Common Genetic Determinants of Asthma and COPD-PROGRAM PROJECT

哮喘和慢性阻塞性肺疾病（COPD）是最常见的慢性肺部疾病。这些疾病的综合医疗费用每年约为360亿美元。遗传学方法有望阐明这些疾病的遗传原因，并为其预测、预防和更有效的治疗提供新的途径。我们试图找到与人类疾病相关的哮喘基因、COPD基因以及哮喘和COPD的共同遗传决定因素。哮喘和COPD具有许多共同的临床表型。支气管收缩反应、支气管扩张反应和肺功能水平是气道疾病的共同中间表型，并且可能在发育过程中发生变化 测定哮喘和慢性阻塞性肺病都是吸烟的共同环境决定因素。最后，只有少数吸烟者会发展为COPD，这表明某些潜在的遗传易感性可能与哮喘表型密切相关。这两种疾病都被证明具有遗传成分，这表明它们可能共享一些共同基因的假设。项目一：在CAMP人群中使用Nlumina Sentrix Human HapSOO BeadChip进行全基因组关联研究，以发现与哮喘患病状态、支气管扩张剂反应和支气管扩张剂后FEV 1和FEV 1/FVC比值相关的基因，并尝试在Sepracor EMGB人群中复制3072个SNP。项目二：检测100个候选基因与COPD患者、对照组和早发COPD患者的COPD病情状态、支气管扩张剂反应、支气管扩张剂后FEV 1和FEV 1/FVC比值的相关性 COPD家族项目3：对36种不同品系小鼠的气道反应性和吸烟相关COPD表型进行表型分析。我们将使用这些数据创建两个回交以绘制基线时和响应于乙酰甲胆碱（Raw）的初始气道阻力、慢性香烟烟雾暴露的气道重塑（气道形态测定和从基线Raw的变化）和肺气肿（平均线性截距）的QTL，并鉴定哮喘和COPD的候选基因。最后，将在项目1和2的6个人群中评估所有三个项目中鉴定的复制SNP和基因，以确定这些复制基因在哮喘和COPD中的重叠。该PPG的目标是复制气道疾病的基因，为新的病理生物学和临床预测指明方向。

Asthma and chronic obstructive pulmonary disease (COPD) are the most common chronic diseases of the lung. The combined health care costs for these conditions approximate $36 billion per year. Genetic approaches offer promise to elucidate genetic causes of these diseases and provide new avenues for their prediction, prevention, and more effective treatment. We seek to find asthma genes, COPD genes and common genetic determinants for asthma and COPD relevant to human disease. Asthma and COPD share many clinical phenotypes. Bronchoconstrictor response, bronchodilator response and level of lung function are shared intermediate phenotypes for airway disease and may be developmentally determined. Asthma and COPD share cigarette smoke exposure as a common environmental determinant. Finally, only a minority of ever-smokers develop COPD, indicating some underlying genetic susceptibility which may well relate to the asthma phenotype. Both disorders have been shown to have a genetic component, suggesting the hypothesis that they could share some genes in common. Project 1: To perform a whole genome association study with the Nlumina Sentrix Human HapSOO BeadChip in the CAMP population to find genes for association with asthma affection status, bronchodilator response, and postbronchodilator FEV1 and FEV1/FVC ratio and attempt to replicate 3072 SNPs in the Sepracor EMGB population. Project 2: Test 100 candidate genes for association with COPD affection status, bronchodilator response, and Post-bronchodilator FEV1, and FEV1/FVC ratio in COPD cases and controls and in early-onset COPD families. Project 3: Phenotype 36 different strains of mice for airway responsiveness and smoking-related COPD phenotypes. We will use these data to create two back- crosses to map QTLs for naive airway resistance at baseline and in response to methacholine (Raw), Airway remodeling with chronic cigarette smoke exposure (airway morphometry and change from baseline Raw), and Emphysema (mean linear intercept) and identify candidate genes for asthma and COPD. Finally, all identified replicated SNPs and genes from all three projects will then be assessed in six human populations in Projects 1 and 2 to determine the overlap of these replicated genes for asthma and COPD. The goal of this PPG is replicated genes for airways disease pointing the way to novel pathobiology and clinical prediction.