Unraveling ancestry and environmental exposure interactions in childhood asthma

揭开儿童哮喘的祖先和环境暴露的相互作用

• 批准号: 9246597
• 负责人: Tesfaye B. Mersha
• 金额: $ 67.66万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246597
• 关键词: Address; Admixture; Affect; African; African American; Age; Architecture; Asthma; Caring; Child; Childhood; Childhood Asthma; Clinic; Clinical Data; Complex; Computerized Medical Record; DNA; Data; Development; Disease; Environmental Exposure; Environmental Risk Factor; Etiology; European; Exhibits; Exposure to; Gene Frequency; Genetic; Genome; Genomic Segment; Genotype; Goals; Haplotypes; Individual; K-Series Research Career Programs; Lead; Medical center; Molds; Morbidity - disease rate; Patient Self-Report; Pattern; Pediatric Hospitals; Persons; Phenotype; Population; Positioning Attribute; Predisposition; Principal Investigator; Probability; Protocols documentation; Public Health; Race; Research; Research Design; Risk; Risk Factors; Running; Sample Size; Sampling; Socioeconomic Status; Subgroup; Testing; Time; Translational Research; United States; Variant; admixture mapping; asthmatic; base; biobank; cigarette smoking; cohort; conditioning; design; epidemiologic data; gene environment interaction; genome wide association study; genome-wide; improved; innovation; insight; minority children; novel; predictive modeling; programs; public health intervention; public health relevance; repository; risk variant; sex; study population; success

 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

 描述（由申请人提供）：这项拟议研究的目标是确定环境暴露风险因素在多大程度上改变非裔美国人 (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很大程度上未知。我们的长期目标是制定一项研究计划，深入了解 AA 儿童哮喘的遗传血统和环境原因之间复杂的相互作用，并利用这些信息来预测和降低 AA 儿童的哮喘风险。尽管哮喘护理取得了进步，但 AA 住院的可能性是非 AA 的四倍，死于哮喘的可能性是非 AA 的七倍。 AA 具有混合的亲本基因组贡献，其中非洲和欧洲血统的比例不同。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危险因素相互作用的染色体片段。我们假设血统和环境暴露风险因素对于哮喘风险至关重要。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) 使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；目标 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 SNP，并开发遗传祖先风险评分 (GARS)，以潜在地解释哮喘风险的很大一部分。为了实现这些目标，我们将分析来自辛辛那提儿童医院医疗中心儿科存储库队列和辛辛那提生物银行的遗传、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影响哮喘风险的血统和环境暴露因素（交通、香烟烟雾、霉菌）之间相互作用的理解。使用独特的基于血统的研究设计，我们特别有能力制定路线图，以阐明遗传和环境暴露差异的相对影响，并揭示少数民族儿童哮喘的病因。预测哮喘的发生或进展是我们研究的最终目标之一。 1