Women are disproportionately affected by stroke and many of the strongest risk factors for ischemic stroke in women are associated with altered metabolism. However, exactly how these metabolic alterations directly impact the pathophysiology of stroke is unclear. Metabolomic techniques measure a full profile of small-molecule metabolites, providing a comprehensive picture of an individual's metabolic status. Although preliminary results for cardiovascular disease are promising, no prospective studies for stroke have been conducted. In this application, we propose to evaluate the associations of individual metabolite and metabolomic profiles with subsequent ischemic stroke among women in the Nurses' Health Study I and Nurses' Health Study II, ongoing longitudinal prospective cohort studies. The proposed investigations will use archived fasting blood specimens in concert with detailed behavioral, medical and lifestyle variables. A validated, state-of- the-art metabolomic platform will characterize over 300 metabolites by liquid chromatography tandem mass spectrometry, as well as provide untargeted data. Utilizing a nested case-control design, a two-phase analysis will be conducted with a discovery cohort of 400 stroke cases and their matched controls and a validation cohort of 300 stroke cases/controls to identify and validate novel metabolite and metabolomic profiles associated with incident ischemic stroke in women. Replication in two external cohorts will also be performed. Exploratory analyses will compare the metabolite profiles by subtype of ischemic stroke. Discovery of novel metabolic pathways not previously known to be involved in the pathogenesis of stroke could ultimately lead to new approaches for prevention in the general population and further reduction in morbidity and mortality from stroke.

Public Health Relevance

This grant will assess novel metabolomic markers, small-molecule metabolites that provide a comprehensive picture of an individual's metabolic status, with risk of stroke, the 3rd leading cause of death in women. Metabolomic approaches may identify novel precursors of disease, effectors of the disease process, and may identify pathways for dietary or drug modulation. While studies in the acute stroke setting have been promising, no prospective studies of metabolomics and stroke have been performed; thus the proposed study may provide new insight into mechanisms contributing to stroke risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088521-08
Application #
9417071
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Nelson, Cheryl R
Project Start
2007-04-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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