APPROACHES TO IDENTIFY RARE AND COMMON GENETIC DETERMINANTS IN SEVERE COPD

描述（由申请人提供）：摘要大量证据表明，慢性阻塞性肺疾病（COPD）的易感性受遗传因素的影响，但致病变异的鉴定仍然具有挑战性。大多数复杂疾病（如COPD）的遗传学研究都集中在常见遗传变异的作用上。然而，一些复杂的疾病研究已经证明了罕见变异的重要性;这些变异通常具有相对较强的影响。该提案将检验以下假设：来自单基因人类综合征、全基因组关联研究和/或小鼠肺气肿模型的候选基因中的罕见和常见变异均有助于COPD易感性。我们将使用第二代测序技术，在来自国家肺气肿治疗试验的400名重度肺气肿受试者和来自规范性衰老研究的400名肺功能正常的吸烟对照者中测试这一假设。具体目标是：1）在Illumina基因组分析仪上使用有针对性的多重方法发现变异; 2）罕见变异分析，使用折叠方法组合联合收割机变异并增加功效; 3）常见变异分析，包括在波士顿早发性COPD研究中进行复制。 公共卫生相关性：公共卫生相关性声明COPD是美国第四大死亡原因。全面了解遗传风险因素和病理生物学可能会导致个性化诊断和治疗的改进。

DESCRIPTION (provided by applicant): ABSTRACT Substantial evidence indicates that susceptibility to chronic obstructive pulmonary disease (COPD) is influenced by genetic factors, yet identification of causative variants remains challenging. Most genetic studies of complex diseases such as COPD have focused on the role of common genetic variation. However, several complex disease studies have demonstrated the importance of rare variants; these variants have typically been of relatively strong effect. This proposal will test the hypothesis that both rare and common variants in candidate genes from monogenic human syndromes, genome-wide association studies, and/or mouse emphysema models contribute to COPD susceptibility. We will test this hypothesis in 400 subjects with severe emphysema from the National Emphysema Treatment Trial and a set of 400 smoking controls with normal lung function from the Normative Aging Study, using second-generation sequencing technology. The specific aims are 1) variation discovery using a targeted, multiplexed approach on the Illumina Genome Analyzer; 2) rare variant analysis, using a collapsing method to combine variants and increase power, and 3) common variant analysis, including replication in the Boston Early-Onset COPD Study. PUBLIC HEALTH RELEVANCE: PUBLIC HEALTH RELEVANCE STATEMENT COPD is the fourth leading cause of death in the US. A comprehensive understanding of the genetic risk factors and pathobiology may lead to improvements in personalized diagnosis and treatment.