Genetic Epidemiology of COPD

慢性阻塞性肺病的遗传流行病学

基本信息

批准号：
7663132
负责人：
James D Crapo
金额：
$ 658.68万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
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/7663132
关键词：
Address Affect African American Alleles Boston Candidate Disease Gene Case-Control Studies Cause of Death Chest Chronic Obstructive Airway Disease Classification Clinical Clinical Data Complex Cross-Sectional Studies Data Development Diagnostic Disease Disease susceptibility Failure Family Frequencies Future Genes Genetic Genetic Determinism Genomics Genotype Goals Gold Haplotypes Heterogeneity International Investigation Lead Lung diseases Maps Masks Measures Natural History Not Hispanic or Latino Obstruction Pharmacological Treatment Phase Phenotype Physiological Population Population Study Predisposition Prevention strategy Pulmonary Emphysema Pulmonary Function Test/Forced Expiratory Volume 1 Race Recruitment Activity Research Sample Size Sampling Severities Severity of illness Signal Transduction Single Nucleotide Polymorphism Smoker Staging Stratification Susceptibility Gene Syndrome Testing United States Validation X-Ray Computed Tomography base case control clinically relevant clinically significant cohort design disease diagnosis disorder control disorder subtype early onset follow-up functional disability genetic association genetic epidemiology genetic risk factor genetic variant genome wide association study genome-wide high risk improved insight mortality novel novel strategies

项目摘要

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）是美国的第四大死亡原因，也是唯一的死亡原因，频率稳步增加。该提案将建立一个种族多样的队列，该队列足够大，并且适当地设计用于COPD的全基因组关联分析。总共将招募10,500名受试者，包括整个COPD严重程度的控制吸烟者和受试者（金阶段1至4）。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。该研究的主要重点将是全基因组关联分析，以确定确定COPD和COPD相关易感性的遗传风险因素表型。 COPD病例的详细表型，包括对肺气肿和气道疾病的胸部CT扫描评估，将允许鉴定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措施对COPD受试者进行精确的表型表征，将提供数据，以使广泛的COPD综合征分解为临床上重要的亚型。 2）全基因组关联研究将确定COPD易感性的遗传决定因素，以洞悉临床相关的COPD亚型。 3）不同的遗传决定因素会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鉴定COPD敏感性基因。具体目的是（1）队列建筑。在两个种族群体（非西班牙裔白人和非裔美国人）中识别和表型COPD病例和控制人群进行遗传和自然史研究。（2）全基因组关联研究。在第1阶段，将测试全基因组核苷酸多态性（SNP），以与每个种族组中COPD病例对照样本中的COPD和与COPD相关的表型关联。在第2阶段，将在第二轮中的独立样本中的第二轮关联分析中验证和测试每个种族组中排名最高的SNP。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，以识别产生已确认关联信号的基因/区域。在第4阶段，将在整个研究人群中进行最终敏感性基因鉴定，并在波士顿早发COPD研究和国际COPD遗传学网络中进行外部验证。（3）将使用放射线，生理和临床数据（包括CT肺气肿和气道表型，功能障碍程度以及COPD的严重程度）对COPD亚型的流行病学表征进行。最后，将测试来自AIM 2的COPD基因中的SNP与这些COPD亚型关联。