Gene-Environment Interactions in Cystic Fibrosis Lung Disease

囊性纤维化肺病中的基因-环境相互作用

• 批准号: 9236216
• 负责人: Joseph Michael Collaco
• 金额: $ 28.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236216
• 关键词: Affect; Age; Candidate Disease Gene; Chronic Disease; Climate; Code; Complex; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Environmental Tobacco Smoke; Family; Forced expiratory volume function; Functional disorder; Genes; Genetic; Genome; Goals; Hereditary Disease; Home environment; Individual; Inflammatory; International; Life; Linear Regressions; Longevity; Lung; Lung diseases; Measurement; Measures; Methods; Modeling; Mutation; Outcome; Phenotype; Population; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Research; Research Personnel; Respiratory physiology; Siblings; Smoke; Smoker; TGFB1 gene; Temperature; Testing; Time; Tobacco smoke; Twin Multiple Birth; Variant; base; cohort; cystic fibrosis patients; environmental intervention; environmental tobacco smoke exposure; experience; family structure; gene environment interaction; genome wide association study; genome-wide; insight; interest; mortality; novel; patient population; population stratification; public health relevance; residence; respiratory; study population; tobacco exposure

 DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is one of the most common genetic disorders in the U.S., affecting over 30,000 people in the U.S. and 70,000 worldwide. It is associated with increased mortality with a median lifespan of 41.1 years in the U.S. Mortality is highly correlated with long-term lung function decline. Although the gene responsible for CF (CFTR) was identified 25 years ago, lung disease remains a complex disease as CF patients with identical mutations may have dramatically different lung function, thus implying involvement of factors other than the CFTR gene itself. Family-based studies by us and others suggest that ~50% of variation in CF lung disease can be attributed to modifier genes and ~50% to environmental modifiers. Although a consortium-based genome-wide association study has identified several regions of interest associated with CF lung function, the identified loci cannot explain a large fraction of the variability of CF lung function, thus suggesting gene-environment (GxE) interactions may be present. It is important to identify these interactions as they may explain the variation seen in CF lung disease, provide additional insight into CF lung disease pathophysiology, and provide data for our long-term of goal of identifying individuals who could benefit most from specific environmental interventions. The primary goal of our research is to identify gene-environment (GxE) interactions in CF lung disease by analyzing existing data from 2086 patients with CF (The CF Twin-Sibling Study) with replication of key findings in a larger international group of ~5000 individuals with CF. We will test for GxE interactions with 3 known environmental modifiers of CF lung disease that could interact with genetic modifiers to account for unexplained variation in lung disease. These modifiers include Pseudomonas aeruginosa, which often colonizes the lungs of CF patients, a micro-environmental factor (secondhand tobacco smoke exposure from smokers living in the home), and a macro-environmental factor (climate: ambient temperature). To increase our ability to detect GxE effects, we propose to use methods new to CF and relevant to GWAS studies, specifically mixed modeling with longitudinal lung function measurements. Completion of this research will enhance our understanding of GxE interactions in CF and the use of mixed models for longitudinal data in other chronic diseases.

 描述（由申请人提供）：囊性纤维化（CF）是美国最常见的遗传性疾病之一，影响了美国3万多人全球7万人它与死亡率增加相关，在美国中位寿命为41.1岁。死亡率与长期肺功能下降高度相关。虽然25年前就发现了CF的基因（CFTR），但肺部疾病仍然是一种复杂的疾病，因为具有相同突变的CF患者可能具有显著不同的肺功能，因此暗示了CFTR基因本身以外的因素的参与。我们和其他人基于家族的研究表明，CF肺病的变异约50%可归因于修饰基因，约50%归因于环境修饰因子。尽管一项基于联盟的全基因组关联研究已经确定了与CF肺功能相关的几个感兴趣区域，但确定的基因座不能 解释了CF肺功能变异性的很大一部分，从而表明可能存在基因-环境（GxE）相互作用。重要的是要确定这些相互作用，因为它们可以解释CF肺病中观察到的变化，为CF肺病病理生理学提供额外的见解，并为我们确定可以从特定环境干预中获益最多的个体的长期目标提供数据。我们研究的主要目标是通过分析2086例CF患者的现有数据（CF孪生兄弟研究）来确定CF肺病中的基因-环境（GxE）相互作用，并在约5000名CF患者的更大国际组中复制关键发现。我们将测试GxE与CF肺病的3种已知环境修饰剂的相互作用，这些环境修饰剂可能与遗传修饰剂相互作用，以解释肺病中无法解释的变异。这些修饰物包括铜绿假单胞菌，其通常定植于CF患者的肺部，微环境因素（来自居住在家中的吸烟者的二手烟草烟雾暴露）和宏观环境因素（气候：环境温度）。为了提高我们检测GxE效应的能力，我们建议使用CF的新方法和GWAS研究相关的方法，特别是纵向肺功能测量的混合建模。这项研究的完成将增强我们对CF中GxE相互作用的理解，并将混合模型用于其他慢性疾病的纵向数据。