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Genetic variants in...
Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke
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- Phuah, Chia-Ling (författare)
- Massachusetts General Hospital,Broad Institute
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- Dave, Tushar (författare)
- University of Maryland School of Medicine
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- Malik, Rainer (författare)
- German Center for Lung Research (DZL)
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- Raffeld, Miriam R (författare)
- Massachusetts General Hospital
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- Ayres, Alison M. (författare)
- Massachusetts General Hospital
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- Goldstein, Joshua N. (författare)
- Massachusetts General Hospital
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- Viswanathan, Anand (författare)
- Massachusetts General Hospital
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- Greenberg, Steven M. (författare)
- Massachusetts General Hospital
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- Jagiella, Jeremiasz M. (författare)
- Jagiellonian University
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- Hansen, Björn M. (författare)
- Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk strokeforskning,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Stroke Research Group,Lund University Research Groups,Skåne University Hospital
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- Norrving, Bo (författare)
- Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk strokeforskning,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Stroke Research Group,Lund University Research Groups,Skåne University Hospital
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- Jimenez-Conde, Jordi (författare)
- Autonomous University of Barcelona
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- Roquer, Jaume (författare)
- Autonomous University of Barcelona
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- Pichler, Alexander (författare)
- Medical University of Graz
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- Enzinger, Christian (författare)
- Medical University of Graz
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- Montaner, Joan (författare)
- Autonomous University of Barcelona
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- Fernandez-Cadenas, Israel (författare)
- Autonomous University of Barcelona,Mutua De Terrassa Hospital
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- Lindgren, Arne (författare)
- Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk strokeforskning,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Stroke Research Group,Lund University Research Groups,Skåne University Hospital
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- Slowik, Agnieszka (författare)
- Jagiellonian University
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- Schmidt, Reinhold (författare)
- Medical University of Graz
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- Biffi, Alessandro (författare)
- Massachusetts General Hospital,Broad Institute
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- Rost, Natalia (författare)
- Massachusetts General Hospital
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- Langefeld, Carl D. (författare)
- Wake Forest University
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- Markus, Hugh S. (författare)
- University of Cambridge
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- Mitchell, Braxton D. (författare)
- Baltimore Veterans Administration Medical Center
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- Worrall, Brad B. (författare)
- University of Virginia
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- Kittner, Steven J. (författare)
- Baltimore Veterans Administration Medical Center,University of Maryland School of Medicine
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- Woo, Daniel (författare)
- University of Cincinnati College of Medicine
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- Dichgans, Martin (författare)
- German Center for Neurodegenerative Diseases (DZNE), Bonn,German Center for Lung Research (DZL)
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- Rosand, Jonathan (författare)
- Massachusetts General Hospital,Broad Institute
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- Anderson, Christopher D. (författare)
- Broad Institute,Massachusetts General Hospital
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(creator_code:org_t)
- 2017-09-12
- 2017
- Engelska 10 s.
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 140:10, s. 2663-2672
- Relaterad länk:
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http://dx.doi.org/10...
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https://academic.oup...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 NINDSSiGN, 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 (P55 - 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Nyckelord
- genetics
- inflammation
- intracerebral haemorrhage
- myeloperoxidase
- stroke
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Phuah, Chia-Ling
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Dave, Tushar
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Malik, Rainer
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Raffeld, Miriam ...
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Ayres, Alison M.
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Goldstein, Joshu ...
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visa fler...
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Viswanathan, Ana ...
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Greenberg, Steve ...
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Jagiella, Jeremi ...
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Hansen, Björn M.
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Norrving, Bo
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Jimenez-Conde, J ...
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Roquer, Jaume
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Pichler, Alexand ...
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Enzinger, Christ ...
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Montaner, Joan
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Fernandez-Cadena ...
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Lindgren, Arne
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Slowik, Agnieszk ...
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Schmidt, Reinhol ...
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Biffi, Alessandr ...
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Rost, Natalia
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Langefeld, Carl ...
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Markus, Hugh S.
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Mitchell, Braxto ...
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Worrall, Brad B.
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Kittner, Steven ...
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Woo, Daniel
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Dichgans, Martin
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Rosand, Jonathan
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Anderson, Christ ...
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- MEDICIN OCH HÄLSOVETENSKAP
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och Neurologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Kardiologi
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