Inhibitor Polymorphisms Research Articles

Plasminogen Activator Inhibitor-1 Polymorphisms and Risk of Coronary Artery Disease: Evidence From Meta-Analysis and Trial Sequential Analysis.

A systematic review and meta-analysis were conducted to find out if there was association between Plasminogen Activator Inhibitor-1 (PAI-1) gene polymorphisms (- 844 G > A and - 675 4G > 5G) and susceptibility to coronary artery disease (CAD). Search of electronic databases was performed and the pooled odds ratio (OR) and 95% confidence interval (CI) were exerted to evaluate the pooled association between the single-nucleotide polymorphisms (SNPs) and risk of CAD. For - 675 4G > 5G SNP, dominant (OR = 0.90), recessive (OR = 0.90), allelic (OR = 0.91), homozygous (OR = 0.84), and heterozygous (OR = 0.96) models were significantly associated with decreased risk of CAD. Moreover, all five genetic models were associated significantly with decreased CAD risk in the Causation and Arab populations. The results in Asians were marginally significant in recessive, allelic, and homozygote models. The male gender was found to be a risk factor in individuals with PAI-1 4G > 5G SNP in the dominant model (OR = 0.89), recessive model (OR = 0.91), allelic model (OR = 0.92), homozygous model (OR = 0.86), and heterozygous model (OR = 0.91). The results of pooled ORs for overall populations and subgroup analysis by ethnicity reject any association between PAI-1 gene - 844 G > A polymorphism and CAD risk under all genetic comparisons. The results of this meta-analysis indicated that PAI-1 4G > 5G SNP was associated with decreased risk of CAD in the overall population as well as in the Asians, Caucasians, and Arab populations. However, the PAI-1 gene - 844 G > A polymorphism had no significant association with susceptibility to CAD.

Plasminogenactivator inhibitor-1 polymorphism and risk of polycystic ovary syndrome in Turkish women

ObjectivePolycystic ovary syndrome(PCOS) is a chronic systemic disease with a multifactorial etiology resulting from complex interactions of environmental and genetic factors rather than a local disease. There are recently identified several abnormalities related to the hemostatic and fibrinolytic systems. Therefore, the study is performed to investigate the association between plasminogen activator inhibitor-1(PAI-1) -844G > A rs2227631 polymorphism and risk of PCOS. Subject and methodsTwo hundred fourteen voluntary premenopausal women (104 healthy controls and 110 PCOS patients) of similar age were included in the study. All volunteers underwent a physical examination and biochemical hormonal evaluation. PAI-1-844G > A rs2227631 variant was analysed using polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP) method. Women were diagnosed with PCOS according to the criteria of the Androgen Excess-PCOS Society. ResultsIn PAI-1-844G > A, “A” additive model, AG vs. GG (OR: 2.6; 95%Cl: 1.09–6.17 p = 0.94) or AA vs. GG (OR: 2.3; 95%Cl: 0.87–5.96 p = 0.094) genotype increased the PCOS risk almost 2.5-fold. “G” dominant model, AG + GG vs. AA (OR: 0.97; 95%Cl: 0.52–1.81 p = 0.93) was not associated with PCOS risk. “G” recessive model, GG vs. AG + AA genotype reduced the risk of PCOS 2.6-fold (OR: 0.39; 95%Cl: 0.17–0.93 p = 0.033). “A” dominant model, AG + AA vs. GG genotype increased the risk of PCOS 2.5-fold (OR: 2.5; 95%Cl: 1.08–5.83 p = 0.033). ConclusionThe rs2227631 is related to PCOS risk in Turkish Women. The study indicated that the “AA” genotype was correlated with an increased risk of PCOS while the “GG” genotype reduced the PCOS risk in Turkish women.

