Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis

Abstract

The effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006. A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068-1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR: 1.833,95% CI: 1.325-2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered.

HDL3, but not HDL2, stimulates plasminogen activator inhibitor-1 release from adipocytes: the role of sphingosine-1-phosphate

“…Because of the high S1P concentrations found in HDL, this lipoprotein fraction has been considered a constant source of S1P which can mediate cellular signaling pathways that infl uence a multitude of cardiovascular functions ( 23 ). Regardless of the biological activity that is affected, the effects of extracellular S1P are clearly mediated through the activation of fi ve specifi c G-protein-coupled receptors termed S1P [1][2][3][4][5] (formerly termed endothelial differentiation gene [Edg]1, -3, -5, -6, and -8) ( 24 ). In this article, we report the biological effects of S1P and HDL-associated S1P on PAI-1 secretion in mouse 3T3 adipocytes, the specifi c S1P receptors that mediate the response, and the signaling pathways involved.…”

“…HDL3, which contains signifi cantly higher amounts of S1P compared with HDL2, stimulated more PAI-1 secretion from adipocytes than HDL2. S1P-stimulated PAI-1 secretion from adipocytes is mediated by the G-protein-coupled receptor S1P 2 The effects of S1P on cell metabolism are mediated by S1P binding to the cell surface receptors S1P [1][2][3][4][5] , which have been reported to be variably expressed and tissuespecifi c ( 14,26 ). We evaluated expression of the genes the medium when adipocytes were incubated with increasing concentrations of S1P-albumin at S1P concentrations comparable to those observed in isolated HDL3.…”

“…3C, increasing S1P content in the HDL2 subfraction increased the concentration of PAI-1 secreted into the medium. Thus, when the S1P 1 GCA AGA ACA TCT CCA AGG GAA GAC ACT CAG GAC AAT G S1P 2 TTA GCA TCC TTC TCT TAG ACT C GTC ACT CCC TTC CCT CTC S1P 3 TGG ACT GTT GAA GTA ACC AGA GTG TCA TTT CCC AAG S1P 4 TAC TGC CTG CTG AAC ATC AGC TGG AAG GTA CGA GTC S1P 5 TCC TTC ACT ACA ACT ACA C AAG TTC TCC AGC ACA ATG GAPDH ATC TTG GGC TAC ACT GAG GCC GTA TTC ATT GTC ATA C Abbreviations: GAPDH, glyceraldehyde phosphate dehydrogenase S1P 1-5 , sphingosine-1-phosphate receptor [1][2][3][4][5] . Fig.…”

Thrombophilia in Assisted Reproductive Technology — Place and Needs of Thromboprophylaxis

“…In the presence of 4G allele and the absence of bound repressor, the basal level of PAI-1 transcription is increased [38]. The 4G allele of PAI-1 has been recently linked to venous thromboembolism [39] and coronary disease [37], however relation with recurrent pregnancy loss and implantation failure is under discussion.…”

Genetics of Antiphospholipid Syndrome

“…In a recent meta-analysis, Tsantes et al investigated the association between the SERPINE1 4G/5G polymorphism and the risk of venous thromboembolism (VTE) in 18 papers; it included patients without another known risk factor, and comprised 2,644 cases and 3,739 controls. Based on their findings, the SERPINE1 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects (Tsantes et al, 2007).…”