Plasminogen Activator Inhibitor-1 Polymorphism Research Articles

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.

Polymorphisms of Plasminogen Activator Inhibitor-1 4G/5G, Coagulation Factor XIII Val34Leu and Angiotensin Converting Enzyme I/D Impact on Recurrent Implantation Failure

Polymorphisms of Plasminogen Activator Inhibitor-1 4G/5G, Coagulation Factor XIII Val34Leu and Angiotensin Converting Enzyme I/D Impact on Recurrent Implantation Failure

Role of plasminogen activator inhibitor-1 gene polymorphisms in osteoporosis: A study in Chinese post-menopausal women

Osteoporosis is a chronic multifactorial disease characterized by deterioration of bone mass and is vulnerable to bone fracture. Plasminogen activator inhibitor-1 (PAI-1) is an important molecule for maintenance of optimum bone mass. Several single-nucleotide polymorphisms (SNPs) in PAI-1 have been reported to alter PAI-1 expression and/or the translational level. In this report, we explored the possible role of common PAI-1 gene polymorphisms on predisposition to osteoporosis in a Chinese cohort. A total of 364 post-menopausal Chinese women diagnosed of having osteoporosis and 350 healthy females hailing from similar areas were enrolled in this study. Five common SNPs (−844G > A, −6754G/5G, +43G > A, +9785G > A and +11053T > G) were genotyped by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Relative expression of PAI-1 mRNA and plasma PAI-1 levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Prevalence of homozygous mutant (5G/5G) and minor allele (5G) of PAI-1 (−675 4G/5G) polymorphism was significantly more frequent in patients than in healthy controls (5G/5G: P < 0.0001, odds ratio (OR) = 3.18; 5G: P < 0.0001, OR = 1.65). Both plasma PAI-1 and relative mRNA expression levels were significantly lower in patients compared to healthy controls. Interestingly, the quantity of plasma PAI-1 and mRNA expression was correlated with PAI-1 (−675 4G/5G) polymorphism: subjects with 4G/4G genotype had elevated PAI-1 in comparison to homozygous mutant, and displayed lower quantity of PAI-1 protein and mRNA values. PAI-1 (−675 4G/5G) mutant is associated with susceptibility to development of osteoporosis in post-menopausal Chinese women. Furthermore, this variant in the promoter region alters plasma protein levels and relative expression of PAI-1.

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.

Association of Plasminogen Activator Inhibitor-1 Gene Polymorphisms and Methylene Tetrahydrofolate Reductase Polymorphisms with Spontaneous Miscarriages

Aim: The objective of this study was to investigate a possible correlation between the plasminogen activator inhibitor-1 (PAI-1) and methylene tetrahydrofolate reductase (MTHFR) polymorphisms and unexplained spontaneous miscarriages (SM). Materials and Methods: PAI-1 polymorphisms were evaluated in 150 women with pregnancy in their history. One hundred women with a history of SM formed the study group and 50 women with normal pregnancies served as the control group. Also, the combination of PAI-1 and MTHFR polymorphisms were evaluated in 138 women out of a total of 150, which included 92 women with SM in their history compared to 46 women in the control group. For statistical analysis, χ² test, Phi, and Cramer V tests were used; p < 0.05 was taken as a statistically significant result. Results: Our findings show: (a) the correlation between SM and PAI-1 mutations reaches statistical significance (p = 0.026); (b) there was a statistically significant difference between heterozygous PAI-1 in women with only 1 SM compared to the control group (p = 0.047); (c) the comparison of combinations of both mutations, PAI-1 and MTHFR, with the control group demonstrates statistical significance in favor of women with SM and both mutations (p = 0.022). Conclusion: PAI-1 and MTHFR polymorphisms may play an important role in pregnancy complications because heterozygous PAI-1 mutations and a combination of both PAI-1 and MTHFR mutations might contribute to SM.

PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. There was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. The decrease in the FEV1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation.

The Plasminogen Activator Inhibitor 1 4G/5G Polymorphism and the Risk of Alzheimer's Disease.