Plasminogen activator inhibitor-1 polymorphisms as a risk factor for chronic periodontitis in North Indian population

ObjectivesImpaired plasminogen activator inhibitor-1 (PAI-1), controlling coagulation and the fibrinolytic system is supposed to be involved in the pathogenesis of periodontitis. This study was performed to examine the association of PAI-1 gene polymorphisms with Chronic Periodontitis (CP) and alveolar bone loss severity involved with the disease and for understanding the role of genetic contributions in disease progression. Methods87 volunteers were included in the study. Genomic DNA was isolated from peripheral blood, subsequently, DNA samples were subjected to polymerase chain reaction and endonuclease digestion. Direct gene sequencing were performed for all the samples to identify genotype polymorphisms (rs 11560324) in the 3’ untranslated region of PAI-1 gene. For bone loss assessment full mouth IOPA was taken. ResultsStatistical analysis showed that for SNP PAI-I in 3’ UTR, genotype CC (homozygous mutant) and allele C (mutant) has a risk associated with CP, although statistically significant association was not found. An increased risk of association of disease severity with CG (heterozygous mutant) and CC (homozygous mutant) genotypes, i.e., an increased carriage rate of genotype CG and CC (homozygous mutant) was evident with the increase in the severity of CP, highlighting an increased susceptibility to CP due to this gene polymorphisms. ConclusionPAI-1 genotype has a risk association with CP and alveolar bone loss severity in North-Indian population.

Plasminogen Activator Inhibitor-1 Polymorphism Confers a Genetic Contribution to the Risk of Recurrent Spontaneous Abortion: An Updated Meta-Analysis.

Various studies have investigated the risk of recurrent spontaneous abortion (RSA) with plasminogen activator inhibitor-1 ( PAI-1) 4G/5G polymorphism. However, the results have been somewhat contradictory. Therefore, an updated meta-analysis based on 31 studies (5617 cases and 3952 controls) was undertaken to clarify this relationship. The degree of RSA risk was estimated using the odds ratio (OR) and the 95% confidence interval (CI). Overall, the random effects OR was 1.464 (95% CI: 1.269-1.690) for 4G versus 5G, 2.075 (95% CI: 1.563-2.754) for 4G/4G versus 5G/5G, 1.457 (95% CI: 1.211-1.753) for 4G/5G versus 5G/5G, 1.743 (95% CI: 1.358-2.236) for 4G/4G versus 4G/5G + 5G/5G, and 1.600 (95% CI: 1.327-1.930) for 4G/4G + 4G/5G versus 5G/5G, indicating that PAI-1 4G/5G polymorphism could confer an increased risk of RSA. Furthermore, a subgroup analysis showed a significantly elevated susceptibility to RSA in Asians, Caucasians, and Africans. Thus, this study demonstrated that PAI-1 4G/5G polymorphism likely confers a genetic contribution to the development of RSA. The results may aid in developing a theoretical basis for effective strategies to prevent and treat RSA.

C0105: Plasminogen Activator Inhibitor-1 Polymorphism is Not Associated with Central Nervous System Bleeding in Pediatric Patients with Factor XIII Deficiency

C0105: Plasminogen Activator Inhibitor-1 Polymorphism is Not Associated with Central Nervous System Bleeding in Pediatric Patients with Factor XIII Deficiency

Association between 4G/4G plasminogen activator inhibitor-1 polymorphism, PAI-1 activity, and diabetic retinopathy

Background Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of fibrinolysis; however, the relationship between PAI-1 and the most common diabetic microvascular complication, retinopathy, is unclear. Objectives To examine the association between the 4G/4G polymorphism of the PAI-1 gene with diabetic retinopathy (DR) as well as with the plasma levels of the PAI-1 enzyme among Egyptian patients. Participants and methods Thirty-three patients who had type 2 diabetes for more than 10 years were compared with 63 patients with proliferative diabetic retinopathy (PDR). Both groups were compared with 48 control individuals. All groups were matched for age and sex. PAI-1 4G/5G genotyping was carried out by a PCR and the PAI-1 levels were measured by enzyme-linked immunosorbent assay testing. Results Higher plasma PAI-1 activity was associated with a higher risk of DR. The overall frequency of the 4G allele was 54.54% among type 2 diabetes patients versus 78.79% among PDR patients (P Conclusion The PAI-1 gene polymorphism 4G/4G contributed to the genetic susceptibility to DR and a higher PAI-1 plasma level was independently associated with a higher risk of retinopathy among Egyptians.

