Epigenome-wide variations and socio-environmental exposures in African American asthmatic children

摘要 哮喘是美国的一个主要公共卫生问题，影响着1100万儿童。尽管 在哮喘治疗方面的进展，非裔美国人(AA)住院的可能性是对照组的4倍 死于哮喘的可能性是欧洲裔美国人(EA)的5倍。有几个因素可能是 对观察到的哮喘种族差异负责，包括遗传和非遗传因素。 虽然表观遗传学似乎是遗传脆弱性和遗传易损性之间的关键生物学开关 社会-环境暴露，有限的研究可直接映射社会- 环境暴露与哮喘的表观基因组/基因组信息。此外，目前 方法不利用现有的地理空间数据，如环境暴露和 提高社区社会经济条件对哮喘风险的预测。在这项提案中，我们 将利用全面的地理编码算法、新的统计方法来整合社会、 将临床、环境、遗传和表观遗传学数据转化为哮喘风险的综合评分 分层和预测。这项研究的总体目标是进行全基因组 甲基序列分析和利用现有的表型良好的AA儿童哮喘队列 广泛的社会环境暴露和血统定制的多种族基因分型阵列 来自辛辛那提儿科知识库的(兆)数据，以准确确定和发展血统- 具体的哮喘风险分层和预测模型。此应用程序的目标是 进行表观基因组范围的关联研究(EWAS)，纳入地理编码邻域- 和个人层面的社会环境预测指标，以及新的分析战略，以创建 包含甲基化风险分数(MRS)、血统、环境的综合风险分数 暴露和社会特征可以预测哮喘。我们将实现这些目标 通过以下具体目标：1)开发特定于祖先的甲基化风险评分(MRS) 并测试其与导致哮喘的社会环境暴露之间的关系 风险。2)确定MRS在遗传血统与哮喘风险之间的中介作用。3) 开发一个多变量哮喘风险预测模型，包括MRS、遗传血统、 临床和社会环境风险因素。拟议的研究具有创新性，因为 这将是首次使用MRS方法来开发基于人群的风险概况 哮喘患者。这项研究将为使用风险分层进行筛查和 有针对性的干预。这项工作具有重要的意义，因为它可以作为研究 MRS、血统、社会环境和临床危险因素对种族的综合影响 除哮喘以外，其他有充分记录的常见复杂疾病之间的差异。

ABSTRACT Asthma is a major public health problem in the United States, affecting 11 million children. Despite advances in asthma care, African Americans (AAs) are 4 times more likely to be hospitalized and 5 times more likely to die from asthma than European Americans (EAs). Several factors could be responsible for the observed asthma racial disparities including genetic and non-genetic factors. While epigenetics appear to serve as a critical biological switch between genetic vulnerability and socio-environmental exposures, limited studies are available that directly map the socio- environmental exposures with asthmatic epigenome/genome information. In addition, current approach do not leverage existing geospatial data such as environmental exposure and neighborhood socioeconomic conditions to improve asthma risk prediction. In this proposal, we will utilize comprehensive geocoding algorithms, novel statistical methods to integrate social, clinical, environmental, genetic, and epigenetic data into a composite score for asthma risk stratification and prediction. The overall objective of this research is to conduct genome-wide Methyl-Seq analysis and leverage existing well-phenotyped AA pediatric asthma cohort with extensive socio-environmental exposures and ancestry-tailored multi-ethnic genotyping array (MEGA) data from Cincinnati Pediatrics Repository to accurately determine and develop ancestry- specific asthma risk stratification and prediction models. The objective of this application is to undertake an epigenome-wide association study (EWAS), incorporating geocoded neighborhood- and individual-level socio-environmental predictors, and novel analytical strategies to create a composite risk score incorporating methylation risk score (MRS), ancestry, environmental exposures and social characteristics to predict asthma. We will accomplish these objectives through the following Specific Aims: 1) Develop an ancestry-specific methylation risk score (MRS) for asthma and test its association with socio-environmental exposures contributing to asthma risk. 2) Determine the mediation effects of MRS between genetic ancestry and asthma risk. 3) Develop a multivariable risk predictive model for asthma incorporating MRS, genetic ancestry, clinical, and socio-environmental risk factors. The proposed research is innovative because this will be the first time a MRS approach will be used to develop a population-based risk profile in asthmatics. The study will provide insights in the use of risk stratification for screening and targeted interventions. This work is significant because it can serve as a model to study the composite effect of MRS, ancestry, socio-environmental, and clinical risk factors on racial disparities in other well-documented common complex diseases beyond asthma.