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Brain. 2017 Oct 1;140(10):2663-2672. doi: 10.1093/brain/awx220.

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

Author information

1
Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA, USA.
2
Division of Neurocritical Care and Emergency Neurology, Department of Neurology, MGH, Boston, MA, USA.
3
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.
4
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
5
J. Philip Kistler Stroke Research Center, Department of Neurology, MGH, Boston, MA, USA.
6
Department of Emergency Medicine, MGH, Boston, MA, USA.
7
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
8
Department of Neurology, Jagiellonian University Medical College, Krakow, Poland.
9
Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
10
Department of Neurology and Rehabilitation Medicine, Neurology, Skåne University Hospital, Lund, Sweden.
11
Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain.
12
Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigacio´ Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain.
13
Department of Neurology, Medical University of Graz, Austria.
14
Division of Neuroradiology, Department of Radiology, Medical University of Graz, Austria.
15
Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
16
Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca Mutua Terrassa, Mutua de Terrassa Hospital, Terrassa, Spain.
17
Division of Behavioral Neurology, Department of Neurology, MGH, Boston, MA, USA.
18
Division of Neuropsychiatry, Department of Psychiatry, MGH, Boston, MA, USA.
19
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
20
Department of Clinical Neurosciences, University of Cambridge, UK.
21
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
22
Department of Neurology, University of Virginia, Charlottesville, VA, USA.
23
Department of Public Health Science, University of Virginia, Charlottesville, VA, USA.
24
Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
25
Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD, USA.
26
University of Cincinnati College of Medicine, Cincinnati, OH, USA.
27
German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for Systems Neurology (SyNergy), Germany.

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.

KEYWORDS:

genetics; inflammation; intracerebral haemorrhage; myeloperoxidase; stroke

PMID:
28969386
PMCID:
PMC5841027
DOI:
10.1093/brain/awx220
[Indexed for MEDLINE]
Free PMC Article

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