The aim of this study was to determine whether plasminogen activator inhibitor 1 (PAI-1) is associated with the risk of Alzheimer's disease (AD) in Tunisian patients. We analyzed the genotype and allele frequency distribution of the PAI-1 polymorphism in 60 Tunisian patients with AD and 120 healthy controls. The results show a significantly increased risk of AD in carriers of the 4G/4G and 4G/5G genotypes versus the wild-type 5G/5G genotype (4G/4G: 28.33% in patients vs 10.0% in controls; P < 10-3; OR = 8.78; 4G/5G: 55.0% in patients vs 38.33% in controls; OR = 4.45; P < 10-3). The 4G allele was also more frequently found in patients compared with controls; P < 10-3; OR = 3.07. For all participants and by gender, homozygotic carriers (4G/4G) were at an increased risk of AD over heterozygotes and women were at an increased risk over their male genotype counterparts. The odds ratio for AD among 4G/4G carriers for any group was approximately twice that of heterozygotes in the same group. Women homozygotes ranked highest for AD risk (OR = 20.8) and, in fact, women heterozygotes (OR = 9.03) ranked higher for risk than male homozygotes (OR = 6.12). These preliminary exploratory results should be confirmed in a larger study.

Polymorphism 4G/5G of the plasminogen activator inhibitor 1 gene as a risk factor for the development of allergic rhinitis symptoms in patients with asthma.

Plasminogen activator inhibitor-1 (PAI-1) is a glycoprotein which has a role in tissue remodelling after inflammatory processes. The objective is to investigate the frequency of PAI-1 gene polymorphism (4G/5G) in patients with a lung ventilation dysfunction in asthma and allergic rhinitis. Genomic DNA was isolated and genotypes of polymorphism of PAI-1 4G/5G and ABO were determined using the methods of RT-PCR and PCR-SSP. Study group includes 145 adult patients diagnosed with chronic asthma, with all clinically relevant parameters and the laboratory markers of pO2, IgE and eosinophils in sputum and nasal swab. In the processing of data, appropriate statistical tests (Kolmogorov-Smirnov test, median, interquartile ranges, χ 2 and Mann-Whitney U tests) were used. Patients with symptoms of allergic rhinitis were significantly younger and had an almost four time higher levels of IgE (P = 0.001), higher pO2 (P = 0.002) and PEF (P = 0.036), compared to those who do not have these symptoms. Genotype PAI 4G/4G is significantly more common in patients with allergic rhinitis (28.1% vs. 16.1%; P = 0.017) compared to the genotype 5G/5G. Carriers of the genotype 4G/5G also have a borderline statistical significance. There were no statistically significant difference in the incidence of allergic rhinitis in the carriers of any ABO genotypes. The frequency of PAI genotype 4G/4G is significantly more common in patients with allergic rhinitis. The results suggest that the carriers of at least one 4G allele are at a higher risk for developing symptoms of allergic rhinitis in asthma.

Association of Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women.

Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene–environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.

Recurrent Arterial and Venous Thrombotic Events in a Patient with Psoriasis. Impact of PAI-1 Polymorphism: A Case Report

SummaryPsoriasis isachronic autoimmune multisystem disease, mainly affecting the skin and joints. Its origin is related to both environmental and genetic factors. The condition affects 1-3%of the population worldwide. Psoriasis is also associated with cardiovascular risk factors, atherothrombotic events, and markers of hypercoagulation (platelet activation and hyperhomocysteinemia). Venous thromboembolism (VTE) isawidespread severe disease. Both VTEand psoriasis are connected with risk factors for cardiovascular disorders (obesity and hypertension). The incidence of VTEevents in patients with psoriasis is higher. Patients with psoriasis should be checked for risk factors (metabolic disorders and cardiovascular diseases).We reportacase of a 53-year old man, diagnosed with plaque psoriasis 20 years ago, andafive year history of hypertension. In 2006, he hadastroke, and in 2011 ‒aheart attack. In 2013 he was diagnosed with thrombophlebitis. The patient was recently diagnosed with Type IIdiabetes, dyslipidemia and metabolic syndrome. The DNAanalysis revealed that the patient wasahomozygous carrier of 4G/4G (rs1799889) polymorphism in plasminogen activator inhibitor 1 (PAI-1) -a risk factor for thrombophilia. This case is important because of the major comorbidities, more particularly thrombotic events in combination withaprothrombotic mutation.

