University of Oulu

Association of Circulating Metabolites in Plasma or Serum and Risk of Stroke. Meta-analysis From 7 Prospective Cohorts. Dina Vojinovic, Marita Kalaoja, Stella Trompet, Krista Fischer, Martin J. Shipley, Shuo Li, Aki S. Havulinna, Markus Perola, Veikko Salomaa, Qiong Yang, Naveed Sattar, Pekka Jousilahti, Najaf Amin, Claudia L. Satizabal, Nele Taba, Behnam Sabayan, Ramachandran S. Vasan, M. Arfan Ikram, David J. Stott, Mika Ala-Korpela, J. Wouter Jukema, Sudha Seshadri, Johannes Kettunen, Mika Kivimaki, Tonu Esko, Cornelia M. van Duijn. Neurology Feb 2021, 96 (8) e1110-e1123; DOI: 10.1212/WNL.0000000000011236

Association of circulating metabolites in plasma or serum and risk of stroke : meta-analysis from seven prospective cohorts

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Author: Vojinovic, Dina1,2; Kalaoja, Marita3; Trompet, Stella4,5;
Organizations: 1Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
2Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, the Netherlands
3Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Finland
4Department of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands
5Department of Cardiology, Leiden University Medical Center, the Netherlands
6Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia
7Institute of Mathematics and Statistics, University of Tartu, Estonia
8Department of Epidemiology and Public Health, UCL, London, UK
9Department of Biostatistics, School of Public Health, Boston University, MA
10Department of Public Health Solutions, Finnish Institute for Health and Welfare
11Institute for Molecular Medicine Finland, University of Helsinki
12BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, UK
13Framingham Heart Study, MA
14Department of Neurology, Boston University School of Medicine
15Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, TX
16Institute of Molecular and Cell Biology, University of Tartu, Estonia
17Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL
18Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
19Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
20Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
21NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio
22Population Health Science, Bristol Medical School, and Medical Research Council Integrative Epidemiology Unit, University of Bristol, UK
23Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia
24Netherlands Heart Institute, Utrecht, the Netherlands
25Broad Institute of MIT and Harvard, Boston, MA
26Nuffield Department of Population Health, University of Oxford, UK
Format: article
Version: published version
Access: open
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Language: English
Published: Wolters Kluwer, 2021
Publish Date: 2021-10-19


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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Series: Neurology
ISSN: 0028-3878
ISSN-E: 1526-632X
ISSN-L: 0028-3878
Volume: 96
Issue: 8
Pages: e1110 - e1123
DOI: 10.1212/WNL.0000000000011236
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: Rotterdam Study: The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organisation for Scientific Research; The Netherlands Organisation for Health Research and Development; the Research Institute for Diseases in the Elderly; The Netherlands Genomics Initiative; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Metabolomics measurements were funded by Biobanking and Biomolecular Resources Research Infrastructure–NL (184.021.007) and the JNPD under the project PERADES (grant 733051021, Defining Genetic, Polygenic and Environmental Risk for Alzheimer's Disease Using Multiple Powerful Cohorts, Focused Epigenetics and Stem Cell metabolomics). This work has been performed as part of the CoSTREAM project (, Memorabel program (project number 733050814) and has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 667375. This work has been performed as part of the CardioVasculair Onderzoek Nederland (CVON 2012-03). Whitehall II: The Whitehall II study is supported by the Medical Research Council (MR/R024227/1) and the British Heart Foundation (32334). M. Kivimaki is supported by the Medical Research Council (S011676/1), NordForsk, the Academy of Finland (311492), and Helsinki Institute of Life Science. The authors thank all of the participating civil service departments and their welfare, personnel, and establishment officers; the British Occupational Health and Safety Agency; the British Council of Civil Service Unions; all participating civil servants in the Whitehall II study; and all members of the Whitehall II study team. The Whitehall II Study team comprises research scientists, statisticians, study coordinators, nurses, data managers, administrative assistants, and data entry staff, who make the study possible. FINRISK97 and DILGOM: The FINRISK studies have received financial support from the National Institute for Health and Welfare and the Academy of Finland (139635) and the Finnish Foundation for Cardiovascular Research (to V.S). Additional funding has been obtained from the Academy of Finland (grants 297338, 307247), the Novo Nordisk Foundation (NNF17OC0026062), the Sigrid Juselius Foundation, and University of Oulu Graduate School. M.A.-K. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia (APP1158958). He also works in a unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1). The Baker Institute is supported in part by the Victorian Government's Operational Infrastructure Support Program. J.K. was supported through funds from the Academy of Finland (grants 297338 and 307247) and Novo Nordisk Fonden (grant NNF17OC0026062). PROSPER: This work (NMR) was supported by the European Federation of Pharmaceutical Industries Associations, Innovative Medicines Initiative Joint Undertaking, European Medical Information Framework grant 115372, and the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme (grant 305507) “Heart ‘omics’ in AGEing” (HOMAGE). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Dr. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). EGCUT: This work was supported by Estonian Research Council (IUT20-60, PUT1660 to T.E., PUT1665 to K.F.); European Union Horizon 2020 (692145); European Union through the European Regional Development Fund (2014-2020.4.01.15-0012 GENTRANSMED, 2014-2020.4.2.2), and Estonian Center of Genomics/Roadmap II (project 2014-2020.4.01.16-0125). FHS: This work was supported by the National Heart, Lung and Blood Institute's FHS (contracts N01-HC-25195 and HHSN268201500001I). A portion of this research used the Linux Cluster for Genetic Analysis funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This work was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS017950 and NS100605), the National Institute of Aging (AG033040, AG033193, AG054076, AG049607, AG008122, AG016495, U01-AG049505, and U01-AG052409), and the National Institute of Diabetes and Digestive and Kidney Diseases (DK-HL081572).
Academy of Finland Grant Number: 297338
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
Copyright information: Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.