An Integrative Genomics Approach to Gene by Environment Interactions in Asthma

摘要 哮喘是儿童期最常见的慢性疾病，占发病率的显著比例， 生活质量像许多其他慢性疾病一样，哮喘被认为是由以下因素之间复杂的相互作用引起的： 基因与环境虽然全基因组扫描的出现为我们提供了丰富的数据集， 数千个基因的多态性，利用这些压倒性的基因环境数据， 互动研究仍然具有挑战性。全基因组表达（mRNA）信号响应于 感兴趣的暴露可以帮助我们关注全基因组数据，因此只有相关基因的多态性， 在基因与环境相互作用模型中测试激活途径。重要的环境 已知影响哮喘发病率和哮喘严重程度的一个因素是暴露于 环境被称为PAMP（病原体相关分子模式）的微生物组分可以调节 免疫系统的方式，要么降低哮喘的易感性，或者，恶化气道 炎症和喘息。该提案概述了一个综合基因组学策略，用于研究遗传 多态性改变了微生物暴露对5个队列中哮喘表型的影响。一是 分析PAMP刺激的免疫细胞的全基因组表达（mRNA）谱以鉴定基因靶标 与环境微生物的相互作用。接下来，我们将确定这些基因中的多态性， 单独地或作为功能相关基因中的SNP组，改变环境细菌和真菌的影响， 哮喘的发病率和严重程度。最后，我们将研究表观遗传修饰（DNA甲基化）是如何影响 PAMP信号基因改变基因表达响应微生物刺激。

ABSTRACT Asthma is the most common chronic disease of childhood, accounting for significant morbidity and reduced quality of life. Like many other chronic diseases, asthma is thought to result from a complex interplay between genes and environment. Although the advent of genome wide scans has provided us with rich datasets of polymorphisms in thousands of genes, utilization of this overwhelming amount of data for gene by environment interaction studies remains challenging. Genome wide expression (mRNA) signals generated in response to exposures of interest can help us focus genome wide data, so that only polymorphisms in relevant gene- activation pathways are tested in gene by environment interaction models. One important environmental factor, known to influence both asthma incidence and asthma severity, is exposure to bacteria and mold in the environment. Microbial components called PAMPs (pathogen associated molecular patterns) can modulate the immune system in ways that either decrease susceptibility to asthma or, alternatively, worsen airway inflammation and wheeze. This proposal outlines an integrative genomics strategy for studying how genetic polymorphisms alter the effects of microbial exposures on asthma phenotypes in five cohorts. First, we will analyze genome wide expression (mRNA) profiles of PAMP-stimulated immune cells to identify gene targets for interaction with environmental microbes. Next, we will determine if polymorphisms in these genes, either individually or as SNP sets in functionally related genes, modify the effects of environmental bacteria and fungi on asthma incidence and severity. Finally, we will examine how epigenetic modifications (DNA methylation) of PAMP signaling genes alter gene expression in response to microbial stimuli.