Fenotipicheskie i genotipicheskie osobennosti sistemy gemostaza u sportsmenov - urozhentsev Evropeyskogo Severa

Exercise is a stress factor, acting on the body, leads to changes in the hemostatic system and in particular - the fibrinolytic activity. The aim of the study was to compare the genetic characteristics of the athletes, the natives of the European north, with phenotypic markers of hemostasis. Method of sampling - continuous. The study involved athletes engaged in different sports, with sports category of the first and above, followed by the Arkhangelsk center of sports medicine. Using PCR and ELISA methods indicators of fibrinolysis and six polymorphisms of genes of the hemostatic system proteins have been evaluated. Research of hemostasiological status and genetic polymorphisms of some hemostatic system proteins in the group of athletes have revealed susceptibility to decreased activity of fibrinolysis and increase blood coagulation potential. The reason for the differences due to the higher, compared with the European, incidence of adverse associated trait in relation to polymorphisms of fibrinogen - 40.5 % in the athletes (CI: 30.3 - 51.1 %) against 20 % in the European population; platelet fibrinogen receptor - 25% (CI: 16.3 - 34.8 %) against 13 % in the European population, plasminogen activator inhibitor - 77.4 % in the athletes (CI: 67.9 - 85.7 %) against 53-61 % in the European population. A direct correlation between the presence of adverse gene polymorphism of plasminogen activator inhibitor-1 and this factor was revealed, which indicates the phenotypic expression of genetically determined depression of fibrinolysis.

The Association between PAI-1 Gene Promoter Polymorphism and Serum Serpin E1, MDA, and Hs-CRP Levels in Coronary Artery Disease

Background: Coronary artery disease (CAD) caused by atherosclerosis. Studies have shown that there are a number of factors which are closely related to the development and progression of CAD that include Cellular binding molecules like Plasminogen Activator Inhibitor-1(PAI-1), Lipid peroxidation, inflammation and hemostasis. Objectives: The present case-control study aimed to evaluate the association between Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G polymorphism and oxidative stress markers and Coronary Artery Disease (CAD). Patients and Methods: Blood was drawn and DNA was extracted from 90 subjects (46 patients with angiographically diagnosed CAD and 44 age- and sex-matched healthy controls). The 4G/5G polymorphism of PAI-1 was detected by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis. Besides, the risk factors, serpin E1, Malondialdehyde (MDA), high-sensitivity C-Reactive Protein (hs-CRP), and lipid profile serum levels were measured by standard methods and were compared between the two study groups using independent samples t-test, one-way ANOVA, and Mann-Whitney U test as appropriated. Results: Results: The frequency of 4G/4G genotype of PAI-1 gene was higher in the CAD patients than in the controls (28/46 (60.87%) vs. 8/44 (18.18%), P < 0.01). Additionally, the serpin E1 plasma level was significantly higher in the CAD group carrying the 4G allele compared to those homozygous for the 5G allele (P = 0.016). Besides, a significant difference was found between the 4G/4G and 5G/5G subjects of the CAD group regarding plasma High-Density Lipoprotein (HDL) (P < 0.01). Also, significant differences were observed among the three genotypes of both groups concerning the plasma levels of cholesterol, triglyceride, and Low-Density Lipoprotein (LDL). However, no significant correlation was found between PAI-1 gene polymorphism and MDA serum level, hs-CRP, and risk of CAD. Conclusion: The findings of this study suggested that 4G/4G PAI-1 polymorphism was associated with cholesterol, triglyceride, LDL, and HDL levels and could be regarded as a biomarker for risk of CAD.

