Plasminogen Activator Inhibitor-1 4G4G Research Articles

Combined Effect of MTHFR C677T and PAI-1 4G/5G Polymorphisms on the Risk of Venous Thromboembolism in Chinese Lung Cancer Patients.

Venous thromboembolism (VTE) is a common and potentially fatal complication in cancer patients. Although several genetic risk factors related to thrombophilia have been identified, their contributions for the occurrence of VTE in cancer patients have conflicting results. The aim of this study was to evaluated the gene polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor-1 (PAI-1) 4G/5G in lung cancer patients, with and without VTE, and the combined effect on the risk of VTE. 92 lung cancer patients diagnosed with VTE (VTE group) and 122 lung cancer patients without VTE (non-VTE group) were enrolled in the study. The gene polymorphisms were analyzed by the method of polymerase chain reaction-restriction fragment length polymorphism. Gene mutation of factor V Leiden was not detected both in non-VTE group and VTE group. The frequency of MTHFR C677T homozygous mutation in VTE group was 25.00%, higher than that in the non-VTE group without statistical difference. It was found that the PAI-1 4G4G genotype is associated with a higher risk of VTE (OR: 2.62, 95%CI: 1.19-5.75). Interestingly, the interaction between MTHFR C677T and PAI-1 4G/5G polymorphisms showed that the coexistence of the 2 homozygous mutation could further increase the risk of VTE. In conclusion, PAI-1 4G/5G polymorphism may be an increased risk factor for VTE among lung cancer patients in Chinese population. The homozygous MTHFR C677T mutation may be not a risk factor for VTE but increases the risk, accompanied with PAI-1 4G5G genotype.

Association between PAI-1 4G/5G Polymorphisms and osteonecrosis of femoral head: A Meta-analysis

The polymorphism of the plasminogen activator inhibitor-1 (PAI-1) 4 G/5 G gene has been correlated with susceptibility to osteonecrosis of the femoral head (ONFH), but study results are controversial. The aim of this study was to derive a more precise estimation of the relationship between the PAI-1 4 G/5 G Gene polymorphism and ONFH by performing a meta-analysis. The meta-analysis was based on five eligible case-control studies involving 419 cases and 969 controls and summarized data indicating the association between PAI-1 polymorphism and risk of osteonecrosis of the femoral head. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to assess the strength of this association in the random-effects model or fixed-effects model. A significant association between PAI-1 4 G/5 G polymorphism and ONFH susceptibility was observed for 4G4G+4G5G vs. 5G5G (OR=1.766, 95% CI 1.279-2.437, P=0.001), 4 G/4G vs. 4 G/5 G+5G/5 G (OR=2.050, 95% CI 1.581-2.657, P=0.000), 4 G/4G vs. 5 G/5G (OR=2.553, 95% CI 1.345-4.846, P=0.004), and 4 G vs. 5 G (OR=1.758, 95% CI 1.236-2.500, P=0.002). No significant association between PAI-1 4 G/5 G polymorphism and ONFH susceptibility was observed for 4 G/5 G vs. 5 G/5G (OR=1.327, 95% CI 0.939-1.877, P=0.109). This meta-analysis suggested that 4 G/5 G polymorphism of the PAI-1 gene was a risk factor for ONFH. This study also suggests that the PAI-1 4G4G genotype may indicate a risk for ONFH.

Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women

Plasminogen activator inhibitor-1 (PAI-1) is important for maintaining pregnancy. Aberrantly increased PAI-1 levels may contribute to thrombosis and inflammation, leading to pregnancy loss. This study investigated the association of PAI-1 polymorphisms (PAI-1 rs2227631 [-844G>A], rs1799889 [-675 4G/5G], rs6092 [43G>A], rs2227694 [9785G>A], and rs7242 [11053T>G]) with idiopathic recurrent pregnancy loss (RPL) in Korean women. We screened 308 RPL patients and 227 control participants for five PAI-1 polymorphisms. Genotyping of PAI-1 was performed by polymerase chain reaction-restriction fragment length polymorphism assay. PAI-1 4G4G and -844AA/4G4G/11053GG genotypes were associated with RPL. PAI-1 -844A/4G/43G/9785G/11053G haplotype was connected to hypofibrinolytic status (i.e. increased levels of plasma PAI-1, increased numbers of platelets, reduced prothrombin time, and reduced activated partial thromboplastin time). Moreover, PAI-1 11053TG+GG frequency was positively related to plasma homocysteine and urate levels, whereas -844AA frequency was associated with plasma folate concentrations according to ordinal logistic regression analysis. Based on these results, we propose that PAI-1 -844G>A, 4G/5G, and 11053T>G polymorphisms are markers of RPL.

