Unraveling ancestry and environmental exposure interactions in childhood asthma

 描述（由申请人提供）：这项拟议研究的目的是确定环境暴露风险因素在多大程度上改变了非洲裔美国人（AA）受试者的哮喘风险。最近的研究已经确定了导致哮喘风险的遗传和环境暴露因素;然而，这些因素在多大程度上解释了一个人患哮喘的风险仍然是未知的。我们的长期目标是开发一个研究项目，深入了解AA儿童哮喘的遗传祖先和环境原因之间的复杂相互作用，并建立这些信息的实用性，以预测和降低AA儿童的哮喘风险。尽管哮喘护理取得了进展，但AA患者住院的可能性是非AA患者的四倍，死于哮喘的可能性是非AA患者的七倍。AA具有混合的亲本基因组贡献，具有来自非洲和欧洲血统的不同比例的祖先。我们计划寻找异常高的非洲或欧洲血统的特定基因组区域，以确定可能与环境暴露哮喘风险因素相互作用的染色体片段。我们假设，祖先和环境暴露的危险因素是至关重要的哮喘风险。提出了三个具体目标来检验我们的假设并实现我们提出的计划：目标1）确定遗传祖先并使用多种族基因分型阵列对AA哮喘儿童进行混合作图;目标2）确定当地祖先和环境暴露风险因素之间在改变哮喘风险方面的相互作用;目标3）复制最有希望的祖先特异性和A：E相互作用的6000个SNPs，并开发一个遗传祖先风险评分（加尔斯），以潜在地解释哮喘风险的一个重要部分。为了完成这些目标，我们将分析来自辛辛那提儿童医院医学中心儿科储存库队列和辛辛那提生物库的遗传、环境暴露因素、临床和流行病学数据。这项研究将提高我们对改变哮喘风险的祖先和环境暴露因素（交通，吸烟，霉菌）之间相互作用的理解。使用独特的基于祖先的研究设计，我们特别有能力制定路线图，以揭示遗传和环境暴露差异的相对贡献，并揭示少数民族儿童哮喘的病因。预测哮喘的发展或进展是我们研究的最终目标之一。1

 DESCRIPTION (provided by applicant): The goal of this proposed research is to determine to what extent asthma risk in African American (AA) subjects is modified by environmental exposure risk factors. Recent studies have identified genetic and environmental exposure factors that contribute to asthma risk; however, the extent to which these factors explain a person's risk to asthma remains largely unknown. Our long-term goal is to develop a program of study that would lead to an in-depth understanding of the complex interplay between genetic ancestry and environmental causes of asthma among AA children, and establish the utility of this information to predict and reduce asthma risk in AA children. Despite advances in asthma care, AAs are four times more likely to be hospitalized and seven times more likely to die from asthma than non-AAs. AAs have a mixed parental genome contribution with varying proportion of ancestry from African and European descents. We plan to search for specific genomic regions of unusually high African or European ancestry to identify chromosomal segments that are likely to interact with environmental exposure asthma risk factors. We hypothesize that ancestry and environmental exposure risk factors are critical in asthma risk. Three Specific Aims are proposed to test our hypothesis and achieve our proposed plan: Aim 1) Determine the genetic ancestry and conduct admixture mapping of AA asthmatic children using a multi-ethnic genotyping array; Aim 2) Identify interactions between local ancestry and environmental exposure risk factors in modifying asthma risk; and Aim 3) Replicate the most promising ancestry-specific and A:E interacting 6000 SNPs and develop a genetic ancestry risk score (GARS) to potentially explain a significant portion of asthma risk. To complete these aims we will analyze genetic, environmental exposure factors, clinical and epidemiologic data from the Cincinnati Children's Hospital Medical Center pediatric repository cohorts and Cincinnati BioBank. This research will improve our understanding of the interplay between ancestry and environmental exposure factors (traffic, cigarette smoke, mold) that modify asthma risk. Using a unique ancestry-based study design, we are particularly well positioned to develop a roadmap to unravel the relative contributions of genetic and environmental exposure variances and uncover the etiology of asthma in minority children. Predicting the development or progression of asthma is one of the ultimate aims of our research. 1