Identifying Genetic Determinants of Severe, Early-Onset COPD

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是美国第三大致死原因。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会患上具有临床意义的COPD，而遗传决定因素会影响这种变异性。大规模DNA测序的低成本使整个外显子组测序成为一种可行的研究设计，而不是局限于对候选基因的分析。全外显子组测序已经成功地识别了单基因综合征的罕见遗传决定因素，并有可能识别影响COPD变异发展的罕见非同义SNPs。由于重度早发性COPD患者的COPD基因决定因素可能丰富，我们将把基因发现工作集中在两个独特的家庭资源上，其中包括大量严重早发性COPD的先证者：波士顿早发性COPD研究和国际COPD遗传学网络。来自这两个研究人群的总共700名受试者将使用基于家庭和病例对照的方法进行完整的外显子组测序和罕见的变异分析。我们将在国际COPD遗传学网络中通过先证者确诊的晚发性COPD家族中复制这些罕见的变异关联。最后，我们将在COPD基因研究中评估具有罕见变异关联的基因在患有特定胸部CT定义的COPD亚型的受试者和非裔美国人中的影响。我们的总体假设是，罕见的功能性遗传变异会影响COPD的发展。通过将重点放在患有严重的早发性复杂疾病的受试者身上，找到有效易感基因的可能性将增加。我们的逐步分析策略将评估这些罕见的变异关联在迟发性COPD、患有COPD的非裔美国人以及特定的COPD影像亚型中的影响。

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.