Metabolomic predictors of stroke in REGARDS

摘要 在非洲裔美国人（AA）和美国人中， 美国东南部，尽管环境和/或遗传基础仍然不完全 定义了由于代谢物整合了环境和遗传因素，因此它们是近端的 人类疾病的标志物。在职业发展奖的支持下，我们建立了一个快速， 这是一个多功能代谢组学平台，可应用于大型流行病学队列。我们现在寻求 我们的研究重点是脑血管疾病的代谢物预测因素，这个领域已经得到了相对的关注 很少注意。为了解决这些知识差距，我们建议在中风中进行代谢组学研究 多民族 中风的地理和种族差异的原因（ 研究，进一步 在杰克逊心脏研究（JHS）和心脏病研究（FHS）中进行了重复。我们将测试 在表型良好人群中代谢组学将阐明卒中相关代谢物的假设 他们之间的种族差异，在目标1中，我们将确定代谢物风险因素， 在REGARDS研究的病例对照队列中，按亚型分层的卒中事件。我们会侧写 在约1200例发病卒中病例和约1200例年龄匹配的对照中， 性别和种族在目标2中，我们将确定已知中风临床风险特征的新代谢物标志物， 包括心房纤颤、高血压、饮食和锻炼。在目标3中，我们将验证新型代谢物 JHS和FHS队列中卒中事件和相关风险特征的预测因子。我们还将测试 决定代谢物水平的遗传变异反过来又通过遗传风险与临床特征相关， 评分分析凭借广泛的研究数据，REGARDS研究具有独特的优势，可以促进 这个提议。利用一种新的小分子分析平台，我们的初步研究表明， 目标的可行性和意义。我们的多学科合作包括MGH的研究人员， UAB和辛辛那提大学，他们带来了代谢物分析，生物标志物，遗传和 人口流行病学、生物信息学、代谢特征和健康差异。最后，所有数据将被 公开提供，为中风研究社区提供独特的科学资源。

Abstract There is a disproportionate burden of stroke among African Americans (AA) and individuals in the Southeastern United States, although the environmental and/or genetic underpinnings remain incompletely defined. Because metabolites integrate both environmental and genetic factors, they serve as proximal markers of human disease. In prior work supported by a Career Development Award, we established a rapid, multifunctional metabolomics platform that can be applied to large epidemiological cohorts. We now seek to focus our study on the metabolite predictors of cerebrovascular disease, an area that has received relatively little attention. To address these gaps in knowledge, we propose conducting metabolomics in stroke in the multiethnic REasons for Geographic and Racial Differences in Stroke ( REGARDS) study, with further replication in the Jackson Heart Study (JHS) and Framingham Heart Study (FHS). We will test the overarching hypothesis that metabolomics in well-phenotyped populations will illuminate stroke-associated metabolite pathways, and unravel racial differences among them. In Aim 1, we will identify metabolite risk factors for incident stroke, stratified by subtype, in the case-control cohort of the REGARDS study. We will profile metabolites from the baseline examination in ~1200 incident stroke cases and ~1200 controls matched for age, sex and race. In Aim 2, we will identify novel metabolite markers of known clinical risk traits for stroke, including atrial fibrillation, hypertension, diet and exercise. In Aim 3, we will validate novel metabolite predictors of incident stroke and associated risk traits in the JHS and FHS cohorts. We will also test whether genetic variants that determine metabolite levels are in turn associated with clinical traits, through genetic risk score analysis. With extensive study data, the REGARDS study is uniquely positioned to catalyze the Aims of this proposal. Leveraging a novel small molecule profiling platform, our preliminary studies demonstrate the feasibility and significance of the Aims. Our multidisciplinary collaboration includes investigators at the MGH, UAB and University of Cincinnati, who bring collective expertise in metabolite profiling, biomarkers, genetic and population epidemiology, bioinformatics, metabolic traits, and health disparities. Finally, all data will be made publicly available, producing a unique scientific resource for the stroke research community.