Integrative genomic, transcriptomic and proteomic studies of pulmonary function and COPD

肺功能和 COPD 的综合基因组学、转录组学和蛋白质组学研究

基本信息

批准号：
10210659
负责人：
MICHAEL H. CHO
金额：
$ 76.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10210659
关键词：
Address Affect African African American Age Biological Biological Markers CRISPR/Cas technology Candidate Disease Gene Cause of Death Cell Line Cells Chronic Obstructive Airway Disease Classification Communities Data Data Set Disease Drug Targeting Epidemiology Ethnic Origin European Family Forced expiratory volume function Funding Gene Expression Gene Frequency Gene Proteins Gene Targeting General Population Genes Genetic Genetic Risk Genetic Variation Genome Genomics Health Hispanics Latino Lung Measures Methods Minor Modeling Molecular Molecular Target Morbidity - disease rate Multi-Ethnic Study of Atherosclerosis Multiomic Data National Heart, Lung, and Blood Institute Participant Pathogenesis Pathway interactions Performance Peripheral Blood Mononuclear Cell Pharmacology Phenotype Population Proteomics Publishing Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary function tests Pulmonology Quantitative Trait Loci Race Research Resources Risk Risk Factors Sample Size Sampling Sequence Analysis Signal Transduction Structure of parenchyma of lung Target Populations Tissues Trans-Omics for Precision Medicine United States Update Validation Variant Vital capacity Whole Blood X Chromosome base biobank bronchial epithelium candidate marker cigarette smoking cohort ethnic diversity experimental study genetic association genetic resource genome wide association study genome-wide genomic locus improved mortality multi-ethnic multiple data sources multiple omics novel novel marker phenome polygenic risk score population based programs pulmonary function rare variant risk prediction risk prediction model risk variant smoking cessation trait transcriptome sequencing transcriptomics whole genome

项目摘要

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. COPD is defined by a decrease in lung function as measured by pulmonary function testing (PFT), namely forced expiratory volume in one second (FEV1) and its ratio to forced vital capacity (FEV1/FVC). While the main risk factor for COPD is cigarette smoking, the risk of COPD also increases with age, and COPD can progress despite smoking cessation. There are no current pharmacologic therapies that slow progression of COPD or affect mortality. Large-scale genome-wide association studies (GWAS) of PFT and COPD have identified > 200 associated genetic loci. However, COPD and PFT GWAS have been limited by imperfect matching and sample sizes of reference panels (e.g. HapMap or 1000 Genomes), and downstream interpretation has been limited by lack of disease- and tissue-specific eQTL and pQTL resources and under-represention in African American and Hispanic/Latino subjects for both common and rare variants. In addition, all studies used for GWAS performed to date have limited representation of rare and infrequent risk-associated variants. The NHLBI TOPMed program is now generating RNA-seq and proteomics data for thousands of TOPMed participants with whole genome sequence (WGS) data. TOPMed specifically is enhanced with subjects of non- European ancestry populations, thereby increasing ethnic diversity and including participants from the population-based Multi-Ethnic Study of Atherosclerosis [MESA], the COPD-enriched COPDGene study, and the Lung Tissue Research Consortium [LTRC]). We hypothesize systematic integration of multi-omic data with novel rare/infrequent variant associations identified through TOPMed will accelerate discovery and validation of novel biomarkers, definition of the molecular mechanisms underlying pathogenesis of COPD, and construction of improved genetic risk models for diverse ancestry populations. To address these overarching hypotheses, we propose two Specific Aims. In Aim 1, we will identify rare/infrequent and common variation underlying PFT and COPD through expanded WGS analysis in TOPMed, perform multi-ancestry fine mapping, and construct new genetic risk prediction models tailored to African ancestry and multi-ancestry applications. In Aim 2, we will identify and validate candidate genes and molecular targets underlying known and novel genetic associations for PFT / COPD through comprehensive multi-omic and functional studies. To accomplish these Aims, we will combine the most current methods for WGS analysis with novel multi-omics approaches to leverage our large-scale high quality RNA-seq and proteomic resources. We have assembled an interdisciplinary collaborative group representing expertise in statistical genetics, pulmonary epidemiology, integrative genomics, proteomics, and pulmonary medicine. Completion of these Aims will establish an expanded view of rare and common genetic variation and their downstream molecular targets in multi-ethnic samples from population-based and COPD-enriched cohorts.

慢性阻塞性肺疾病（COPD）是美国第四大死因。 COPD 的定义是通过肺功能测试 (PFT) 测量的肺功能下降，即一秒用力呼气量 (FEV1) 及其与用力肺活量的比率 (FEV1/FVC)。虽然主要慢性阻塞性肺病的危险因素是吸烟，慢性阻塞性肺病的风险也随着年龄的增长而增加，并且慢性阻塞性肺病可以进展尽管戒烟了。目前尚无药物疗法可以减缓 COPD 的进展或影响死亡率。 PFT 和 COPD 的大规模全基因组关联研究 (GWAS) 已确定 > 200 个相关遗传位点。然而，COPD 和 PFT GWAS 受到不完善匹配和参考面板的样本大小（例如 HapMap 或 1000 个基因组），以及下游解释由于缺乏疾病和组织特异性 eQTL 和 pQTL 资源以及非洲代表性不足而受到限制美国和西班牙/拉丁裔受试者的常见和罕见变异。此外，所有研究均用于迄今为止进行的 GWAS 对罕见和不常见的风险相关变异的代表性有限。这 NHLBI TOPMed 项目现在正在为数千名 TOPMed 生成 RNA 测序和蛋白质组学数据参与者拥有全基因组序列（WGS）数据。 TOPMed 特别针对非欧洲血统人口，从而增加了种族多样性，并包括来自欧洲的参与者基于人群的动脉粥样硬化多种族研究 [MESA]、富含 COPD 的 COPDGene 研究，以及肺组织研究联盟 [LTRC]）。我们假设多组学数据的系统整合通过 TOPMed 识别的新的罕见/不常见变异关联将加速发现和验证新的生物标志物、COPD发病机制的分子机制的定义和构建改进不同血统人群的遗传风险模型。为了解决这些总体假设，我们提出两个具体目标。在目标 1 中，我们将识别潜在的罕见/不常见和常见变异 PFT 和 COPD 通过 TOPMed 中的扩展 WGS 分析，执行多祖先精细映射，并构建适合非洲血统和多血统的新遗传风险预测模型应用程序。在目标 2 中，我们将识别并验证候选基因和潜在的分子靶标通过综合多组学和研究发现 PFT / COPD 的已知和新颖的遗传关联功能研究。为了实现这些目标，我们将结合最新的 WGS 分析方法通过新颖的多组学方法来利用我们的大规模高质量 RNA-seq 和蛋白质组学资源。我们组建了一个跨学科合作小组，代表统计遗传学方面的专业知识，肺部流行病学、综合基因组学、蛋白质组学和肺部医学。完成这些目标将建立罕见和常见遗传变异及其下游分子的扩展视野来自基于人群和富含慢性阻塞性肺病的队列的多种族样本中的目标。