Identifying Genetic Determinants of Severe, Early-Onset COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是美国第三大死亡原因。虽然吸烟显然是导致COPD的主要环境因素，但只有一小部分吸烟者发展为临床显著的COPD，并且遗传决定因素影响这种变异性。低成本的大规模DNA测序的可用性使得全外显子组测序成为可行的研究设计，而不是将分析局限于候选基因。全外显子组测序已成功鉴定单基因综合征的罕见遗传决定因素，并有可能鉴定影响COPD可变发展的罕见非同义SNP。由于重度早发COPD受试者可能富含COPD遗传决定因素，我们将把基因发现工作集中在两个独特的以家庭为基础的资源上，这些资源包括大量重度早发COPD先证者：波士顿早发COPD研究和国际COPD遗传学网络。来自这两个研究人群的共700名受试者将使用基于家族和病例对照的方法进行全外显子组测序和罕见变异分析。我们将在通过国际COPD遗传学网络中晚发COPD先证者确定的家族中复制这些罕见变异相关性。最后，我们将在COPD基因研究中评估具有罕见变异相关性的基因对特定胸部CT定义的COPD亚型受试者和非裔美国人的影响。我们的总体假设是，罕见的功能性遗传变异影响COPD的发展。通过关注患有严重的早发性复杂疾病的受试者，将提高发现有效易感基因的可能性。我们的逐步分析策略将评估这些罕见变异相关性对迟发性COPD、非裔美国人COPD和特定影像学亚型COPD的影响。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality in the United States. While smoking is clearly the main environmental factor leading to COPD, only a fraction of smokers develop clinically significant COPD, and genetic determinants influence this variability. The availability of large-scale DNA sequencing at low cost has made whole exome sequencing a feasible study design, rather than limiting analysis to candidate genes. Whole exome sequencing has been successful in the identification of rare genetic determinants of monogenic syndromes, and it has the potential to identify rare nonsynonymous SNPs influencing the variable development of COPD. Since subjects with severe, early-onset COPD may be enriched for COPD genetic determinants, we will focus our gene discovery efforts on two unique family-based resources which have included large numbers of severe, early-onset COPD probands: the Boston Early-Onset COPD Study and the International COPD Genetics Network. A total of 700 subjects from these two study populations will undergo whole exome sequencing and rare variant analysis using family-based and case- control methods. We will replicate these rare variant associations in families ascertained through probands with later-onset COPD in the International COPD Genetics Network. Finally we will assess the impact of genes with rare variant associations in subjects with specific chest CT-defined subtypes of COPD and in African Americans in the COPDGene Study. Our overall hypothesis is that rare, functional genetic variants influence the development of COPD. By focusing on subjects with a severe, early-onset form of a complex disease, the likelihood of finding valid susceptibility genes will be enhanced. Our step-wise analytical strateg will assess the impact of these rare variant associations in later-onset COPD, in African Americans with COPD, and in specific imaging subtypes of COPD.