Prevalence of the fibrinogen β‐chain, angiotensin‐converting enzyme and plasminogen activator inhibitor‐1 polymorphisms in Costa Rican young adults with thrombotic disease

Thrombotic disease is a multifactorial condition that involves both classical and genetic risk factors. We studied the association between the classical risk factors of hypertension and smoking, and polymorphisms on the genes of the angiotensin-converting enzyme (ACE), the beta-chain of fibrinogen (FG), and the plasminogen activator inhibitor-1 (PAI-1) in patients with venous and arterial thrombosis. The present investigation is a retrospective case-control study. A total of 340 participants were analyzed, including 162 patients and 178 healthy controls. Hypertension and smoking showed a significant association with thrombotic disease (p < 0.05) but FG level was found significant risk factor only for the venous thrombosis (VT) group (p < 0.04). Significant differences between thrombotic groups were found for the studied polymorphisms of PAI-1 (p < 0.0014), but for both FG beta-chain gene polymorphisms, none of the molecular analyses showed a positive sample for any mutating allele (p > 0.05). For the ACE polymorphism, the I allele present a protective effect in the general thrombotic group. This is one of the first reports in a Latin-American population dealing with these molecular markers and thrombotic diseases.

Fibrogenic Polymorphisms (TGF-β, PAI-1, AT) in Mexican Patients With Established Liver Fibrosis. Potential Correlation With Pirfenidone Treatment

Background/AimThe aim of this work was to establish a potential correlation between specific polymorphisms and presence of hepatic fibrosis in Mexican patients with established liver fibrosis (ELF). Second, necroinflammatory index...

The Human G147D-Protein Phosphatase 1 Inhibitor-1 Polymorphism Is Not Associated with Altered Clinical Characteristics in Heart Failure

Objectives: A human protein phosphatase inhibitor-1 polymorphism, G147D (c.440G>A, p.147G>D), has been previously demonstrated to blunt the contractile responses of cardiomyocytes to β-adrenergic agonists. The present study sought to examine whether the G147D inhibitor-1 polymorphism may be associated with specific clinical characteristics of heart failure carriers. Methods: Clinical information of 963 heart failure patients was analyzed according to race, inhibitor-1 genotype, treatment with β-blockers and mortality patterns. Results: The G147D inhibitor-1 genetic variant was found almost exclusively in black subjects and its frequency was similar between normals and heart failure patients, indicating that it was not a primary risk factor for developing heart failure. Comparison of the major cardiac functional parameters and transplant-free survival patterns between carrier and noncarrier patients did not reveal any significant differences. Furthermore, echocardiographic evaluation showed similar outcomes of β-blocker treatment between G147D carriers and noncarriers. Conclusions: The present findings indicate that the human inhibitor-1 G147D polymorphism, found almost exclusively in blacks, may act as a modifier rather than risk factor in heart failure development.

Tranexamic acid effects on postoperative bleeding in cardiopulmonary bypass surgery according to the plasminogen activator inhibitor-1 polymorphism

The objective was to determine the effects of tranexamic acid (TA) on postoperative bleeding in cardiopulmonary bypass (CPB) surgery according to the 4G/5G plasminogen activator inhibitor-1 (PAI-1) gene polymorphism, the main endogenous regulator of fibrinolysis.

Role of plasminogen activator inhibitor-1 polymorphism on the development of vasoplegic syndrome associated with cardiopulmonary bypass

Vasoplegic syndrome (VS) after cardiac surgery with cardiopulmonary bypass (CPB) can vary from mild to severe complication and it appears with an incidence ranging between 5% and 15%. The etiology is not completely elucidated but risk factors such as temperature and duration of cardiopulmonary bypass and preoperative treatment with angiotensin-converting enzyme (ACE) inhibitors have been associated [1]. We wanted to investigate the possible role of several genetic polymorphisms in patients with VS after elective CPB.

