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Circulation. 2019 Jan 8;139(2):256-268. doi: 10.1161/CIRCULATIONAHA.118.035905.

Genetically Determined Levels of Circulating Cytokines and Risk of Stroke.

Author information

Institute for Stroke and Dementia Research, University Hospital of Ludwig-Maximilians-University, Munich, Germany (M.K.G., J.B., R.M., M.D.).
Graduate School for Systemic Neurosciences, Ludwig-Maximilians-University, Munich, Germany (M.K.G.).
Department of Biostatistics and Epidemiology, School of Public Health, Imperial College London, UK (D.G., C.L.M.S.).
Centre for Clinical Brain Sciences, University of Edinburgh, UK (K.R.).
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, UK (M.T.).
Center for Genomic Medicine (C.D.A.), Massachusetts General Hospital, Boston.
Division of Neurocritical Care and Emergency Neurology, Department of Neurology (C.D.A.), Massachusetts General Hospital, Boston.
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (C.D.A.).
Department of Neurology, Radiology, and Biomedical Engineering, Washington University School of Medicine, St Louis, MO (J.-M.L.).
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (Y.K.).
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, UK (J.C.H.).
Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville (B.B.W.).
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B., M.D.).
Institute for Genetics and Molecular Medicine, University of Edinburgh, UK (C.L.M.S.).
German Centre for Neurodegenerative Diseases, Munich (M.D.).



Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study.


Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data.


Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls.


Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.


Mendelian randomization analysis; atherosclerosis; chemokine CCL2; cytokines; human genetics; inflammation; stroke

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