Association Between Plasminogen Activator Inhibitor-1 Genetic Polymorphisms and Stroke Susceptibility

The plasminogen activator inhibitor-1 (PAI-1) is a candidate gene for stroke based on PAI-1's crucial role in fibrinolytic system. However, association studies have yielded conflicting results regarding the association between PAI-1 polymorphisms and stroke susceptibility. To further elucidate the putative association, we performed a systematic review and meta-analysis to provide a complete picture of the loci investigated for association of PAI-1 polymorphism with stroke risk and to derive a precise estimation. PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases were searched until June 2015 to identify eligible studies. Forty data sets from 39 studies with a total of 8336 cases and 14,403 controls were included. The most commonly investigated polymorphism was -675 4G/5G, followed by -844 G/A, 11053 T>G, HindIII C/G, and (CA)n. Overall, our meta-analysis provided evidence for the significant association of PAI-1 4G/5G polymorphism with an increased risk of adult but not pediatric ischemic stroke (adult: 4G/4G vs. 4G/5G + 5G/5G, OR = 1.21, 95% CI = 1.04-1.42). In the subgroup analysis, significant association was detected in Asians (4G/4G vs. 4G/5G + 5G/5G, OR = 1.45, 95% CI = 1.14-1.85) but not Caucasians. Moreover, we found that -844 G/A but not 11053 T>G polymorphism was associated with an increased risk of ischemic stroke (-844G/A: A/A vs. G/G: OR = 1.32, 95% CI = 1.01-1.73). A tendency of PAI-1 4G/5G polymorphism towards a decreased risk of hemorrhagic stroke was observed (4G/4G + 4G/5G vs. 5G/5G, OR = 0.77, 95% CI = 0.59-1.02, P = 0.066). Future well-designed studies in large well-characterized sample size and presenting results stratified by gender, age, and stroke subtype are warranted.

Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy.

In the present study we determined the association of angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR) 1.870 [95% confidence interval (CI) = 1.04–3.36]) and its sub-clinical class non-proliferative DR (NPDR) (p = 0.006, OR 2.250 [95% CI = 1.098–4.620]), while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR).

Association of plasminogen activator inhibitor-1 gene polymorphism and type 2 diabetic nephropathy

Background: We investigated the relationship between plasminogen activator inhibitor-1 (PAI-1) 4G/5G insertion/deletion polymorphism and prevalence of diabetic nephropathy (DN) in Chinese patients. Methods: A total of 107 patients with type 2 diabetes were randomly recruited in the study, and 102 healthy subjects were selected as Control. Patients were divided into three groups according to their urinary albumin–creatinine ratio (UACR). Group A (n = 44), had patients without DN (serum creatinine <106 µmol/L and UACR <30 µg/mg); Group B (n = 30), had patients with micro-albuminuria (UACR 30–299 µg/mg), and Group C (n = 33), had patients with macro-albuminuria (UACR ≥300 µg/mg and creatinine <200 µmol/L). Plasma level of PAI-1 was measured by ELISA. PAI-1 polymorphism was determined by a polymerase chain reaction (PCR) method and DNA sequencing. Results: (1) The plasma PAI-1 levels of group A (60.39 ± 17.01 ng/L), group B (68.76 ± 17.81 ng/L) and group C and (68.63 ± 18.30 ng/L) are higher than that of controls (46.26 ± 26.04 ng/L); (2) Patients with genotype 4G/4G tended to exhibit higher PAI-1 level; (3) The distribution frequency of genotype 4G/4G in group C was significantly higher than in group A (42.4% vs. 28.7%, p < 0.05) and (4) In type 2 diabetic patients, the occurrence of diabetes nephropathy in genotype 4G/4G, 4G/5G and 5G/5G is 35.0%, 30.2% and 21.4%, respectively. Conclusions: (1) Plasma PAI-1 level was elevated in Type 2 diabetic patients; (2) The level of plasma PAI-1 is closely related to PAI-1 gene 4G/5G polymorphism and (3) PAI-1 4G/5G polymorphism is associated with the development and progression of predominant proteinuria diabetes nephropathy.

