Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine

BBMRI Metabolomics Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine.

METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses.

RESULTS: Decreases in the level of apolipoprotein A1 (β -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status.

CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

Original languageEnglish
Pages (from-to)e1899-e1911
Number of pages13
JournalNeurology
Volume92
Issue number16
Early online date3 Apr 2019
DOIs
Publication statusPublished - 16 Apr 2019

Bibliographical note

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Funding

From the Departments of Neurology (G.L.J.O., J.A.P., D.A.K., R.Z., I.d.B., M.D.F., G.M.T., A.M.J.M.v.d.M.), Human Genetics (A.D., L.S.V., P.A.C.’tH., A.M.J.M.v.d.M.), Molecular Epidemiology (M.B., P.E.S.), Radiology (D.A.K.), and Medical Statistics (J.J.G.), Leiden University Medical Centre; Department of Biological Psychology (L.L., R.P., D.I.B.), Vrije Universiteit Amsterdam; Amsterdam Public Health Institute (L.L.); Amsterdam Neuroscience and Amsterdam Public Health (M.B., C.S.T., Y.M., D.I.B., B.W.P.); Department of Psychiatry (M.B., C.S.T., Y.M., B.W.P.), VU University Medical Centre/GGZ inGeest, Amsterdam; Departments of Epidemiology (A.D., J.L., K.-x.W., N.A., M.A.I., C.M.v.D.) and Neurology (M.A.I.), Erasmus Medical Centre, Rotterdam; Departments of Genetics (J.F., L.F., C.W.) and Pediatrics (J.F.), University Medical Centre Groningen; Department of Internal Medicine (C.J.H.v.d.K., F.H.M.V., M.M.J.v.G., M.T.S., C.D.A.S.) and Heart and Vascular Center (M.T.S.), Maastricht University Medical Centre; CARIM School for Cardiovascular Diseases (C.J.H.v.d.K., M.M.J.v.G., I.C.W.A., M.T.S., P.C.D., C.D.A.S.), Department of Epidemiology (I.C.W.A.), MaCSBio Maastricht Centre for Systems Biology (I.C.W.A.), and Department of Epidemiology (P.C.D.), Maastricht University; Department of Radiology (M.A.I.), Erasmus MC University Medical Centre, Rotterdam; Leiden Academic Centre in Drug Research, Faculty Science (C.M.v.D.), Leiden University; and Centre for Molecular and Biomolecular Informatics (P.A.C.’tH.), Radboud University Medical Centre Nijmegen, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. This work was performed within the framework of the Bio-banking and BioMolecular resources Research Infrastructure (BBMRI) Metabolomics Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government (Netherlands Organization for Scientific Research [NWO], no. 184.021.007 and 184033111). The Leiden University Migraine Neuro-Analysis (LUMINA) study is supported by grants obtained from the Netherlands Organization for the Health Research and Development (ZonMw; no. 90700217), NWO Gravitation Netherlands Organ-on-Chip Initiative (024.003.001); VIDI (ZonMw; no. 91711319) (to G.M.T.); NWO VICI (no. 918.56.602) and Spinoza prize (2009) grants (to M.D.F.); the Centre for Medical Systems Biology (CMSB) and Netherlands Consortium for Systems Biology (NCSB), both within the framework of the Netherlands Genomics Initiative (NGI)/NWO (to A.M.J.M.v.d.M.); and the FP7 EU project EUROHEADPAIN (no. 602633) (to M.D.F., A.M.J.M.v.d.M. & G.M.T.). The Erasmus Rucphen Family (ERF) study has received funding from the Centre for Medical Systems Biology (CMSB) and Netherlands Consortium for Systems Biology (NCSB), both within the framework of NGI/NWO. The ERF study is part of EUROSPAN (European Special Populations Research Network) (FP6 STRP no. 018947 [LSHG-CT-2006-01947]); European Network of Genomic and Genetic Epidemiology (ENGAGE) from the European Community’s Seventh Framework Programme (FP7/ 2007-2013)/grant agreement HEALTH-F4-2007-201413; “Quality of Life and Management of the Living Resources” of FP5 (no. QLG2-CT-2002-01254); the “Internationale Stichting Alzheimer Onderzoek” (ISAO); the “Hersenstichting Nederland” (HSN); and the JNPD under the project PERADES (no. 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 (cost-ream.eu) and has received funding from the European Union’s Horizon 2020 research and innovation programme (no. 667375). Ayse Demirkan is supported by a VENI grant. The ERF follow-up study is funded by CardioVasculair Onderzoek Nederland (CVON 2012-03). The Rotterdam Study (RS) is supported by the Erasmus MC University Medical Centre and Erasmus University Rotterdam; NWO; The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); NGI; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); the JNPD under the project PERADES (no. 733051021, Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics); and the Municipality of Rotterdam. This work has been performed as part of the CoSTREAM project (costream.eu) and has received funding from the European Union’s Horizon 2020 research and innovation programme (no. 667375). Netherlands Twin Register (NTR) is supported by funding from multiple grants from NWO and MagW/ZonMW (grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 911-09-032); the Amsterdam Public Health (APH) institute; the Avera Institute, Sioux Falls, South Dakota; and the NIH (no. R01D0042157-01A, no. MH081802, no. 1RC2 MH089951). Computing was supported by BiG Grid, the Dutch e-Science Grid (NWO, no. 176.010.2005.009). R.P. was supported by BBRMI-NL (184.033.111). Also supported by grant NWO 480-15-001/ 674, Netherlands Twin Registry Repository (NWO Groot 480-15-001/674), Netherlands Twin Registry Repository, and a Royal Netherlands Academy of Science Professor Award (PAH/6635) to D.I.B. The Netherlands Study of Depression and Anxiety (NESDA) (nesda.nl) infrastructure is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Centre, Leiden University, GGZ Rivierduinen, University Medical Centre Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoeks-centrum). The LifeLines Deep cohort is a subcohort of LifeLines, which has been funded by a number of public sources, notably the Dutch Government, NWO, the Northern Netherlands Collaboration of Provinces (SNN), the European fund for regional development, Dutch Ministry of Economic Affairs, Pieken in de Delta, Provinces of Groningen and Drenthe, the Target project, the University of Groningen, and the University Medical Centre Groningen, the Netherlands. J.F. is supported by a VIDI (NWO: no. 864.13.013) grant and CardioVasculair Onderzoek Nederland (CVON 2012-03). L.F. is supported by a VIDI (NWO: no 917.14.374) and a European Research Council (ERC) Starting Grant 637640. C.W. is funded by an ERC advanced grant (FP/2007-2013/ERC grant 2012-322698), a NWO Spinoza prize (NWO SPI 92-266), and the NWO Gravitation Netherlands Organ-on-Chip Initiative (024. 003.001), Top Institute of Food and Nutrition (TiFN GH0001), the Stiftelsen Kristian Gerhard Jebsen foundation (Norway), and the RuG investment agenda grant Personalized Health. The Maastricht Study is supported by the European Regional Development Fund as part of OP-ZUID; the Province of Limburg; the department of Economic Affairs of the Netherlands (no. 310.041); Stichting the Weijerhorst, the Pearl String Initiative Diabetes; the Cardiovascular Centre Maas-tricht; the Cardiovascular Research Institute Maastricht; School of Nutrition, Toxicology and Metabolism; Stichting Annadal; Health Foundation Limburg; and unrestricted grants from Janssen, Novo Nordisk, and Sanofi.

