Evidence map›Paper›PMID 26839351›Full record

ArticleStroke2016

Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype.

Loes C A Rutten-Jacobs, Matthew Traylor, Poneh Adib-Samii, Vincent Thijs, Cathie Sudlow, Peter M Rothwell, Giorgio Boncoraglio, Martin Dichgans, James Meschia, Jane Maguire and 6 more

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In one paragraph

Article in Stroke, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
33citing papers in PubMed, 4 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

33 citing papers in PubMed, 4 syntheses or guidelines pooled it.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Genetic susceptibility to cerebrovascular disease: A systematic review.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2018
    Pooled it
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  16. Association of the methylenetetrahydrofolate reductase (The Journal of international medical research · 2022
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  18. Pathogenesis and research progress in leukoaraiosis.Frontiers in human neuroscience · 2022
    Review
  19. Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Loes C A Rutten-JacobsFrom 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.
Matthew TraylorFrom 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.).
Poneh Adib-SamiiFrom 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.).
Vincent ThijsFrom 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.).
Cathie SudlowFrom 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.).
Peter M RothwellFrom 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.).
Giorgio BoncoraglioFrom 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.).
Martin DichgansFrom 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.).
James MeschiaFrom 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.).
Jane MaguireFrom 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.).
Christopher LeviFrom 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.).
Natalia S RostFrom 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.).
Jonathan RosandFrom 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.).
Ahamad HassanFrom 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.).
Steve BevanFrom 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.).
Hugh S MarkusFrom 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.).

Funding

British Heart Foundation RG/10/8/28561Medical Research Council G0900295Medical Research Council MR/K026992/1The Dunhill Medical Trust OSRP2/1006Wellcome Trust 072952Wellcome Trust 095626
6 · The paper itself

Abstract

background and purposeElevated 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.

methodsWe 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.

resultsMTHFR 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).

conclusionsMTHFR 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.

Indexed as

Genetic Association StudiesGenotypeBrain IschemiaCerebral Small Vessel DiseasesCohort StudiesFemaleHumansMaleMethylenetetrahydrofolate Reductase (NADPH2)Risk FactorsStroke, LacunarMethylenetetrahydrofolate Reductase (NADPH2)MTHFR protein, humancerebral small vessel diseasegenetic associationhomocysteinehypertensionlacunar strokeMTHFR

Identifiers

PMID26839351
PMCPMC4760380

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.