4G Polymorphism Research Articles

FNTB Promoter Polymorphisms Are Independent Predictors of Survival in Patients with Triple Negative Breast Cancer.

Simple SummaryIn breast cancer, the promising efficacy of farnesyltransferase inhibitors (FTIs) in preclinical studies is in contrast to only limited effects in clinical trials. Therefore, this study focussed on the clinical relevance of polymorphisms in FNTB, the gene encoding the catalytically active β-subunit of farnesyltransferase, in early breast cancer. This is the first study on breast cancer suggesting that FNTB promoter polymorphisms are independent prognostic biomarkers, particularly in patients with early triple negative breast cancer (TNBC), and possibly modulate FNTB transcriptional activity. Taken together, we describe for the first time, a link between FNTB promoter polymorphism and the prognosis of breast cancer patients. We propose that FNTB genotyping, which is easily possible from a single blood drawing, may allow independent prognostic stratification, particularly in TNBC, in order to identify patients with a high risk of recurrence and poor prognosis. Ultimately, our results encourage further prospective evaluations of the role of FNTB promoter polymorphisms in predicting response to FTIs, particularly in TNBC patients.In breast cancer, the promising efficacy of farnesyltransferase inhibitors (FTIs) in preclinical studies is in contrast to only limited effects in clinical Phase II–III trials. The objective of this study was to explore the clinical relevance of farnesyltransferase β-subunit (FNTB) single nucleotide promoter polymorphisms (FNTB-173 6G > 5G (rs3215788), -609 G > C (rs11623866) and -179 T > A (rs192403314)) in early breast cancer. FNTB genotyping was performed by pyrosequencing in 797 patients from a prospective multicentre observational PiA trial (NCT 01592825). In the total cohort, the FNTB-173 6G > 5G polymorphism was an independent predictor of RFI (HR = 0.568; 95% CI = 0.339–0.949, p = 0.031), OS (HR = 0.629; 95% CI = 0.403–0.980, p = 0.040) and BCSS (HR = 0.433; 95% CI = 0.213–0.882; p = 0.021), whereas the FNTB-609 G > C polymorphism was an independent predictor of RFI (HR = 0.453; 95% CI = 0.226–0.910, p = 0.026) and BCSS (HR = 0.227; 95% CI = 0.075–0.687, p = 0.009). Subtype analysis revealed the independent prognostic relevance of FNTB promoter polymorphisms, particularly in TNBC but not in luminal or HER2-positive intrinsic subtypes. Finally, we used electrophoretic mobility shift assays (EMSAs) to confirm in vitro that the polymorphism FNTB-173 6G > 5G resulted in the differential binding of nuclear proteins from five different breast cancer cell lines. This is the first study on breast cancer suggesting that FNTB promoter polymorphisms (i) are independent prognostic biomarkers, particularly in patients with early TNBC, and (ii) could modulate FNTB’s transcriptional activity.

The susceptibility of SERPINE1 rs1799889 SNP in diabetic vascular complications: a meta-analysis of fifty-one case-control studies

BackgroundThe serine protease inhibitor-1 (SERPINE1) rs1799889 single nucleotide polymorphism (SNP) has been constantly associated with diabetes mellitus (DM) and its vascular complications. The aim of this meta-analysis was to evaluate this association with combined evidences.MethodsThe systematic search was performed for studies published up to March 2021 which assess the associations between SERPINE1 rs1799889 SNP and the risks of DM, diabetic retinopathy (DR), diabetic cardiovascular disease (CVD) and diabetic nephropathy (DN). Only case-control studies were identified, and the linkage between SERPINE1 rs1799889 polymorphism and diabetic vascular risks were evaluated using genetic models.Results51 comparisons were enrolled. The results revealed a significant association with diabetes risk in overall population (allelic: OR = 1.34, 95 % CI = 1.14–1.57, homozygous: OR = 1.66, 95 % CI = 1.23–2.14, heterozygous: OR = 1.35, 95 % CI = 1.08–1.69, dominant: OR = 1.49, 95 % CI = 1.18–1.88, recessive: OR = 1.30, 95 % CI = 1.06–1.59) as well as in Asian descents (allelic: OR = 1.45, 95 % CI = 1.16–1.82, homozygous: OR = 1.88, 95 % CI = 1.29–2.75, heterozygous: OR = 1.47, 95 % CI = 1.08-2.00, dominant: OR = 1.64, 95 % CI = 1.21–2.24, recessive: OR = 1.46, 95 % CI = 1.09–1.96). A significant association was observed with DR risk (homozygous: OR = 1.25, 95 % CI = 1.01–1.56, recessive: OR = 1.20, 95 % CI = 1.01–1.43) for overall population, as for the European subgroup (homozygous: OR = 1.32, 95 % CI = 1.02–1.72, recessive: OR = 1.38, 95 % CI = 1.11–1.71). A significant association were shown with DN risk for overall population (allelic: OR = 1.48, 95 % CI = 1.15–1.90, homozygous: OR = 1.92, 95 % CI = 1.26–2.95, dominant: OR = 1.41, 95 % CI = 1.01–1.97, recessive: OR = 1.78, 95 % CI = 1.27–2.51) and for Asian subgroup (allelic: OR = 1.70, 95 % CI = 1.17–2.47, homozygous: OR = 2.46, 95 % CI = 1.30–4.66, recessive: OR = 2.24, 95 % CI = 1.40–3.59) after ethnicity stratification. No obvious association was implied with overall diabetic CVD risk in any genetic models, or after ethnicity stratification.ConclusionsSERPINE1 rs1799889 4G polymorphism may outstand for serving as a genetic synergistic factor in overall DM and DN populations, positively for individuals with Asian descent. The association of SERPINE1 rs1799889 SNP and DR or diabetic CVD risks was not revealed.

