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.
There are geographic and racial disparities in the burden of stroke across the United States. In this proposal, we will apply novel metabolite profiling techniques developed by our group to test the hypothesis that metabolomics will illuminate stroke-associated markers and unravel racial differences in that risk. These efforts have the potential to improve our ability to identify individuals at risk for stroke and improve the understanding of underlying mechanisms of disease.
|Kimberly, W Taylor; Dutra, Bruna Garbugio; Boers, Anna M M et al. (2018) Association of Reperfusion With Brain Edema in Patients With Acute Ischemic Stroke: A Secondary Analysis of the MR CLEAN Trial. JAMA Neurol 75:453-461|
|Bevers, Matthew B; Battey, Thomas W K; Ostwaldt, Ann-Christin et al. (2018) Apparent Diffusion Coefficient Signal Intensity Ratio Predicts the Effect of Revascularization on Ischemic Cerebral Edema. Cerebrovasc Dis 45:93-100|
|Irvine, Hannah J; Ostwaldt, Ann-Christin; Bevers, Matthew B et al. (2018) Reperfusion after ischemic stroke is associated with reduced brain edema. J Cereb Blood Flow Metab 38:1807-1817|
|Sheth, Kevin N; Petersen, Nils H; Cheung, Ken et al. (2018) Long-Term Outcomes in Patients Aged ?70 Years With Intravenous Glyburide From the Phase II GAMES-RP Study of Large Hemispheric Infarction: An Exploratory Analysis. Stroke 49:1457-1463|
|Ostwaldt, Ann-Christin; Battey, Thomas W K; Irvine, Hannah J et al. (2018) Comparative Analysis of Markers of Mass Effect after Ischemic Stroke. J Neuroimaging 28:530-534|
|Kimberly, W Taylor; Bevers, Matthew B; von Kummer, Rüdiger et al. (2018) Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial. Neurology 91:e2163-e2169|
|Bevers, Matthew B; Kimberly, W Taylor (2017) Critical Care Management of Acute Ischemic Stroke. Curr Treat Options Cardiovasc Med 19:41|
|Kimberly, W Taylor; O'Sullivan, John F; Nath, Anjali K et al. (2017) Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis. JCI Insight 2:|
|Grunwald, Zachary; Beslow, Lauren A; Urday, Sebastian et al. (2017) Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage. Neurocrit Care 26:205-212|
|Wolcott, Zoe; Batra, Ayush; Bevers, Matthew B et al. (2017) Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke. Ann Clin Transl Neurol 4:553-563|
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