Common Genetic Determinants of Asthma and COPD - PROGRAM PROJECT

哮喘和慢性阻塞性肺疾病(COPD)是最常见的肺部慢性疾病。这些疾病每年的总医疗费用约为360亿美元。遗传学方法为阐明这些疾病的遗传原因提供了希望，并为其预测、预防和更有效的治疗提供了新的途径。我们寻求寻找哮喘基因、COPD基因以及与人类疾病相关的哮喘和COPD的共同基因决定因素。哮喘和COPD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呼吸道疾病的共同中间表型，可能是发育性的 下定决心。哮喘和慢性阻塞性肺病是共同的环境决定因素。最后，只有少数曾经吸烟的人会患上COPD，这表明一些潜在的遗传易感性可能与哮喘表型很好地相关。这两种疾病都被证明有遗传成分，这表明他们可能有共同的一些基因的假设。项目1：在cAMP人群中与NLumina Sentrix Human HapSOO珠片进行全基因组关联研究，以寻找与哮喘病情、支气管扩张剂反应和支气管扩张剂后FEV1和FEV1/FVC比率相关的基因，并试图在Sepror EMGB人群中复制3072个SNPs。项目2：测试100个候选基因与COPD患者、对照组和早发性患者的COPD影响状态、支气管扩张剂反应和后支气管扩张剂FEV1，以及FEV1/FVC比率相关 慢性阻塞性肺病患者家属。项目3：36个不同品系小鼠的呼吸道反应性和吸烟相关COPD表型的表型。我们将使用这些数据创建两个回交，以定位基线和对乙酰甲胆碱(Raw)、慢性香烟烟雾暴露下的气道重塑(气道形态测量和与基线Raw的变化)以及肺气肿(平均线性截距)的初始气道阻力和对乙酰甲胆碱(Raw)的反应的QTL，并确定哮喘和COPD的候选基因。最后，来自所有三个项目的所有已识别的复制SNPs和基因将在项目1和2中的六个人类群体中进行评估，以确定这些复制基因与哮喘和COPD的重叠。这种PPG的目标是复制呼吸道疾病的基因，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.