ABO blood group but not haemostasis genetic polymorphisms significantly influence thrombotic risk: a study of 180 homozygotes for the Factor V Leiden mutation

Limited data exist on the impact of additional genetic risk factors on the clinical manifestations of factor (F) V Leiden homozygotes. A retrospective multi-centre cohort study was performed to assess the role of the FII G20210A gene mutation, the protein C (PC) promoter CG haplotype, the combination of two PC polymorphisms (A-1641G, C-1654T), the FXIII Val34Leu polymorphism, two thrombin-activatable fibrinolysis inhibitor polymorphisms (Thr325Ile, Ala147Thr), two plasminogen activator inhibitor-1 polymorphisms (-675 4G/5G, A-844G), the methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism and the ABO blood group on the thrombotic phenotype in FV Leiden homozygotes. 127 subjects with venous thrombosis and 53 asymptomatic subjects were analysed. The T allele of MTHFR C677T was more frequent in symptomatic subjects than in asymptomatic ones (68% vs. 45%, P = 0.02; odds ratio (OR) 2.8, 95% CI 1.3-5.8, after adjustment for potential confounders). For the other polymorphisms, no difference was observed between symptomatic and asymptomatic subjects. The non-O blood group was more frequent among symptomatic carriers (84% vs. 57%, P = 0.0002; OR 4.1, 95% CI 1.7-9.7). In conclusion, except for the ABO blood group, none of the polymorphisms studied contribute strongly to the thrombotic risk in FV Leiden homozygotes.

Plasminogen activator inhibitor-1 polymorphism is associated with increased risk for oral cancer

In light of the recently observed contribution of thrombosis-related factors to carcinogenesis, we investigated the possible association of plasminogen activator inhibitor-1 (PAI-1) with increased risk for oral cancer. In DNA samples of 104 patients with oral squamous cell carcinoma and 106 healthy controls of comparable ethnicity, age and sex, we studied the 4G/5G polymorphism in the PAI-1 gene, which affects its expression. The mutant 4G allele and carrier frequencies were significantly increased in patients compared to controls (65.9% versus 49.5%; 88.5% versus 69.8% respectively, P<0.01). That increase was even higher in patients with a positive family history for thrombophilia or without one for cancer (P<0.001). Interestingly, significant difference from controls was observed only in patients with cancer stages I and II. These findings suggest that the 4G allele, by resulting in higher PAI-1 expression, is a major contributing factor in early stages of oral oncogenesis. Possibly, increased PAI-1 promotes initial development of oral cancer through regulation of cell detachment and delays further tumor progression by inhibiting vascularization.

4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia

Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor-1 (PAI-1) is a characteristic feature of meningococcal sepsis. Previously, an association between mortality and the functional 4G/5G promoter polymorphism of the PAI-1gene in a cohort of UK and Dutch children with meningococcal sepsis was reported. We carried out a prospective, multicentre study to investigate the association of the 4G/5G PAI-1 polymorphism, diagnosis, and outcome in meningococcal disease in a Central European and UK population. Blood samples and clinical information of 347 previously healthy children with meningococcal infection were collected from 95 paediatric hospitals in Germany, Switzerland, Italy, the United Kingdom, and Austria from 2000 until 2002. Mortality was significantly associated with the 4G/4G genotype (12 of 90 (13%) vs. 15 of 240 (6%), P = 0.037), resulting in an odds ratio of 2.31. The diagnosis of sepsis (independent of symptoms of meningitis) was significantly more frequent in carriers of the 4G/4G genotype (P = 0.01), resulting in an odds ratio of 2.21 to develop sepsis. Meningitis was not associated with the PAI-1 4G/5G polymorphism, and allele frequencies were similar in patient and control groups. Our data show a correlation between the 4G/4G genotype in the plasminogen activator inhibitor-1 gene and poor outcome in children with meningococcal infection. In addition, 4G homozygous patients were prone to develop sepsis. We found no influence of the plasminogen activator inhibitor-1 polymorphism on the susceptibility to invasive meningococcal infection.

