An Integrative Genomics Approach to Gene by Environment Interactions in Asthma

摘要 哮喘是儿童最常见的慢性病，占儿童发病率的显著下降 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相互作用的复杂结果 基因和环境。尽管全基因组扫描的出现为我们提供了丰富的数据集 数以千计的基因的多态，环境对这些压倒性的数据的利用 互动研究仍然具有挑战性。全基因组表达(MRNA)信号的响应 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- 激活途径通过环境交互作用模型在基因中得到验证。一个重要的环境问题 已知影响哮喘发病率和哮喘严重程度的因素是接触细菌和霉菌 环境。被称为PAMPs(病原体相关分子模式)的微生物成分可以调节 免疫系统可以降低哮喘的易感性，或者使呼吸道状况恶化 发炎和喘息。这项建议概述了一种综合基因组学策略，用于研究基因如何 在五个队列中，基因多态改变了微生物暴露对哮喘表型的影响。首先，我们将 分析PAMP刺激的免疫细胞全基因组表达谱以确定基因靶点 与环境微生物相互作用。接下来，我们将确定这些基因的多态是否 单独或作为功能相关基因中的SNP集，改变环境细菌和真菌的影响 关于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 PAMP信号基因改变基因表达以响应微生物刺激。

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.