Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes.

Antihypertensive Agents / therapeutic use Blood Pressure / genetics Cerebral Small Vessel Diseases / etiology Genetic Predisposition to Disease / genetics Genome-Wide Association Study Humans Hypertension / complications Mendelian Randomization Analysis Stroke / drug therapy

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
28 07 2020
Historique:
received: 28 06 2019
accepted: 05 01 2020
pubmed: 3 7 2020
medline: 3 10 2020
entrez: 3 7 2020
Statut: ppublish

Résumé

We employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH). Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH. This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.

Identifiants

DOI: 10.1212/WNL.0000000000009814 PMID: 32611631 PMC: PMC7455321
pubmed: 32611631
pii: WNL.0000000000009814
doi: 10.1212/WNL.0000000000009814
pmc: PMC7455321
doi:

Substances chimiques

Antihypertensive Agents 0

Types de publication

Journal Article Observational Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e353-e361

Subventions

Organisme : Wellcome Trust
ID : 206589/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L01341X/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom

Informations de copyright

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Marios K Georgakis (MK)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Dipender Gill (D)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Alastair J S Webb (AJS)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Evangelos Evangelou (E)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.
ORCID: 0000-0002-5488-2999

Paul Elliott (P)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Cathie L M Sudlow (CLM)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Abbas Dehghan (A)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Rainer Malik (R)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Ioanna Tzoulaki (I)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.
ORCID: 0000-0002-4275-9328

Martin Dichgans (M)

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany. martin.dichgans@med.uni-muenchen.de.
ORCID: 0000-0002-0654-387X

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents cardiovasculaires › Antihypertenseurs › Genetically determined blood pressure,...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiologiques cardiovasculaires › Hémodynamique › Pression sanguine › Genetically determined blood pressure,...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Angiopathies intracrâniennes › Maladies des petits vaisseaux cérébraux › Genetically determined blood pressure,...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Genetically determined blood pressure,...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genetically determined blood pressure,...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetically determined blood pressure,...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Hypertension artérielle › Genetically determined blood pressure,...
questionsmedicales.fr › Techniques d'investigation › Analyse de randomisation mendélienne › Genetically determined blood pressure,...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Angiopathies intracrâniennes › Accident vasculaire cérébral › Genetically determined blood pressure,...