Gene-Environment Interactions in Cystic Fibrosis Lung Disease

 描述(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，在美国有超过30,000人受到影响，全世界有70,000人受到影响。它与死亡率的增加有关，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。尽管早在25年前就发现了导致肺纤维化(CFTR)的基因，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，从而暗示除了CFTR基因本身之外的其他因素参与其中。我们和其他人基于家庭的研究表明，大约50%的CF肺病变异可归因于修饰基因，约50%可归因于环境修饰基因。尽管一项基于联盟的全基因组关联研究已经确定了几个与CF肺功能相关的感兴趣区域，但所确定的基因座不能 解释了肺功能变异的很大一部分，从而提示可能存在基因-环境(GxE)交互作用。确定这些相互作用是很重要的，因为它们可以解释在CF肺部疾病中看到的变化，提供对CF肺部疾病病理生理学的更多洞察，并为我们确定谁可以从特定环境干预中获得最大好处的长期目标提供数据。我们研究的主要目标是通过分析2086名CF患者(CF双胞胎兄弟姐妹研究)的现有数据，以及在一个更大的国际CF组(约5000人)中的关键发现的重复，来确定CF肺部疾病中的基因-环境(GxE)交互作用。我们将测试GxE与3个已知的慢性肺病环境修饰物的相互作用，这些环境修饰物可能与遗传修饰物相互作用，以解释肺部疾病的不明原因的变异。这些修饰因素包括经常在CF患者肺部定居的铜绿假单胞菌、微观环境因素(居家吸烟者接触二手烟)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，我们建议使用新的方法来检测GxE效应，尤其是使用与纵向肺功能测量相结合的建模方法。这项研究的完成将加强我们对GxE在CF中的相互作用以及在其他慢性疾病中使用纵向数据的混合模型的理解。

 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.