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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099209-02
Application #
9385315
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Bosetti, Francesca
Project Start
2016-12-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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