FundersFunder number
Seventh Framework Programme667375, 637640, 322698, 201413, 602633

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      Onderwater, G. L. J. (Contributor), Ligthart, L. (Contributor), Bot, M. (Contributor), Demirkan, A. (Contributor), Fu, J. (Contributor), Van Der Kallen, C. J. H. (Contributor), Vijfhuizen, L. S. (Contributor), Pool, R. (Contributor), Liu, J. (Contributor), Vanmolkot, F. H. M. (Contributor), Beekman, M. (Contributor), Wen, H. (Contributor), Amin, N. (Contributor), Thesing, C. S. (Contributor), Pijpers, J. A. (Contributor), Kies, D. A. (Contributor), Zielman, R. (Contributor), De Boer, I. (Contributor), Van Greevenbroek, M. M. J. (Contributor), Arts, I. C. W. (Contributor), Milaneschi, Y. (Contributor), Schram, M. T. (Contributor), Dagnelie, P. C. (Contributor), Franke, L. (Contributor), Ikram, M. A. (Contributor), Ferrari, M. D. (Contributor), Goeman, J. J. (Contributor), Slagboom, P. E. (Contributor), Wijmenga, C. (Contributor), Stehouwer, C. D. A. (Contributor), Boomsma, D. (Contributor), Van Duijn, C. M. (Contributor), Penninx, B. W. (Contributor), ’T Hoen, P. A. C. (Contributor), Terwindt, G. M. (Contributor) & Van Den Maagdenberg, A. M. J. M. (Contributor), Unknown Publisher, 1 Jan 2019

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