肺疾病（COPD）是美国第四大死亡原因，也是唯一一个频率稳步上升的主要死亡原因。该建议将建立一个足够大且设计适当的种族多样化队列，用于COPD的全基因组关联分析。总共将招募10,500名受试者，包括对照吸烟者和COPD严重程度的所有受试者（GOLD阶段1至4）。该队列将用于横断面分析，尽管长期的纵向随访将是未来的目标。该研究的主要重点将是全基因组关联分析，以确定决定COPD易感性和COPD相关的遗传风险因素