Unraveling ancestry and environmental exposure interactions in childhood asthma

 描述(由申请人提供)：这项拟议研究的目标是确定非裔美国人(AA)受试者的哮喘风险在多大程度上受到环境暴露风险因素的影响。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在很大程度上尚不清楚。我们的长期目标是制定一项研究计划，深入了解再生障碍性贫血儿童哮喘的遗传祖先和环境原因之间的复杂相互作用，并建立这些信息在预测和降低再生障碍性贫血儿童哮喘风险方面的效用。尽管哮喘治疗取得了进展，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具有混合的父母基因组贡献，其祖先来自非洲和欧洲的后代比例不同。我们计划寻找非洲或欧洲血统异常高的特定基因组区域，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。我们假设血统和环境暴露危险因素在哮喘风险中起关键作用。为了检验我们的假设并实现我们提出的计划，我们提出了三个具体目标：目的1)利用多种族基因分型阵列确定AA哮喘儿童的遗传祖先，并进行混合图谱；目的2)确定当地血统和环境暴露风险因素在改变哮喘风险方面的交互作用；以及目标3)复制最有希望的祖先特有和A：E相互作用的6000个SNP，并开发遗传祖先风险评分(GARS)，潜在地解释很大一部分哮喘风险。为了实现这些目标，我们将分析来自辛辛那提儿童医院医学中心儿科资料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祖先和环境暴露因素(交通、香烟烟雾、霉菌)之间相互作用的理解，这些因素会改变哮喘的风险。使用独特的基于祖先的研究设计，我们特别适合制定路线图，以揭示遗传和环境暴露差异的相对贡献，并揭示少数族裔儿童哮喘的病因。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