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Published on: January 31, 2025
Association of Circulating Metabolites in Plasma or Serum and Risk of Stroke: Meta-analysis From 7 Prospective
Dina Vojinovic1, Marita Kalaoja1, Stella Trompet1
1From the Department of Epidemiology (D.V., N.A., M.A.I., C.M.v.D.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Computational Medicine (M. Kalaoja, M.A.-K., J.K.), Faculty of Medicine, University of Oulu and Biocenter Oulu, Finland; Departments of Gerontology and Geriatrics (S.T.), and Cardiology (S.T., J.W.J.), Leiden University Medical Center, the Netherlands; Estonian Genome Centre (K.F., N.T., T.E.), Institute of Genomics, and Institute of Molecular and Cell Biology (N.T.), University of Tartu, Estonia; Department of Epidemiology and Public Health (M.J.S., M. Kivimaki), UCL, London, UK; Department of Biostatistics (S.L., O.Y.), School of Public Health, Boston University, MA; Department of Public Health Solutions (A.S.H., M.P., V.S., P.J., J.K.), Finnish Institute for Health and Welfare; Institute for Molecular Medicine Finland (A.S.H., M.P.), University of Helsinki; BHF Glasgow Cardiovascular Research Centre (N.S.), Faculty of Medicine, UK; Department of Neurology (B.S.), Feinberg School of Medicine, Northwestern University, Chicago, IL; Framingham Heart Study (C.L.S., R.S.V., S.S.), MA; Department of Radiology and Nuclear Medicine (M.A.I.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Institute of Cardiovascular and Medical Sciences (D.J.S.), College of Medical, Veterinary and Life Sciences, University of Glasgow, UK; Systems Epidemiology (M.A.-K.), Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; NMR Metabolomics Laboratory (M.A.-K.), School of Pharmacy, University of Eastern Finland, Kuopio; Population Health Science (M.A.-K.), Bristol Medical School, and Medical Research Council Integrative Epidemiology Unit (M.A.-K.), University of Bristol, UK; Department of Epidemiology and Preventive Medicine (M.A.-K.), School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia; Netherlands Heart Institute (J.W.J.), Utrecht, the Netherlands; Department of Neurology (C.L.S., S.S.), Boston University School of Medicine; Broad Institute of MIT and Harvard (T.E.), Boston, MA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (C.L.S., S.S.), UT Health San Antonio, TX; Nuffield Department of Population Health (C.M.v.D.), University of Oxford, UK. D.V. is currently at the Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, the Netherlands, and K.F. is currently at the Institute of Mathematics and Statistics, University of Tartu, Estonia.
Objective:
To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings.
Methods:
We investigated the association of metabolites with risk of stroke in 7 prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by nuclear magnetic resonance technology. The relationship between metabolites and stroke was assessed with Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately.
Results:
The analyses revealed 10 significant metabolite associations. Amino acid histidine (hazard ratio [HR] per SD 0.90, 95% confidence interval [CI] 0.85, 0.94; p = 4.45 × 10-5), glycolysis-related metabolite pyruvate (HR per SD 1.09, 95% CI 1.04, 1.14; p = 7.45 × 10-4), acute-phase reaction marker glycoprotein acetyls (HR per SD 1.09, 95% CI 1.03, 1.15; p = 1.27 × 10-3), cholesterol in high-density lipoprotein (HDL) 2, and several other lipoprotein particles were associated with risk of stroke. When focused on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD 1.12, 95% CI 1.05, 1.19; p = 4.13 × 10-4) and total and free cholesterol in large HDL particles.
Conclusions:
We found association of amino acids, glycolysis-related metabolites, acute-phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.
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