Year: 2017
Type: article
Study design: Observational Study
Abstract: Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.
Source: Brain
DOI: 10.1093/brain/awx220
Authors: Chia-Ling Phuah, Tushar Dave, Rainer Malik, Miriam R Raffeld, Alison M Ayres, Joshua N Goldstein, Anand Viswanathan, Steven M Greenberg, Jeremiasz M Jagiella, Björn M Hansen, Bo Norrving, Jordi Jimenez-Conde, Jaume Roquer, Alexander Pichler, Christian Enzinger, Joan Montaner, Israel Fernandez-Cadenas, Arne Lindgren, Agnieszka Slowik, Reinhold Schmidt, Alessandro Biffi, Natalia Rost, Carl D Langefeld, Hugh S Markus, Braxton D Mitchell, Brad B Worrall, Steven J Kittner, Daniel Woo, Martin Dichgans, Jonathan Rosand, Christopher D Anderson, on behalf of METASTROKE
Institutions: Massachusetts General Hospital, University of Maryland, Baltimore, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, Broad Institute, Jagiellonian University, Lund University, Skåne University Hospital, Universitat Autònoma de Barcelona, Hospital Del Mar, Municipal Institute for Medical Research, Medical University of Graz, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Hospital Terrassa, University Hospital Mútua de Terrassa, Mútua Terrassa, Wake Forest University Health Sciences, Wake Forest University, University of Cambridge, Baltimore VA Medical Center, University of Virginia, Veterans Health Administration, University of Cincinnati, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: California Department of Fish and Game, Corona-Stiftung, National Institute for Health and Care Research, University of Cambridge, European Commission, Deutsche Forschungsgemeinschaft, Fondation Leducq, Bundesministerium für Bildung und Forschung, Lunds Universitet, STROKE-Riksförbundet, National Institutes of Health, Instituto de Salud Carlos III, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G1474772629, G1894287339, NIHR Senior Investigator Award, Apathy and Depression following Intracerebral Hemorrhage, ERICH-GENE, Vascular Dysfunction in Cerebral Amyloid Angiopathy, G3546975210, Genetic and Environmental Risk Factors for Hemorrhagic Stroke, Sharing capacity across Europe in high-throughput sequencing technology to explore genetic variation in health and disease, G4208450424, G434337789, Comparison of Hemorrhagic & Ischemic Stroke Among Blacks and Whites, Proyecto GENERACION: Estudio GENEtico de mutaciones RAras en el ictus isquémico y creación de un score clínico-genético de predicCION de riesgo, G573982542, G5862193114, Gene Discovery for Warfarin-Related Intracerebral Hemorrhage, Genetic variation in white matter hyperintensity and risk of ischemic stroke, Common mechanisms and pathways in Stroke and Alzheimer's disease., G9000040700, Genetic Analyses of Lipids in Cerebral Hemorrhage and Small Vessel Disease
OpenAlex ID: W2765465440