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

Gerrit L J Onderwater; Lannie Ligthart; Mariska Bot; Ayse Demirkan; Jingyuan Fu; Carla J H van der Kallen; Lisanne S Vijfhuizen; René Pool; Jun Liu; Floris H M Vanmolkot; Marian Beekman; Ke-Xin Wen; Najaf Amin; Carisha S Thesing; Judith A Pijpers; Dennis A Kies; Ronald Zielman; Irene de Boer; Marleen M J van Greevenbroek; Ilja C W Arts; Yuri Milaneschi; Miranda T Schram; Pieter C Dagnelie; Lude Franke; M Arfan Ikram; Michel D Ferrari; Jelle J Goeman; P Eline Slagboom; Cisca Wijmenga; Coen D A Stehouwer; Dorret I Boomsma; Cornelia M van Duijn; Brenda W Penninx; Peter A C 't Hoen; Gisela M Terwindt; Arn M J M van den Maagdenberg; BBMRI Metabolomics Consortium

doi:10.1212/WNL.0000000000007313

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

Neurology. 2019 Apr 16;92(16):e1899-e1911. doi: 10.1212/WNL.0000000000007313. Epub 2019 Apr 3.

Authors

Gerrit L J Onderwater¹, Lannie Ligthart¹, Mariska Bot¹, Ayse Demirkan¹, Jingyuan Fu¹, Carla J H van der Kallen¹, Lisanne S Vijfhuizen¹, René Pool¹, Jun Liu¹, Floris H M Vanmolkot¹, Marian Beekman¹, Ke-Xin Wen¹, Najaf Amin¹, Carisha S Thesing¹, Judith A Pijpers¹, Dennis A Kies¹, Ronald Zielman¹, Irene de Boer¹, Marleen M J van Greevenbroek¹, Ilja C W Arts¹, Yuri Milaneschi¹, Miranda T Schram¹, Pieter C Dagnelie¹, Lude Franke¹, M Arfan Ikram¹, Michel D Ferrari¹, Jelle J Goeman¹, P Eline Slagboom¹, Cisca Wijmenga¹, Coen D A Stehouwer¹, Dorret I Boomsma¹, Cornelia M van Duijn¹, Brenda W Penninx¹, Peter A C 't Hoen¹, Gisela M Terwindt¹, Arn M J M van den Maagdenberg²; BBMRI Metabolomics Consortium

Affiliations

¹ 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.
² 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. A.M.J.M.van_den_Maagdenberg@lumc.nl.

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Biomarkers / blood
Cohort Studies
Fatty Acids, Omega-3 / blood
Female
Humans
Lipoproteins, HDL / metabolism*
Male
Metabolome
Metabolomics
Middle Aged
Migraine Disorders / blood*
Nuclear Magnetic Resonance, Biomolecular
Proton Magnetic Resonance Spectroscopy
Sex Factors

Substances

Biomarkers
Fatty Acids, Omega-3
Lipoproteins, HDL