title: Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype.
abstract: OBJECTIVE
  Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels-associated genetic variant MTHFR C677T for association with magnetic resonance imaging-confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes.
  
  
  METHODS
  We included 1359 magnetic resonance imaging-confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status.
  
  
  RESULTS
  MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30).
  
  
  CONCLUSIONS
  MTHFR C677T was associated with magnetic resonance imaging-confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.). LR406@medschl.cam.ac.uk.
authors.forename: Loes C A
authors.initials: LC
authors.lastname: Rutten-Jacobs
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Traylor
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Poneh
authors.initials: P
authors.lastname: Adib-Samii
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Thijs
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Cathie
authors.initials: C
authors.lastname: Sudlow
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rothwell
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Giorgio
authors.initials: G
authors.lastname: Boncoraglio
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: James
authors.initials: J
authors.lastname: Meschia
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Jane
authors.initials: J
authors.lastname: Maguire
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Levi
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rost
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Ahamad
authors.initials: A
authors.lastname: Hassan
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.affiliation: From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (L.C.A.R.-J., M.T., H.S.M.); Department of Medical & Molecular Genetics, King's College London, London, UK (M.T.); Stroke and Dementia Research Centre, Department of Clinical Neuroscience, St George's University of London, London, UK (P.A.-S.); KULeuven Department of Experimental Neurology and Leuven Research Institute for Neuroscience and Disease, University of Leuven, and Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium and Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, UK (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich and Munich Cluster of Systems Neurology, SyNergy, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville (J.M.); School of Nursing and Midwifery (J.M.) and Hunter Medical Research Institute (J.M., C.L.), University of Newcastle, NSW, Australia; Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston (N.S.R., J.R.); Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK (A.H.); and School of Life Science, University of Lincoln, Lincoln, UK (S.B.).
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
mesh_terms: D002545:Brain Ischemia / Q000175:diagnosis / Q000235:genetics*; D059345:Cerebral Small Vessel Diseases / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D012307:Risk Factors; D059409:Stroke, Lacunar / Q000175:diagnosis / Q000235:genetics*
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: MTHFR; cerebral small vessel disease; genetic association; homocysteine; hypertension; lacunar stroke
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