Influence of inherited and acquired thrombophilic defects on the clinical manifestations of mixed cryoglobulinaemia

To investigate the contribution of inherited and acquired thrombophilic defects to the clinical manifestations of mixed cryoglobulinaemia vasculitis. The following thrombophilic defects were investigated in 64 consecutive patients with HCV-associated mixed cryoglobulinaemia: aPLs, lupus anti-coagulant, homocysteinaemia, protein C and protein S concentrations, activated protein C resistance, plasminogen activator inhibitor-1 4G4G and 5G5G genotypes, and the presence of mutations of factor V (Leiden and H1299R), of prothrombin (G20210A) and of methyl tetrahydrofolate reductase (C677T and A1298C). Additional variables were demographic data, duration of the disease, cryocrit level and vascular risk factors (diabetes, hypertension, hypercholesterolaemia and smoking habit). The following clinical manifestations of mixed cryoglobulinaemia were analysed as dependent covariates: severity of purpura, presence of necrotic skin ulcers, presence of peripheral neuropathy and presence of kidney disease. Logistic regression analysis identified hyperhomocysteinaemia as a risk factor for severe purpura (P < 0.0001) and for the presence of skin ulcers (P < 0.0001), whereas none of the other thrombophilic defects influenced the clinical presentation of mixed cryoglobulinaemia. Purpura improved in two patients after lowering homocysteine with vitamin supplementation. Hyperhomocysteinaemia may be a risk factor for severe cutaneous manifestations in mixed cryoglobulinaemia.

Ocular Vascular Thrombotic Events: Central Retinal Vein and Central Retinal Artery Occlusions

We prospectively assessed associations of thrombophilia- hypofibrinolysis with central retinal vein occlusion (CRVO) (40 patients) and central retinal artery occlusion (CRAO) (9 patients). We used polymerase chain reaction measures for thrombophilia (factor V Leiden, prothrombin, C677T MTHFR, platelet glycoprotein PlA1/A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). Serologic thrombophilia measures included protein C, protein S (total and free) and antithrombin III, homocysteine, lupus anticoagulant, anticardiolipin antibodies IgG-IgM, and factors VIII and XI. Serologic hypofibrinolysis measures included Lp(a) and plasminogen activator inhibitor activity. For comparison with 40 CRVO and 9 CRAO patients, 80 and 45 race-gender matched controls were studied. The factor V mutation was more common in CRVO (3/40, 8%) than controls (0/79, 0%), P = .036, as was high (>150%) factor VIII (12/40, 30%) versus (4/77, 5%), P = .0002. Low antithrombin III (<80%) was more common in CRVO (5/39, 13%) than in controls (2/73, 3%), P = .049. Homocysteine was high (> or =13.5 micromol/L) in 5/39 (13%) CRVO patients versus 2/78 controls (3%), P = .04. Three of 9 CRAO patients (33%) had low (<73%) protein C versus 2/37 controls (5%), P = .044. Two of 9 CRAO patients (22%) had high (> or =13.5 micromol/L) homocysteine versus 0/42 controls (0%), P =. 028. Four of 9 CRAO patients had the lupus anticoagulant (44%) versus 4/33 (12%) controls (P = .050). CRVO is associated with familial thrombophilia (factor V Leiden, factor VIII, low antithrombin III, homocysteinemia), and CRAO is associated with familial and acquired thrombophilia (low protein C, homocysteinemia, lupus anticoagulant), providing avenues for thromboprophylaxis, and triggering family screening.

