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Genetic association between plasminogen activator inhibitor-1 rs1799889 polymorphism and venous thromboembolism: Evidence from a comprehensive meta-analysis.

ABSTRACT: BACKGROUND:Association between plasminogen activator inhibitor-1 (PAI-1) rs1799889 polymorphism and venous thromboembolism (VTE) were explored by many previous studies, yet the findings of these studies were conflicting. HYPOTHESIS:PAI-1 rs1799889 polymorphism may serve as a genetic marker of VTE. We aimed to better clarify the relationship between PAI-1 rs1799889 polymorphism and VTE in a larger combined population by performing a meta-analysis. METHODS:Literatures were searched in Pubmed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI). We used Review Manager to combine the results of individual studies. RESULTS:Forty-eight studies involving 14?806 participants were eligible for inclusion. Combined results revealed that PAI-1 rs1799889 polymorphism was significantly associated with VTE in Caucasians (dominant comparison: odds ratio [OR] 1.20, 95% confidence interval [CI] 1.09-1.32; recessive comparison: OR 0.84, 95% CI 0.76-0.94; allele comparison: OR 1.08, 95% CI 1.02-1.15) and East Asians (dominant comparison: OR 1.60, 95% CI 1.17-2.19; allele comparison: OR 1.53, 95% CI 1.21-1.93). Further analyses obtained similar significant associations in these with deep vein thrombosis (DVT) and these with Factor V Leiden mutation. CONCLUSIONS:Our findings supported that PAI-1 rs1799889 polymorphism may serve as one of the predisposing factors of VTE in both Caucasians and East Asians, especially in these with DVT and these with Factor V Leiden mutation.

SUBMITTER: Huang G

PROVIDER: S-EPMC6906978 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Genetic association between plasminogen activator inhibitor-1 rs1799889 polymorphism and venous thromboembolism: Evidence from a comprehensive meta-analysis.

Huang Guangbin G Wang Pan P Li Tao T Deng Xuejun X

Clinical cardiology 20191108 12

<h4>Background</h4>Association between plasminogen activator inhibitor-1 (PAI-1) rs1799889 polymorphism and venous thromboembolism (VTE) were explored by many previous studies, yet the findings of these studies were conflicting.<h4>Hypothesis</h4>PAI-1 rs1799889 polymorphism may serve as a genetic marker of VTE. We aimed to better clarify the relationship between PAI-1 rs1799889 polymorphism and VTE in a larger combined population by performing a meta-analysis.<h4>Methods</h4>Literatures were se ...[more]

PMID: 31701558

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Project description:The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma.

Dataset Information

Genetic association between plasminogen activator inhibitor-1 rs1799889 polymorphism and venous thromboembolism: Evidence from a comprehensive meta-analysis.

Publications

Genetic association between plasminogen activator inhibitor-1 rs1799889 polymorphism and venous thromboembolism: Evidence from a comprehensive meta-analysis.

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