Plasminogen-activator inhibitor-1 polymorphisms are associated with obesity and fat distribution in the Qu??bec Family Study: evidence of interactions with menopause

Obesity is associated with increased plasma levels of plasminogen-activator inhibitor-1 (PAI1), the major fibrinolysis inhibitor. PAI1 levels are also increased at menopause, a condition that is associated with fat mass gain, especially in the abdominal area. We hypothesized that genetic variations within PAI1 gene are related to the amount of body fat and its regional distribution. We genotyped 666 subjects of the Quebec Family Study for five PAI1 gene polymorphisms. Stratified analyses were performed with analysis of covariance in men (n = 280) and women (n = 386) separately. PAI1-675 4G/5G polymorphism was strongly associated with body mass index (P < or = 0.01) and fat mass (P < or = 0.05) in women. The PAI1-675 4G/5G promoter polymorphism and the c.43G<A (p.A15T, rs6092) variant within the exon 1 were associated with abdominal visceral fat but only in postmenopausal women (P < or = 0.05). More specifically, homozygotes for the -675 5G and the 43A alleles had about 50% more visceral fat compared to carriers of the -675 4G allele as well as carriers of the 43G allele. No association was observed in men. Taken together, these results suggest that the PAI1 gene is associated with obesity and may modulate the changes in adipose tissue distribution generally observed at menopause.

Plasminogen Activator Inhibitor-1 Polymorphism in Women with Pre-eclampsia

We determined whether or not genetic variability in the promoter region of the gene encoding plasminogen activator inhibitor-1 (PAI1) contributes to individual differences in susceptibility to the development of preeclampsia. The study involved 133 preeclamptic and 115 healthy control pregnant women who were genotyped for a single-nucleotide insertion/deletion polymorphism (4G/5G) at position -675 in the PAI1 gene promoter. Furthermore, the frequencies of the alleles in the general middle-aged population are presented for comparison. Chi-square analysis was used to assess genotype and allele frequency differences between preeclamptic women and controls. A similar allelic distribution of PAI1 4G/5G polymorphism was observed in the two groups, with the frequency of the variant 4G allele being 50.4% in the preeclampsia group and 54.3% in the control group (p = 0.377; OR = 0.85, 95% CI = 0.60-1.22). Accordingly, the genotype distribution of the PAI1 4G/5G polymorphism in the preeclamptic and control groups was found to be similar (p = 0.68). Overall, this genotype data on fertile women is almost identical to that in the general middle-aged Finnish population. The 4G/5G polymorphism of the PAI1 gene promoter is unlikely to be a major genetic predisposing factor as regards preeclampsia in subjects from eastern Finland. These results are not suggestive of an important contribution of the PAI1 genotype on preeclampsia across populations.

Plasminogen activator inhibitor-1 polymorphism is associated with progressive renal dysfunction after acute rejection in renal transplant recipients.

Plasma level of plasminogen activator inhibitor (PAI)-1 is genetically determined by a polymorphism in the promoter region, involving two alleles, 4G and 5G. Plasma PAI-1 concentrations are higher in subjects homozygous for the 4G allele than other genotypes (5G/5G and 4G/5G). Such genetic variation in fibrinolytic system may affect the long-term renal transplant outcome. We determined PAI-1 4G/5G-promoter genotype polymorphism among our renal transplant recipients between 1985 and 2001. Primary event was defined as doubling of baseline serum-creatinine level. Over a median period of 79 months, 130 patients with 132 kidney grafts were assessed. Baseline clinical variables were comparable among three genotype groups. There was no association between primary event and PAI-1 genotype among the entire cohort. However, among subjects with prior acute rejection episodes, those homozygous for 4G had significantly higher risk of serum creatinine doubling than the other two genotypes (relative risk 2.45, 95% confidence interval 1.19-5.04). PAI-1 genotype does not predict primary events in patients without rejection (relative risk 0.57, 95% confidence interval 0.07-4.17). PAI-1 4G/5G-promoter polymorphism modulates the risk of renal transplant outcomes after acute rejection(s). Recipients homozygous for PAI-1 4G allele have a higher risk of progressive renal damage after acute rejection episode(s). PAI-1 promoter polymorphisms are potentially important determinants of renal response to rejection.