4G/5G and A-844G Polymorphisms of Plasminogen Activator Inhibitor-1 Associated with Glioblastoma in Iran--a Case-Control Study.

Glioblastoma is a highly aggressive and malignant brain tumor. Risk factors are largely unknown however, although several biomarkers have been identified which may support development, angiogenesis and invasion of tumor cells. One of these biomarkers is PAI-1. 4G/5G and A-844G are two common polymorphisms in the gene promotor of PAI 1 that may be related to high transcription and expression of this gene. Studies have shown that the prevalence of the 4G and 844G allele is significantly higher in patients with some cancers and genetic disorders. We here assessed the association of 4G/5G and A-844G polymorphisms with glioblastoma cancer risk in Iranians in a case-control study. All 71 patients with clinically confirmed and 140 volunteers with no history and symptoms of glioblastoma as control group were screened for 4G/5G and A-844G polymorphisms of PAI-1, using ARMS-PCR. Genotype and allele frequencies of case and control groups were analyzed using the DeFinetti program. Our results showed significant associations between 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms of the PAI-1 gene with glioblastoma cancer risk in our Iranian population. The results of this study supporting an association of the PAI-1 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms with increasing glioblastoma cancer risk in Iranian patients.

Polymorphisms on PAI-1 and ACE genes in association with fibrinolytic bleeding after on-pump cardiac surgery.

BackgroundCarriers of plasminogen activator inhibitor -1 (PAI-1) -675 genotype 5G/5G may be associated with lower preoperative PAI-1 plasma levels and higher blood loss after heart surgery using cardiopulmonary bypass (CPB). We speculate if polymorphisms of PAI-1 -844 A/G and angiotensin converting enzyme (ACE) intron 16 I/D also might promote fibrinolysis and increase postoperative bleeding.MethodsWe assessed PAI-1 -844 A/G, and ACE intron 16 I/D polymorphisms by polymerase chain reaction technique and direct sequencing of genomic DNA from 83 open heart surgery patients that we have presented earlier. As primary outcome, accumulated chest tube drainage (CTD) at 4 and 24 h were analyzed for association with genetic polymorphisms. As secondary outcome, differences in plasma levels of PAI-1, t-PA/PAI-1 complex and D-dimer were determined for each polymorphism. SPSS® was used for statistical evaluation.ResultsThe lowest preoperative PAI-1 plasma levels were associated with PAI-1 -844 genotype G/G, and higher CTD, as compared with genotype A/A at 4 and 24 h after surgery. Correspondingly, 4 h after the surgery CTD was higher in carriers of ACE intron 16 genotype I/I, as compared with genotype D/D. PAI-1 plasma levels and t-PA/PAI-1 complex reached nadir in carriers of ACE intron 16 genotype I/I, in whom we also noticed the highest D-dimer levels immediately after surgery. Notably, carriers of PAI-1 -844 genotype G/G displayed higher D-dimer levels at 24 h after surgery as compared with those of genotype A/G.ConclusionsIncreased postoperative blood loss secondary to enhanced fibrinolysis was associated with carriers of PAI-1 -844 G/G and ACE Intron 16 I/I, suggesting that these genotypes might predict increased postoperative blood loss after cardiac surgery using CPB.Electronic supplementary materialThe online version of this article (doi:10.1186/s12871-015-0101-1) contains supplementary material, which is available to authorized users.

The 4G/4G Genotype of PAI-1 Polymorphism Is Associated with Higher Plasma PAI-1 Concentrations and Mortality in Patients with Severe Sepsis.

