Genetic variations in the thrombin-activatable fibrinolysis inhibitor gene and risk of cardiovascular disease: A systematic review and meta-analysis

Shi, Jianghong; Zhi, Pengke; Chen, Jian; Wu, Peng; Tan, Suxu

doi:10.1016/j.thromres.2014.06.023

Cited by 17 publications

(14 citation statements)

References 29 publications

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“…We showed that when the Ala147Thr variant is analyzed in males and females combined, there is no observed association with thrombotic events (OR = 0.94, p = 0.128). These results are consistent with previous results of a meta-analysis of this variant with coronary heart disease [34] but inconsistent with a recent meta-analysis with venous thrombosis [56], which reported an association across all genetic models.…”

Section: Discussionsupporting

confidence: 69%

“…A previous meta-analysis examining Thr325Ile and coronary artery disease observed an overall increased risk (OR = 1.25, 95% CI: 1.02, 1.54) in mixed ethnicities, including: European, Asian, and African study populations [34]. However, in a subgroup analysis of only European studies, the association did not reach statistical significance (OR = 1.13, 95% CI: 0.90, 1.40) [34]. The opposing effect of the variant for venous thrombosis compared to coronary artery disease seems contradictory but it is biologically plausible.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the critical hemostatic role of TAFI, epidemiological studies on the effect of the above common TAFI-associated variants on the risk venous thrombosis are inconclusive [32, 34–55] with inconsistent results between studies, and a recent meta-analysis [56] that has important methodological limitations. We speculate that these inconsistencies could be due to the interaction of these variants with sex on the risk of thrombotic events, and to the lack of statistical power of individual studies.…”

Section: Introductionmentioning

confidence: 99%

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Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis

et al. 2017

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BackgroundThrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis.MethodsA comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models.ResultsA total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96–1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71–0.97, p = 0.021) for venous thrombosis.ConclusionsA comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis

et al. 2017

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“…The imbalance between coagulation and the fibrinolytic system serves an important role in the progression and pathogenesis of arterial thrombosis (7). Aspirin is effective and safe in the secondary prevention of cerebral infarction, as previously reported in a number of randomized, double-blind trials (8,9).…”

Section: Introductionmentioning

confidence: 63%

Aspirin ameliorates cerebral infarction through regulation of TLR4/NF‑κB‑mediated endoplasmic reticulum stress in mouse model

et al. 2017

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Cerebral infarction is a cerebrovascular disease caused by local brain ischemic necrosis or softening, which is associated with diabetes, obesity, hypertension and rheumatic heart arrhythmia. Previous studies have indicated that aspirin is a potential oral anticoagulant in the treatment of cerebral ischemic stroke. However, the potential mechanism mediated by aspirin in cerebral infarction therapy is not well understood. The present study analyzed the therapeutic effects of aspirin on cerebral infarction and investigated the underlying molecular mechanism of aspirin‑ameliorated benefits for thrombolysis. The results demonstrated that aspirin inhibited inflammation and apoptosis of cerebrovascular endothelial cells in a mouse model of cerebral infarction. Aspirin treatment suppressed toll‑like receptor (TLR)4 and nuclear factor (NF)‑κB expression in cerebrovascular endothelial cells. Endoplasmic reticulum (ER) stress was suppressed by aspirin treatment through the downregulation of protein kinase R‑like endoplasmic reticulum kinase, eukaryotic translation initiation factor 2 subunit 1 and C/EBP homologous protein expression levels in cerebrovascular endothelial cells. It was identified that knockdown of TLR4 inhibited aspirin‑mediated downregulation of NF‑κB signaling pathway and ER stress in cerebrovascular endothelial cells. Expression levels of adenosine diphosphate plasminogen activator inhibitors, von Willebrand factor and thromboxane were downregulated in cerebrovascular endothelial cells and in serum in experimental mice. The results demonstrated that aspirin was beneficial forthrombolysis by decreasing thrombin‑activatable fibrinolysis inhibitor and plasminogen activator inhibitor‑1 expression in a mouse model of cerebral infarction. These results suggested that aspirin may improve cerebral infarction by downregulating TLR4/NF‑κB‑mediated ER stress in a mouse model.

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“…Plasma levels of TAFIa are elevated in patients with acute myocardial infarction [28] . Some studies observed that TAFI gene polymorphisms influence venous [29] , arterial [30,31] thrombosis and t-PA-induced recanalization resistance in AIS patients [32] . Correlation between TAFI concentration and AIS severity and outcome has been described in single center studies.…”

Section: Introductionmentioning

confidence: 99%

Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome

et al. 2016

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Background and Purpose: Thrombin-activatable fibrinolysis inhibitor (TAFI) activation following thrombolysis may affect thrombolysis effectiveness in acute ischemic stroke (AIS). To support this hypothesis, we propose to study the relationship between TAFI consumption, activated/inactivated TAFI (TAFIa/ai) and stroke severity and outcome in 2 groups of AIS patients, one treated and one untreated with intravenous recombinant tissue type plasminogen activator (rt-PA). Methods: In this prospective, longitudinal, multicenter, observational study, we aimed to study the association between TAFIa/ai and stroke outcome. TAFI levels were sequentially measured in patients treated with intravenous rt-PA thrombolysis (T), and in patients not given any thrombolytic therapy (NT). Baseline reference values were established in healthy subjects matched for age and gender. The National Institutes of Health Stroke Scale (NIHSS) score assessed at baseline and on day 2 was dichotomized into 2 severity groups (0-7 vs. >7). The modified Rankin Scale (mRS) score at day 90 was dichotomized for favorable (0-1) and unfavorable (2-6) outcomes. Results: A total of 109 patients were included, with 41 receiving rt-PA. At admission, patients had higher TAFIa/ai levels than reference. A significant increase in TAFIa/ai levels was observed at the end of thrombolysis (mean change from baseline of 963%) and lasted up to 4 h (191%). Higher TAFIa/ai levels were associated with a more severe day 2 NIHSS score (p = 0.0098 at T2h post thrombolysis) and an unfavorable mRS score from T48h (p = 0.0417) to day 90 (p = 0.0046). In NT patients, higher TAFIa/ai levels at admission were associated with a more severe stroke, as assessed by day 2 NIHSS score (p = 0.0026) and mRS score (p = 0.0003). Conclusion: These data demonstrate a consistent relationship between TAFI levels and early clinical severity during rt-PA treatment.

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Genetic variations in the thrombin-activatable fibrinolysis inhibitor gene and risk of cardiovascular disease: A systematic review and meta-analysis

Cited by 17 publications

References 29 publications

Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis

Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis

Aspirin ameliorates cerebral infarction through regulation of TLR4/NF‑κB‑mediated endoplasmic reticulum stress in mouse model

Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome

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