SYSTEMS GENOMICS OF THE ASTHMA-COPD OVERLAP SYNDROME

 描述（由申请人提供）：慢性阻塞性肺疾病（COPD）和哮喘传统上被认为是两种独立的疾病。然而，15-45%的COPD患者还报告了哮喘史。患有COPD和哮喘的受试者是一个重要的临床亚组，其症状增加、加重和住院。COPD可以很容易地使用肺量测定法进行诊断，但没有哮喘的金标准测试。因此，最近的指南提供了一系列主要的临床特征，以识别患有哮喘-COPD重叠综合征（ACOS）的患者。我们推测，在ACOS的流行病学和基因组学的人群研究中取得进展，需要改进表型定义。然而，很少有大的队列是服从这项调查。在COPD遗传流行病学研究（COPDGene）中，我们的研究小组通过问卷调查确定了ACOS的临床、影像学和遗传学特征。在本提案中，我们将通过以下具体目标解决ACOS的表型和基因组学问题。(1)ACOS表型的外周血生物标志物：我们将检验哮喘生物标志物可以改善ACOS定义的假设。我们将在COPDGene中测量总免疫球蛋白E和特异性免疫球蛋白E（IgE）水平。血液嗜酸性粒细胞计数正在COPDGene的第2阶段进行测量。我们将研究与普通COPD相比，过敏性致敏和/或外周嗜酸性粒细胞增多的ACOS受试者的基线和纵向临床和胸部CT成像特征。(2)ACOS中的基因表达：我们将检验ACOS与普通COPD相比具有不同生物学影响的假设。我们将对外周血样本进行RNA测序，以确定与普通COPD相比，过敏性致敏或外周嗜酸性粒细胞增多的ACOS受试者中差异表达的转录本。我们将整合RNA-seq结果与全基因组单核苷酸多态性（SNP）数据，以确定与差异表达基因的转录水平相关的eQTL SNP。(3)ACOS中的系统基因组学：我们将测试潜在的功能机制和遗传调控作用的重要ACOS，确定使用网络的方法。在子目标（a）中，我们将使用RNA-seq数据构建基因网络，比较ACOS和普通COPD中的调控连接，并确定对这些网络之间差异最重要的基因。在子目标（B）中，我们将使用来自患有ACOS和普通COPD的受试者的淋巴母细胞系中关键基因的siRNA敲低来进行网络的体外验证。使用哮喘生物标志物和RNA-seq数据来发现对临床相关的哮喘-COPD重叠综合征的遗传影响，可以确定ACOS的客观诊断标志物或新的途径和靶点，朝着COPD精准医学的目标迈进。大规模生物标志物和RNA-seq数据集将作为COPDGene和COPD研究者社区的资源。

 DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) and asthma are traditionally considered as two separate diseases. However, between 15-45% of COPD patients additionally report a history of asthma. Subjects with both COPD and asthma are an important clinical subgroup, with increased symptoms, exacerbations and hospitalizations. COPD can be readily diagnosed using spirometry, yet there is no gold standard test for asthma. Therefore, recent guidelines have provided a list of largely clinical features to identify patients with the asthma-COPD overlap syndrome (ACOS). We hypothesize that improvements in phenotype definition will be required to make progress in population studies of the epidemiology and genomics of ACOS. However, few large cohorts are amenable to this investigation. In the Genetic Epidemiology of COPD Study (COPDGene), our group has identified clinical, imaging, and genetic features of ACOS, defined by questionnaire. In this proposal, we will address the phenotyping and genomics of ACOS through the following Specific Aims. (1) Peripheral blood biomarkers of the ACOS phenotype: We will test the hypothesis that asthma biomarkers can improve the definition of ACOS. We will measure total and specific Immunoglobulin E (IgE) levels in COPDGene. Blood eosinophil counts are being measured in phase 2 of COPDGene. We will examine baseline and longitudinal clinical and chest CT imaging features of ACOS subjects with allergic sensitization and/or peripheral eosinophilia compared to usual COPD. (2) Gene expression in ACOS: We will test the hypothesis that ACOS has distinct biologic influences compared to usual COPD. We will perform RNA sequencing on peripheral blood samples to identify differentially expressed transcripts in ACOS subjects with allergic sensitization or peripheral eosinophilia compared to usual COPD. We will integrate the RNA-seq results with genomewide single nucleotide polymorphism (SNP) data to identify eQTL SNPs associated with transcript levels of the differentially expressed genes. (3) Systems genomics in ACOS: We will test potential functional mechanisms and genetic regulatory effects important in ACOS, identified using network methods. In sub-aim (a), we will construct gene networks using the RNA-seq data, compare regulatory connections in ACOS and usual COPD, and identify the genes most central to the differences between these networks. In sub-aim (b), we will perform in vitro validation of the networks using siRNA knockdown of key genes in lymphoblastoid cell lines from subjects with ACOS and usual COPD. Using asthma biomarkers and RNA-seq data to discover genetic influences on the clinically-relevant asthma-COPD overlap syndrome could identify objective diagnostic markers of ACOS or novel pathways and targets, moving towards the goal of precision medicine in COPD. The large-scale biomarker and RNA-seq datasets will serve as resources for COPDGene and the community of COPD investigators.