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）：该提案是对 PAR-13-382 的回应，支持对现有大型基因组数据集进行二次数据分析，以识别基因与环境 (GxE) 的相互作用。肺功能及其在老年时的衰退可能是遗传和环境影响的结果。吸烟是导致肺功能随时间丧失的一个关键环境因素。全基因组关联研究 (GWAS) 确定了 26 个与肺功能横断面肺活量测量相关的基因位点。最近肺功能纵向变化的 GWAS 发现了其他新的位点。迄今为止，只有一项已发表的 GxE 相互作用对肺功能的全基因组研究将吸烟视为感兴趣的环境。这项全基因组 GxE 研究使用了肺功能和吸烟的常见变异和横截面信息，以确定以前与肺功能无关的三个新位点。总的来说，这些已发表的研究为了解肺功能的病因学做出了重要贡献，并得到了基因组流行病学心脏和衰老队列 (CHARGE) 联盟和 CHARGE 肺工作组的组织结构和支持的促进。需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。 该提案的目的是利用利用现有数据资源的最先进的统计方法和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对来自 Illumina HumanExome BeadChip（“外显子芯片”）的数据进行分析，该芯片针对约 33,800 名欧洲血统个体进行了肺功能肺功能测量，所有这些人还对吸烟史和肺功能进行了纵向测量。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) 及其比率 (FEV1/FVC)。这些肺功能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。 它随着时间的推移而进展。 CHARGE 联盟内提供的大量表型和外显子组芯片数据为应用新的分析途径和方法提供了独特且经济高效的机会。该应用有两个新颖的方面：1）研究罕见变化和环境相互作用，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之间相互作用的“下一步”。 这项研究的结果可能会揭示对吸烟暴露的新的遗传易感性，或者更好地了解吸烟在肺功能下降的发生、进展和严重程度中的作用。