Type 2 diabetes significantly modulates the cardiovascular risk conferred by the PAI-1 − 675 4G/5G polymorphism in angiographied coronary patients

Background The association of the − 675 4G/5G polymorphism of the plasminogen activator inhibitor-1 ( PAI-1) gene with cardiovascular disease in patients with type 2 diabetes (T2DM) is unknown. Methods Genotyping was performed in 672 consecutive Caucasian patients undergoing coronary angiography for the evaluation of stable coronary artery disease (CAD). Vascular events were recorded over 4 years. Results In non-diabetic subjects ( n = 524), the homozygous PAI-1 4G4G genotype was significantly associated with significant coronary stenoses ≥ 50% (adjusted odds ratio (OR) OR = 1.84 [1.17–2.92]; p = 0.009); however, in T2DM patients ( n = 148) no such association was observed (OR = 0.67 [0.26–1.71]; p = 0.401). An interaction term T2DM × 4G4G genotype was significant ( p = 0.006), indicating a significantly stronger association of the polymorphism with CAD in non-diabetic subjects than in patients with T2DM. Also prospectively, the 4G4G genotype conferred an increased risk of vascular events in non-diabetic subjects but not in T2DM patients (hazard ratios 1.76 [1.13–2.74]; p = 0.014 and 0.68 [0.30–1.54]; p = 0.360, respectively). Again, the interaction T2DM × 4G4G genotype was significant ( p = 0.018). Conclusions Presence of T2DM significantly modulates the vascular risk conferred by the PAI-1 − 675 4G/5G polymorphism in angiographied coronary patients.

Ocular Vascular Thrombotic Events: A Diagnostic Window to Familial Thrombophilia (Compound Factor V Leiden and Prothrombin Gene Heterozygosity) and Thrombosis

In a 12-member, 3-generation kindred with conjoint inheritance of G1691A factor V Leiden (FVL) and G20210A prothrombin gene (PTG) mutations, identified through a proband with amaurosis fugax and his father with nonarteritic ischemic optic neuropathy (NAION), the authors' hypothesis was that ocular thrombosis was a diagnostic window to familial thrombophilia-thrombosis. The authors used polymerase chain reaction (PCR) measures for thrombophilia (FVL, PTG, C677T-A1298C methylenetetrahydrofolate reductase [MTHFR], platelet glycoprotein PLA1A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). The 39-year-old white male proband, with amaurosis fugax and transient ischemic attacks (TIA), was found to be a compound heterozygote for FVL and PTG mutations. His symptoms resolved only after coumadin. His 44-year-old brother (deep venous thrombosis [DVT]) and 46-year-old sister (DVT, pulmonary embolus [PE]) were compound FVL-PTG gene heterozygotes. Of 4 asymptomatic children born to these 3 siblings, 2 were FVL heterozygotes and 2 PTG heterozygotes. The proband's 69-year-old father, with NAION and ischemic stroke, had PTG heterozygosity, familial high factor VIII, and compound MTHFR C677T-A1298C mutation with homocysteinemia. The proband's 61-year-old aunt had PTG heterozygosity, recurrent DVT, and mesenteric artery thrombosis. The proband's 67-year-old mother, free of thrombotic events, was a FVL heterozygote, had high factor VIII, and PAI-1 4G4G homozygosity. In this extended kindred, ocular thrombotic events (amaurosis fugax, NAION) were associated with variegated thrombotic events, including TIA, ischemic stroke, DVT, PE, and mesenteric artery thrombosis, and opened a diagnostic window to family screening and treatment for complex thrombophilias, which had previously been undiagnosed.

Plasminogen activator inhibitor-1 4G4G genotype is associated with myocardial infarction but not with stable coronary artery disease

A case control study was conducted to test the hypothesis that plasminogen activator inhibitor type-1 (PAI-1) 4G/5G gene polymorphism confers an increased risk for myocardial infarction (MI) in patients with known coronary atherosclerosis. One hundred fifty-six consecutive patients who presented with acute MI and 111 stable coronary artery disease (SCAD) patients with documented critical coronary artery stenoses were prospectively enrolled. PAI-1 4G/5G gene polymorphism and conventional atherosclerotic risk factors were studied in all patients. PAI-1 4G/5G gene polymorphism was studied in another 281 healthy blood bank donors. The frequency 4G4G genotype was significantly higher in the MI group as compared to SCAD group (32.7% vs. 15.3%, P = 0.001) while it was not statistically significant between MI and healthy control groups (32.7% vs. 26.0%, P = 0.136). Comparing with healthy controls SCAD group had significantly lower frequency of 4G4G genotype (P = 0.024). In comparison with SCAD group PAI-1 4G/4G genotype, male sex and smoking habits favored to MI in univariate analysis with a P value of less than 0.2. These variables were included in multivariate regression model to estimate the associated risk for MI. PAI-1 4G/4G genotype was the only independent variable (OR 2.67, 95%CI 1.43-4.96, P = 0.002) associated with MI in this regression model. Comparing with healthy control group 4G4G genotype was not associated with MI (OR 1.38, 95%CI 0.90-2.12). However, presence of 4G4G genotype had a protective effect against development of SCAD (OR 0.52, 96%CI 0.29-0.92). Compared to patients with critical coronary stenoses, PAI-1 4G/4G genotype was found to be an independent predictor for development of MI in this population. PAI-1 4G4G genotype have a protective effect against development of high grade stable coronary stenoses.