ObjectiveTwo studies have reported that patients with the 4G/4G genotype of the plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism had higher plasma PAI-1 concentrations and higher risk of death than those with the 4G/5G or 5G/5G genotypes; one study involved 175 children with meningococcal disease, and the other included 88 adult patients with septic shock. Thus, the objective of this study was to determine whether there is an association between carriage of the 4G/4G genotype, plasma PAI-1 concentrations and mortality in a large series of adult septic patients.MethodsAn observational, prospective, multicenter study was carried out in six Spanish Intensive Care Units including severe septic patients. We determined the PAI-1 4G/5G polymorphism and plasma PAI-1 concentrations in all patients. The end-points of the study were 30-day and 6-month mortality.ResultsWe included a total of 260 patients, 82 (31.5%) with 4G/4G, 126 (48.5%) with 4G/5G and 52 (20.0%) with 5G/5G genotype. Multivariate logistic regression analysis showed that the 4G/4G genotype was associated with higher mortality at 30 days (Odds Ratio = 1.95; 95% CI = 1.063–3.561; p = 0.03) and at 6 months (Odds Ratio = 2.19; 95% CI = 1.221–3.934; p = 0.01), and that higher plasma PAI-1 concentrations were associated with higher mortality at 30 days (Odds Ratio = 1.01; 95% CI = 1.002–1.022; p = 0.02) at 6 months (Odds Ratio = 1.01; 95% CI = 1.003–1.023; p = 0.01). Multivariate linear regression analysis showed that increased plasma PAI-1 concentrations were associated with the PAI-1 4G/4G genotype (regression coefficient = 4.82; 95% CI = 3.227 to 6.406; p<0.001).ConclusionsThe major findings of our study, to our knowledge the largest series reporting data about 4G/5G polymorphism of the PAI-1 gene, plasma PAI-1 concentrations and mortality in septic patients, were that septic patients with the 4G/4G genotype had higher plasma PAI-1 concentrations and higher risk of death than those with 4G/5G or 5G/5G genotypes.

Association between PAI-1 polymorphisms and plasma PAI-1 level with sepsis in severely burned patients.

We investigated the association between plasminogen activator inhibitor-1 (PAI-1) polymorphisms and plasma PAI-1 level with sepsis in severely burned patients. A total of 182 patients with burn areas lager than 30% of the body surface area were enrolled in this study. Peripheral blood samples were obtained from 103 patients with sepsis (sepsis group) and 79 patients without sepsis (control group). An allele-specific polymerase chain reaction assay was used to determine PAI-1 polymorphism 4G/5G distribution. Plasma PAI-1 levels were detected using an enzyme-linked immunosorbent assay. The frequency of the 4G/4G genotype and the 4G allele frequency in the sepsis group were 42.7 and 62.1% respectively, which were significantly higher than those in the control group (P < 0.05). Sepsis patients had a significantly higher plasma PAI-1 level than the control group (P < 0.05). Compared with the 5G/5G genotype, PAI-1 concentrations were significantly higher in the 4G/4G genotype (P < 0.05). The study indicates that the 4G/5G promoter polymorphism of PAI-1 gene may be related to the susceptibility to burn sepsis and that the 4G/4G genotype may be an important genetic risk factor of burn sepsis. Additionally, PAI-1 concentrations in the serum are increased in patients with burn sepsis.

The -844 G>A PAI-1 polymorphism is associated with acute coronary syndrome in Mexican population.

Background. Acute coronary syndrome (ACS) has an important impact in public health with high morbidity and mortality. Prothrombotic and proinflammatory states are involved in the pathogenesis of the disease. Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of the fibrinolysis and also is part of immune response. The -844 G>A gene polymorphism is related to increased PAI-1 protein levels. The aim of the study is to evaluate the association of -844 G>A PAI-1 polymorphism with ACS. Methods. A total of 646 individuals were recruited from Western Mexico: 350 unrelated healthy subjects and 296 patients with diagnosis of ACS. Results. The most important risk factor in our population was hypertension, followed by smoking. The genetic distribution showed an association of the A allele (OR = 1.27, P = 0.04) and AA genotype (OR = 1.86, P = 0.02) with ACS. The recessive model displayed similar results (OR = 1.76, P = 0.02). As additional finding, we observed significant differences in the genetic distribution of ACS dyslipidemic patients (OR = 1.99, P = 0.04). The A allele and AA genotype of -844 polymorphism of PAI-1 gene are risk factors for ACS. The AA genotype might be associated with the development of dyslipidemia in ACS patients.