Genome-wide gene-by-smoking interaction analysis of pulmonary 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，以确定基因-环境（GxE）相互作用。肺功能及其在老年期的衰退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（GWAS）确定了26个与肺功能横断面肺活量测定相关的遗传位点。最近对肺功能纵向变化的GWAS发现了额外的新位点。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研究利用肺功能和吸烟的共同变异和横断面信息，确定了三个以前与肺功能无关的新位点。总的来说，这些已发表的研究对理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与衰老队列（cohort for Heart and Aging In Genomic Epidemiology， CHARGE）联盟和CHARGE肺部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从而影响肺功能，需要进一步的研究。本提案的目的是利用现有数据资源，利用最先进的统计方法和分析策略阐明肺功能中基因和环境的复杂相互作用。CHARGE肺工作小组正在进行的工作包括分析来自Illumina HumanExome BeadChip（“外显子组芯片”）的数据，这些数据来自约33,800名欧洲血统的人，他们都有肺功能的肺功能测量，所有这些人都有吸烟史和肺功能的纵向测量。另外约6000名非洲血统的人有肺功能、吸烟史和外显子组芯片数据的测量，约3800人也有纵向测量。肺活量测量包括用力呼气量（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

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.