Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke

Chia-Ling Phuah, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.Follow
Tushar Dave, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.
Rainer Malik, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
Miriam R. Raffeld, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.
Alison M. Ayres, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.
Joshua N. Goldstein, Department of Emergency Medicine, MGH, Boston, MA, USA.
Anand Viswanathan, Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Steven M. Greenberg, J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA, USA.
Jeremiasz M. Jagiella, Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.
Björn M. Hansen, Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
Bo Norrving, Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
Jordi Jimenez-Conde, Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain.
Jaume Roquer, Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain.
Alexander Pichler, Department of Neurology, Medical University of Graz, Austria.
Christian Enzinger, Department of Neurology, Medical University of Graz, Austria.
Joan Montaner, Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
Israel Fernandez-Cadenas, Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
Arne Lindgren, Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
Agnieszka Slowik, Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.
Reinhold Schmidt, Department of Neurology, Medical University of Graz, Austria.
Alessandro Biffi, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.
Natalia Rost, J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA, USA.
Carl D. Langefeld, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Hugh S. Markus, Department of Clinical Neurosciences, University of Cambridge, UK.
Braxton D. Mitchell, Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
Brad B. Worrall, Department of Neurology, University of Virginia, Charlottesville, VA, USA.
Steven J. Kittner, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Daniel Woo, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Martin Dichgans, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
Jonathan Rosand, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.
Christopher D. Anderson, Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.

Document Type

Article

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.

Medical Subject Headings

Aged; Aged, 80 and over; Case-Control Studies; Cerebral Hemorrhage (etiology, genetics); Cohort Studies; Databases, Factual (statistics & numerical data); Female; Genome-Wide Association Study; Humans; Male; Middle Aged; Peroxidase (genetics, metabolism); Risk Factors; Statistics, Nonparametric; Stroke (complications)

Publication Date

10-1-2017

Publication Title

Brain : a journal of neurology

E-ISSN

1460-2156

Volume

140

Issue

10

First Page

2663

Last Page

2672

PubMed ID

28969386

Digital Object Identifier (DOI)

10.1093/brain/awx220

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