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

• 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
• 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

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)：这项建议是对PAR-13-382的响应，支持对现有大型基因组数据集的二级数据分析，以确定基因与环境(GxE)的相互作用。老年人的肺功能和肺功能下降可能是遗传和环境影响的结果。随着时间的推移，吸烟是导致肺功能丧失的关键环境因素。全基因组关联研究确定了26个与肺功能的横断面肺活量测量相关的遗传位点。最近GWA发现了肺功能纵向变化的新的基因座.到目前为止，只有一项已发表的关于GxE相互作用对肺功能影响的全基因组研究将吸烟视为感兴趣的环境。这项全基因组的GxE研究使用了关于肺功能和吸烟的共同变异和横断面信息，以确定三个以前与肺功能无关的新基因座。总体而言，这些已发表的研究对理解肺功能的病因做出了重要贡献，并得到了基因组流行病学心脏和衰老队列(CHARE)联盟和CHARE肺工作组的组织结构和支持。为了进一步了解吸烟如何与遗传因素相互作用影响肺功能，有必要进行进一步的研究。这项建议的目的是利用最先进的统计方法和利用现有数据资源的分析策略来阐明肺功能背后的基因和环境的复杂相互作用。Charge肺工作组正在进行的工作包括分析来自Illumina Human Exome BeadChip(“Exome芯片”)的数据，对大约33,800名欧洲血统的人进行肺功能的肺活量测量，所有这些人都有吸烟史和肺功能的纵向测量。另外约6,000名非洲血统的人有肺功能、吸烟史和外显子芯片数据的测量，约3,800人也有纵向测量。肺活量测量包括一秒用力呼气量(FEV1)、用力肺活量(FVC)及其比值(FEV1/FVC)。这些肺功能指标是诊断肺部疾病、对其严重程度进行分类和评估的重要临床工具。 它会随着时间的推移而发展。Charge联盟内可获得的大量表型和外显子组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。这种应用有两个新的方面：1)稀有变化和环境相互作用的调查，2)环境因素的纵向测量的调查。这项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之间的相互作用的“下一步”。 这项研究的结果可能揭示吸烟暴露的新的遗传易感性，或者更好地理解吸烟在肺功能下降的发展、进展和严重程度中所起的作用。