TY - JOUR
T1 - Association of Circulating Metabolites in Plasma or Serum and Risk of Stroke
T2 - Meta-analysis From 7 Prospective Cohorts
AU - Vojinovic, Dina
AU - Kalaoja, Marita
AU - Trompet, Stella
AU - Fischer, Krista
AU - Shipley, Martin J.
AU - Li, Shuo
AU - Havulinna, Aki S.
AU - Perola, Markus
AU - Salomaa, Veikko
AU - Yang, Qiong
AU - Sattar, Naveed
AU - Jousilahti, Pekka
AU - Amin, Najaf
AU - Satizabal, Claudia L.
AU - Taba, Nele
AU - Sabayan, Behnam
AU - Vasan, Ramachandran S.
AU - Ikram, M. Arfan
AU - Stott, David J.
AU - Ala-Korpela, Mika
AU - Jukema, J. Wouter
AU - Seshadri, Sudha
AU - Kettunen, Johannes
AU - Kivimaki, Mika
AU - Esko, Tonu
AU - Van Duijn, Cornelia M.
N1 - Funding Information:
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 ( costream.eu ), 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).
Publisher Copyright:
© American Academy of Neurology.
PY - 2021/2/23
Y1 - 2021/2/23
N2 - ObjectiveTo conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings.MethodsWe 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.ResultsThe 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.ConclusionsWe 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.
AB - ObjectiveTo conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings.MethodsWe 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.ResultsThe 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.ConclusionsWe 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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U2 - 10.1212/WNL.0000000000011236
DO - 10.1212/WNL.0000000000011236
M3 - Article
C2 - 33268560
AN - SCOPUS:85110287093
SN - 0028-3878
VL - 96
SP - E1110-E1123
JO - Neurology
JF - Neurology
IS - 8
ER -