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Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

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.

SUBMITTER: Phuah CL

PROVIDER: S-EPMC5841027 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

Phuah Chia-Ling CL Dave Tushar T Malik Rainer R Raffeld Miriam R MR Ayres Alison M AM Goldstein Joshua N JN Viswanathan Anand A Greenberg Steven M SM Jagiella Jeremiasz M JM Hansen Björn M BM Norrving Bo B Jimenez-Conde Jordi J Roquer Jaume J Pichler Alexander A Enzinger Christian C Montaner Joan J Fernandez-Cadenas Israel I Lindgren Arne A Slowik Agnieszka A Schmidt Reinhold R Biffi Alessandro A Rost Natalia N Langefeld Carl D CD Markus Hugh S HS Mitchell Braxton D BD Worrall Brad B BB Kittner Steven J SJ Woo Daniel D Dichgans Martin M Rosand Jonathan J Anderson Christopher D CD

Brain : a journal of neurology 20171001 10

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 ...[more]

PMID: 28969386

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Project description:BackgroundStress hyperglycemia has served as a reliable biomarker to predict poor outcomes after ischemic stroke. However, recent studies have reported some contrary conclusions. Different stroke subtypes may respond inconsistently to stress hyperglycemia. The progression of intracranial atherosclerotic stenosis (ICAS) is tightly related to hyperglycemia. Thus, this study aims to determine the relationship between stress hyperglycemia and recurrent stroke in ischemic stroke patients with or without intracranial atherosclerotic stenosis.MethodsThis is a multicenter retrospective observational cohort study. Patients with acute minor ischemic stroke and eligible computed tomography and magnetic resonance imaging data were enrolled. The severity of stress hyperglycemia is measured by the stress hyperglycemia ratio (SHR). SHR was calculated based on fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels. The primary outcome was stroke recurrence during hospitalization. The interaction of SHR levels with the presence of ICAS on the primary outcome was investigated using univariable and multivariable Cox proportional hazards models. Restricted cubic splines were applied to determine the nonlinear relationship between SHR and primary outcome. A two-piecewise linear regression model was used to identify the threshold of SHR.ResultsA total of 610 participants were included in the study. The average age of the patients was 61.4 ± 12.9 years old, and approximately 70% of participants were males. A total of 189 (30.98%) patients had ICAS. The patients were categorized into 3 groups based on the tertiles of SHR. Compared with the group with a lower SHR, a higher SHR was significantly associated with the risk of stroke recurrence in the ICAS group (hazard ratio [HR], 8.52, 95% confidence interval [CI], 3.16-22.96, P<0.001). When SHR was treated as a continuous variable, each 0.1-unit increase in SHR in the ICAS group was associated with a 1.63-fold increase in the risk of recurrence (HR, 1.63, 95% CI, 1.39-1.9, P<0.001) with a threshold of 0.75. FPG but not HbA1c was associated with stroke recurrence in ICAS patients (HR, 1.17, 95% CI, 1.08-1.26, P<0.001). Sensitive analyses showed consistent results after adjusting for previous diabetes mellitus, oral hypoglycemic agents and insulin injection.ConclusionsSHR represents a better biomarker to predict the risk of stroke recurrence in patients with ICAS than FPG and HbA1c regardless of previous diabetes mellitus.Trial registrationhttps://www.chictr.org.cn/showproj.aspx?proj=125817; Identifier, [ChiCTR2100046958].

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Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

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Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

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