SYSTEMS GENOMICS OF THE ASTHMA-COPD OVERLAP SYNDROME

哮喘-慢性阻塞性肺病重叠综合征的系统基因组学

• 批准号: 9226025
• 负责人: CRAIG P HERSH
• 金额: $ 88.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226025
• 关键词: Address; Age; Allergic; Asthma; Biological Markers; Blood specimen; Characteristics; Chronic Obstructive Airway Disease; Clinical; Communities; Complement; Data; Data Set; Diagnosis; Disease; Eosinophilia; Epidemiology; Etiology; Exclusion Criteria; Frequencies; Gene Expression; Genes; Genetic; Genomics; Goals; Gold; Guidelines; Healthcare; Hospitalization; IgE; In Vitro; Investigation; Lead; Learning; Lung diseases; Measures; Methods; Obstruction; Parents; Pathway interactions; Patient Self-Report; Patients; Peripheral; Phase; Phenotype; Physicians; Population Study; Questionnaires; Recording of previous events; Reporting; Research Personnel; Resources; Risk Factors; Single Nucleotide Polymorphism; Small Interfering RNA; Smoker; Spirometry; Subgroup; Suggestion; Symptoms; Syndrome; System; Testing; Transcript; Validation; X-Ray Computed Tomography; atopy; chest computed tomography; cigarette smoking; clinical care; clinical imaging; clinically relevant; cohort; diagnostic biomarker; differential expression; disorder control; eosinophil; genetic epidemiology; genome wide association study; genome-wide; imaging genetics; improved; insight; knock-down; lymphoblastoid cell line; novel; patient population; peripheral blood; personalized approach; precision medicine; public health relevance; transcriptome sequencing

 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.

 描述（由申请人提供）：慢性阻塞性肺病（COPD）和哮喘传统上被认为是两种不同的疾病，然而，15-45% 的 COPD 患者还报告有哮喘病史。临床亚组，症状增加、病情加重和住院治疗可以通过肺活量测定轻松诊断，但目前还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临床特征。我们认为，要在 ACOS 的流行病学和基因组学研究中取得进展，需要改进表型定义，但很少有大型队列适合这项研究。 COPD 的遗传流行病学研究 (COPDGene)，我们小组通过调查问卷确定了 ACOS 的临床、影像和遗传特征。在本提案中，我们将通过以下具体内容来解决 ACOS 的表型和基因组学问题。目的 (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。我们将测量 COPDGene 中测量的总免疫球蛋白 E (IgE) 水平和特异性免疫球蛋白 E (IgE) 水平。 COPDGene 的第 2 期研究将检查与普通 COPD 相比具有过敏性致敏和/或外周嗜酸性粒细胞增多的 ACOS 受试者的基线、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，以识别与普通患者相比，患有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。 COPD。我们将 RNA-seq 结果与全基因组单核苷酸多态性 (SNP) 数据相结合，以确定与差异表达基因转录水平相关的 eQTL SNP (3) 系统基因组学。 ACOS：我们将测试使用网络方法识别的 ACOS 中重要的潜在功能机制和遗传调控效应，在子目标 (a) 中，我们将使用 RNA-seq 数据构建基因网络，比较 ACOS 和常见 COPD 中的调控连接，并确定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 ACOS 和普通慢性阻塞性肺病 (COPD) 受试者的淋巴母细胞系中的关键基因的 siRNA 敲除来进行网络的体外验证。生物标志物和RNA-seq 数据发现对临床相关的哮喘-COPD 重叠综合征的遗传影响，可以识别 ACOS 的客观诊断标记或新的途径和靶点，从而朝着 COPD 精准医学的目标迈进。数据集将作为 COPDGene 和 COPD 研究人员社区的资源。