AN INTEGRATIVE GENOMICS APPROACH TO GENE BY ENVIRONMENT INTERACTIONS IN ASTHMA

描述(申请人提供)：哮喘是儿童最常见的慢性疾病，占很大的发病率和生活质量下降。像许多其他慢性疾病一样，哮喘被认为是基因和环境之间复杂的相互作用的结果。尽管全基因组扫描的出现为我们提供了数千个基因的丰富多态数据集，但利用这些海量数据进行基因与环境相互作用研究仍然具有挑战性。对感兴趣的暴露做出响应而产生的全基因组表达信号可以帮助我们聚焦全基因组数据，以便只在基因与环境相互作用的模型中检验相关基因激活途径的多态。已知影响哮喘发病率和哮喘严重程度的一个重要环境因素是暴露于环境中的细菌和霉菌。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，降低哮喘的易感性，或者加重呼吸道炎症和喘息。这项建议概述了一种综合基因组学策略，用于研究遗传多态如何改变微生物暴露对五个队列中哮喘表型的影响。首先，我们将分析PAMP刺激的免疫细胞的全基因组表达(MRNA)谱，以确定与环境微生物相互作用的基因靶点。接下来，我们将确定这些基因的多态，无论是单独的，还是作为功能相关基因中的SNP集，是否会改变环境细菌和真菌对哮喘发病率和严重性的影响。最后，我们将研究PAMP信号基因的表观遗传修饰(DNA甲基化)如何改变基因表达，以响应微生物刺激。

DESCRIPTION (provided by applicant): 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.