An Integrative Genomics Approach to Gene by Environment Interactions in Asthma

通过环境相互作用研究哮喘基因的综合基因组学方法

• 批准号: 9066168
• 负责人: JOANNE ELAINE SORDILLO
• 金额: $ 16.29万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-11-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066168
• 关键词: Accounting; Affect; Asthma; Bacteria; Binding; Birth; Candidate Disease Gene; Cells; Child; Childhood; Chronic; Chronic Disease; Cohort Studies; Complex; DNA Methylation; DNA Sequence; Data; Data Set; Development; Development Plans; Disease; Endotoxins; Enrollment; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Exposure to; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Targeting; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome Scan; Genomic approach; Genomics; Goals; Grant; Immune; Immune response; Immune system; Incidence; Individual; Inflammatory; Methods; Methylation; Microbe; Modeling; Modification; Molds; Molecular; Molecular Profiling; Morbidity - disease rate; Pathogenesis; Pathway interactions; Pattern; Peptidoglycan; Peripheral Blood Mononuclear Cell; Phenotype; Play; Predisposition; Production; Quality of life; Regulatory T-Lymphocyte; Research; Research Personnel; Risk; Severities; Signal Transduction; Single Nucleotide Polymorphism; Stimulus; Symptoms; Testing; Tissue-Specific Gene Expression; Toll-like receptors; Up-Regulation; Wheezing; airway inflammation; asthmatic; career development; cohort; cytokine; differential expression; environmental intervention; fungus; gene environment interaction; gene interaction; genetic epidemiology; genome-wide; improved; infancy; interest; mRNA Expression; microbial; novel; pathogen; public health relevance; response

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.

抽象的 哮喘是儿童期最常见的慢性疾病，发病率很高，并且发病率降低 生活质量。与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 数千个基因的多态性，通过环境利用大量的基因数据 相互作用研究仍然具有挑战性。响应于产生的全基因组表达（mRNA）信号 感兴趣的暴露可以帮助我们关注全基因组数据，这样只有相关基因的多态性 通过环境相互作用模型在基因中测试激活途径。一项重要的环境 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。称为 PAMP（病原体相关分子模式）的微生物成分可以调节 以降低哮喘易感性或恶化气道的方式影响免疫系统 炎症和喘息。该提案概述了一种综合基因组学策略，用于研究遗传如何 多态性改变了五个队列中微生物暴露对哮喘表型的影响。首先，我们将 分析 PAMP 刺激的免疫细胞的全基因组表达 (mRNA) 谱，以确定基因靶标 用于与环境微生物的相互作用。接下来，我们将确定这些基因是否存在多态性 单独或作为功能相关基因中的 S​​NP 设置，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）如何 PAMP 信号基因改变基因表达以响应微生物刺激。