Significant impact of the presence of type 2 diabetes on the cardiovascular risk conferred by the plasminogen activator inhibitor-1–675 5G/4G polymorphism

Background/Aims: The -675 5G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene has been associated with increased plasma levels of PAI-1 and, in some studies, with increased vascular risk. Hardly any data on the vascular risk conferred by this polymorphism are available for patients with type 2 diabetes (T2DM). We therefore aimed at investigating i) the association of this polymorphism with angiographiaclly diagnosed coronary artery disease (CAD) and ii) its impact on future vascular events in patients with T2DM and in nondiabetic individuals. Methods: Genotyping was performed in 672 consecutive Caucasian patients (463 men and 209 women, mean age 62±10 years) undergoing coronary angiography for the evaluation of stable CAD. Prospectively, we recorded vascular events over 4 years. Results: The prevalence rates of the 5G/5G, the 5G/4G, and the 4G/4G genotypes were 17.6%, 52.7%, and 29.7% in patients with T2DM (n=148) and 23.5%, 48.3%, and 28.2% in non-diabetic subjects (n=524). In non-diabetic subjects the homozygote PAI-1 4G4G genotype after adjustment for age, gender, hypertension, smoking, BMI, LDL cholesterol, and HDL cholesterol was significantly associated with significant stenoses (adjusted odds ratio (OR) 1.77 [95% CI 1.13–2.78], p=0.013), whereas no such association was observed in patients with T2DM (OR 0.81 [0.34–1.93]; p=0.635). An interaction term T2DM x 4G4G genotype was significant (p=0.026), indicating that the association of the polymorphism with CAD was significantly stronger in non-diabetic subjects than in patients with T2DM. Also prospectively, the 4G4G genotype conferred an increased risk of vascular events in non-diabetic subjects but not in T2DM patients, with hazard ratios of 1.66 [1.05–2.64], p=0.031 and 0.72 [0.33–1.60], p=0.423, respectively (adjusted for age, gender, hypertension, smoking, BMI, LDL cholesterol, and HDL cholesterol). Again, an interaction term T2DM x 4G4G genotype was significant (p=0.042). Conclusions: We conclude that presence of T2DM significantly modulates the vascular risk conferred by the PAI-1–675 5G/4G polymorphism.

Amaurosis Fugax Caused by Heritable Thrombophilia-Hypofibrinolysis in Cases Without Carotid Atherosclerosis

Nineteen patients (age 60 +/- 14) with amaurosis fugax associated with heritable thrombophilia-hypofibrinolysis without ipsilateral atherosclerotic carotid plaque or other causes of amaurosis fugax were studied. Our hypothesis was that case-specific thromboprophylaxis would prevent subsequent amaurosis fugax episodes. Prospective treatment data were available for 13 cases. Thrombophilic disorders included high Factors VIII and XI, G20210A prothrombin heterozygosity, low proteins C and S, MTHFR mutations, and the PL A1/A2 mutation. Hypofibrinolytic disorders included plasminogen activator inhibitor-1 4G4G, and high lipoprotein (a). Treatments included Coumadin; Lovenox, folic acid-vitamin B6-vitamin B12, discontinuation of estrogens-selective estrogen receptor modulators, Glucophage, and aspirin, as appropriate. Usually within 1 month on therapy, patients became asymptomatic and have remained asymptomatic for > or = 1 year on therapy, without adverse treatment side effects. When amaurosis fugax occurs without carotid artery atherosclerosis or other known causes, thrombophilia or hypofibrinolysis, or both are nearly universal, safely treatable, reversible pathoetiologies.

Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review.

It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction. Methods and Results- We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G-455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P=0.12 and OR 0.89, 95% CI 0.59 to 1.35, P=0.6, respectively). Inclusion of the studies that investigated young patients (<55 years) made the association significant for factor V Leiden (OR 1.29, 95% CI 1.03 to 1.61, P=0.02). Homozygosity for the fibrinogen -455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, P=0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, P=0.04). Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.

Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women.

A common 4G allele of a 4G/5G polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with increased transcription of the PAI-1 protein, which may lead to decreased fibrinolysis. It has therefore been proposed as a candidate risk factor for myocardial infarction or stroke. We studied the relationship between PAI-1 4G/5G genotype and the risk of cardiovascular mortality in a prospective cohort study among 12 239 women initially aged between 52 and 67 years, with a maximum follow-up time of 18 years (153 732 follow-up years). PAI-1 4G/5G genotype was measured in DNA obtained from urine samples, which were collected at baseline, of 498 women who died of a cardiovascular disease and a random sample of 512 women from the same cohort who did not die of cardiovascular disease. The PAI-1 4G/5G genotype was not associated with risk of myocardial infarction or other cardiovascular mortality. However, PAI-1 4G4G homozygotes had a markedly reduced risk of cerebrovascular mortality compared with PAI-1 5G5G homozygotes: the relative risk was 0.4, with a 95% CI of 0.2 to 0.7, whereas the relative risk of cerebrovascular mortality in PAI-1 4G5G heterozygotes compared with PAI-1 5G5G homozygotes was 0.7, with a 95% CI of 0.4 to 1.1. These findings are suggestive of an important contribution of PAI-1 in cerebrovascular pathology, probably via pathways other than fibrinolysis. PAI-1 may protect against destabilization of the atherosclerotic plaque, or it may inhibit neurotoxicity of tissue plasminogen activator in the brain.

Polymorphisms of angiotensin converting enzyme and plasminogen activator inhibitor-1 genes in diabetes and macroangiopathy

An insertion or deletion (I/D) polymorphism in the angiotensin converting enzyme (ACE) gene and a 4/5-guanine tract polymorphism (4G/5G) in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene are associated with the plasma activities of these substances and with coronary heart disease. In smooth muscle cells and mesangial cells, the angiotensin II synthesized by ACE increases mRNA expression and the activity of PAI-1, which promotes antifibrinolysis and the accumulation of extracellular matrix. Therefore, ACE and PAI-1 polymorphisms may have a synergistic effect on diabetic nephropathy and macroangiopathy. Using multivariate logistic regression analyses, we investigated the independent or synergistic effects of the ACE I/D and PAI-1 4G/5G polymorphisms on the development of diabetic nephropathy and macroangiopathy in 208 patients with non-insulin dependent diabetes mellitus (NIDDM) over a 15 year period. Advanced diabetic nephropathy, defined as impaired renal function and diabetic retinopathy, was present in 98 patients. Manifest macrovascular diseases, confirmed by both clinical signs and physical and laboratory examinations, were present in 56 patients. There was no significant difference in the genotype distribution of ACE or PAI-1 polymorphisms between subjects with advanced nephropathy and those with normal renal function. There was no significant difference in the renal survival rate between patients with differing ACE or PAI-1 genotypes. Subjects with macroangiopathy had a higher frequency of the DD genotype than those without macroangiopathy. Subjects with both DD and 4G4G genotypes had a higher incidence of macroangiopathy than those with any other pair of genotypes. Multivariate logistic regression analysis showed that there was no association between ACE or PAI-1 polymorphisms and diabetic nephropathy. The ACE DD genotype and its interaction with the PAI-1 4G4G genotype and the presence of advanced diabetic nephropathy were positively associated with macrovascular disease. These results indicate that the ACE DD genotype and its interaction with the PAI-1 4G4G genotype are independent risk factors for macroangiopathy, but not for the progression of diabetic nephropathy in NIDDM patients, and that the genotyping of PAI-1 and ACE polymorphisms, especially in patients with advanced diabetic nephropathy, may be useful for predicting and preventing macroangiopathy-related events.