Genome-wide gene-by-smoking interaction analysis of pulmonary function

肺功能的全基因组基因与吸烟的相互作用分析

基本信息

批准号：
8807329
负责人：
Alanna C Morrison
金额：
$ 15.4万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8807329
关键词：
Adult Affect African Aging Architecture Biological Chronic Obstructive Airway Disease Cigarette Smoker Clinical Complex Data Data Analyses Data Set Development Diagnosis Environment Environmental Risk Factor Epidemiology Equation Etiology European Family Study Forced expiratory volume function Frequencies Genes Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomics Genotype Heart Heritability Individual Investigation Joints Lung Lung diseases Measures Methods Open Reading Frames Pathway interactions Phenotype Play Publishing Pulmonary Function Test/Forced Expiratory Volume 1 Reporting Research Research Infrastructure Resources Respiratory physiology Risk Risk Factors Role Severities Single Nucleotide Polymorphism Smoking Smoking History Statistical Methods Testing Time Twin Studies Variant Vital capacity Work base bead chip cigarette smoking cohort cost effective exome gene environment interaction genome wide association study genome-wide genome-wide analysis insight interest novel organizational structure public health relevance pulmonary function rare variant response tool trait working group

项目摘要

DESCRIPTION (provided by applicant): This proposal is in response to PAR-13-382, supporting secondary data analyses of existing large genomic datasets for the purpose of identifying gene-by-environment (GxE) interactions. Lung function and its decline in older adulthood is likely the result of genetic and environmental influences. Cigarette smoking is a key environmental context for loss of lung function over time. Genome-wide association studies (GWAS) identified 26 genetic loci associated with cross-sectional spirometric measures of lung function. Recent GWAS of the longitudinal change in lung function have identified additional novel loci. To date, there is only one published genome-wide study of GxE interaction on lung function that considers smoking as the environment of interest. This genome-wide GxE study used common variation and cross-sectional information on lung function and smoking to identify three novel loci not previously associated with lung function. In aggregate, these published studies made important contributions to understanding the etiology of lung function, and were facilitated by the organizational structure and support of the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium and the CHARGE Pulmonary Working Group. Additional investigation is warranted to further understand how smoking interacts with genetic factors to influence lung function. The objective of this proposal is to elucidate the complex interplay of genes and environment underlying lung function using state-of-the-art statistical methods and analysis strategies that leverage available data resources. Ongoing work within the CHARGE Pulmonary Working Group includes analysis of data from the Illumina HumanExome BeadChip (the "exome chip") for ~33,800 individuals of European ancestry with spirometric measures of lung function, all of whom also have longitudinal measures of smoking history and lung function. An additional ~6,000 individuals of African ancestry have measures of lung function, smoking history, and exome chip data, and ~3,800 also have longitudinal measures. Spirometric measures include forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and their ratio (FEV1/FVC). These measures of lung function are important clinical tools for diagnosing pulmonary disease, classifying its severity, and evaluating its progression over time. The large volume of phenotype and exome chip data available within the CHARGE consortium provides a unique, cost-effective opportunity to apply new analytical approaches and methods. This application has two novel aspects: 1) investigation of rare variation and environmental interactions, and 2) investigation of longitudinal measures of environmental factors. The proposed research represents the "next step" in the efforts to investigate the interplay of genetic variation and environmental factors influencing lung function. Results from this study may disclose novel genetic susceptibilities to smoking exposure or a greater understanding of the role of smoking in the development, progression, and severity of declining lung function.

描述（由申请人提供）：该建议是对PAR-13-382的响应，支持现有大型基因组数据集的辅助数据分析，目的是鉴定基因环境（GXE）相互作用。肺功能及其成年期的下降可能是遗传和环境影响的结果。吸烟是随着时间的流逝肺功能丧失功能的关键环境。全基因组关联研究（GWAS）确定了与肺功能的横截面肺活量测量相关的26个遗传基因座。肺功能纵向变化的最新GWA已经确定了其他新型基因座。迄今为止，只有一项针对肺功能的GXE相互作用的全基因组相互作用研究，将吸烟视为感兴趣的环境。这项全基因组GXE研究使用了有关肺功能和吸烟的常见变异和横截面信息，以识别三个以前与肺功能无关的新型基因座。总体而言，这些已发表的研究为理解肺功能的病因做出了重要贡献，并由基因组流行病学（电荷）联盟和电荷肺部工作组的心脏和衰老的组织结构和支持促进。有必要进行额外的研究，以进一步了解吸烟如何与遗传因素相互作用以影响肺功能。该提案的目的是使用利用可用数据资源的最先进的统计方法和分析策略来阐明基因和环境的复杂相互作用。电荷肺部工作组中的正在进行的工作包括对〜33,800个欧洲血统的人的数据分析，其中包括肺功能的肺部功能，所有这些人都具有纵向吸烟史和肺功能的纵向测量。另外约6,000名非洲血统的人具有肺功能，吸烟史和外显子芯片数据的衡量标准，约3,800个也有纵向措施。肺活量测量包括一秒钟（FEV1），强制生命力（FVC）的强迫呼气量及其比率（FEV1/FVC）。这些肺功能的测量是诊断肺部疾病，对其严重程度进行分类和评估的重要临床工具随着时间的流逝，它的进展。电荷财团内可用的大量表型和外显子芯片数据为应用新的分析方法和方法提供了独特的，具有成本效益的机会。该应用具有两个新的方面：1）研究罕见变化和环境相互作用，以及2）研究环境因素的纵向测量。拟议的研究代表了研究遗传变异和影响肺功能的环境因素相互作用的努力的“下一步”。这项研究的结果可能会揭示吸烟暴露的新遗传敏感性或对吸烟在发育，进展和肺功能下降的严重程度中的作用的更多了解。