AN INTEGRATIVE GENOMICS APPROACH TO GENE BY ENVIRONMENT INTERACTIONS IN ASTHMA

哮喘中基因与环境相互作用的综合基因组学方法

• 批准号: 8165785
• 负责人: JOANNE ELAINE SORDILLO
• 金额: $ 13.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165785
• 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 Targeting; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; 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; career development; cohort; cytokine; environmental intervention; fungus; gene environment interaction; gene interaction; genetic epidemiology; genome wide association study; genome-wide; improved; infancy; interest; mRNA Expression; microbial; novel; pathogen; response

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. PUBLIC HEALTH RELEVANCE: The K99/R00 grant proposes to identify novel gene by environment interactions in asthma incidence and asthma severity by integrating genome wide expression profiles, genetic polymorphisms and epigenetic data. This research will uncover genetic polymorphisms and epigenetic modifications that modify an individual's risk of asthma development or asthma exacerbation in response to bacteria and mold in the environment. These genetic susceptibility markers will help us to better understand asthma pathogenesis, and will also allow us to focus environmental interventions on those individuals who would benefit most.

描述（由申请人提供）：哮喘是儿童期最常见的慢性疾病，导致发病率显着并降低生活质量。与许多其他慢性疾病一样，哮喘被认为是基因与环境之间复杂相互作用的结果。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性数据集，但利用如此大量的数据进行基因与环境相互作用的研究仍然具有挑战性。响应感兴趣的暴露而产生的全基因组表达（mRNA）信号可以帮助我们集中全基因组数据，以便通过环境相互作用模型在基因中仅测试相关基因激活途径中的多态性。已知会影响哮喘发病率和哮喘严重程度的一项重要环境因素是接触环境中的细菌和霉菌。称为 PAMP（病原体相关分子模式）的微生物成分可以通过降低哮喘易感性或恶化气道炎症和喘息的方式调节免疫系统。该提案概述了一种综合基因组学策略，用于研究遗传多态性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标。接下来，我们将确定这些基因中的多态性（无论是单独的还是作为功能相关基因中的 S​​NP 集合）是否会改变环境细菌和真菌对哮喘发病率和严重程度的影响。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。 公共健康相关性：K99/R00 资助计划通过整合全基因组表达谱、遗传多态性和表观遗传数据，通过环境相互作用来识别哮喘发病率和哮喘严重程度的新基因。这项研究将揭示基因多态性和表观遗传修饰，这些修饰可以改变个体因环境中的细菌和霉菌而发生哮喘或哮喘恶化的风险。这些遗传易感性标记将帮助我们更好地了解哮喘发病机制，也将使我们能够将环境干预重点放在那些最受益的个体上。