Plasminogen Activator Inhibitor Type 1 (PAI-1) and Thrombophilia: A 10 Year Retrospective Review of Clinical Data at a Large Children's Hospital

Introduction: Plasminogen activator inhibitor type 1 (PAI-1) is the most important regulator of fibrinolysis. Elevated PAI-1 levels are reported to be prothrombotic and have been associated with cardiovascular disease, obesity and cancer. PAI-1 synthesis is regulated by insulin, glucocorticoids and cytokines like tumor necrosis factor-α. The single base pair guanine deletion 4G PAI-1 genetic polymorphism has been linked to elevation of PAI-1 antigen and/or activity levels. Genotype frequencies in Caucasian populations have been estimated at 0.25 (5G/5G), 0.49 (4G/5G) and 0.26 (4G/4G). Increased thrombosis risk has been reported in patients with the combination of PAI-1 4G and factor V Leiden (FVL) genetic polymorphisms. Our pediatric specialty laboratory offers PAI-1 genotyping, PAI-1 antigen and PAI-1 activity assays as part of thrombophilia testing. The laboratory at the children's hospital is also a reference lab for the community. We retrospectively reviewed the results of PAI-1 testing over the last 10 years.We hypothesized that the PAI-1 4G polymorphism would be more prevalent in young patients with thrombosis. We also hypothesized that there would be an additive thrombophilia risk from the combination of PAI-1 4G and FVL in young patients with thrombosis.Methods: After IRB approval, using information from Cerner and EPIC, we created a deidentified thrombophilia database of 11,459 unique patients who had thrombophilia testing between March 8, 2007 and June 6, 2017. We identified 1,896 who had PAI-1 genotyping and 2,573 who had antigen and activity testing. Removing those <3 months of age for whom normal ranges for PAI-1 have not been established, we identified 1,418 subjects who had genotype, antigen and activity levels. We also evaluated a subset of 510 pediatric patients with thrombosis, of whom 338 had all three PAI-1 tests and were 3 months or older, and 292 who had both PAI-1 and FVL genotyping. Local genotype frequency was established by the clinical laboratory on 100 controls and was in agreement with published estimates. All comparisons were made using two-sided Fisher's Exact tests. Significance was assessed at the 0.05 level.Results: Ages for subjects tested for PAI-1 ranged from 0.1 - 89.7 years with a mean of 14.3 years, and 41% were male. Compared to the local genotype frequency, PAI-1 4G was not significantly altered in either the thrombophilia cohort or in the subset with pediatric thrombosis (Table 1). This was true even when we re-evaluated by gender or by selecting for those with thrombophilia testing <22 years of age. Among 53 pediatric thrombosis patients with cancer, genotype frequencies for PAI-1 4G did not differ strongly from control group (p=0.14), but numbers were very small. Of the 1,418 thrombophilia testing subjects who had PAI-1 genotype, antigen and activity, correlation between abnormal antigen (p=0.07) or activity (p=0.28) levels and the 4G polymorphism did not reach statistical significance, though it did for those with both abnormal antigen and activity (p=0.05). Among 292 pediatric thrombosis patients with testing (Table 2), there was a suggestion of an effect from the combination of FVL and PAI-1 4G polymorphisms and thrombosis (p=0.06).Conclusions: Abnormal PAI-1 antigen and activity levels are not solely dependent upon the 4G genotype and are likely influenced by other congenital and acquired factors. Among pediatric patients with thrombosis and particularly those with cancer and thrombosis, a possible effect from the PAI-1 4G polymorphism alone or in combination of FVL should be validated in a larger cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

An integrated approach to assess the complications of deforming osteoarthritis in sports medicine

Objective: prognosis of thromboembolic complications using clinical diagnostic markers.Materials and methods. The study involved 151 patients who underwent total arthroplasty (TA) of large joints of the lower extremities. Blood serum was studied at the patient’s admission to the hospital, after surgery, and at discharge from the hospital. The following parameters were determined: cell-molecular marker vascular endothelial growth factor (VEGF), a genetic study was performed using the “Plasma screen. Plasma factors of the blood clotting system”. The content of VEGF was determined in blood serum using solid-phase enzyme immunoassay. The effectiveness of diagnostics based on sensitivity and specificity analysis was considered by constructing a ROC analysis at different points of separation of the values of the studied indicators.Results. Diagnostic significance of VEGF and the efficiency of determining PAI-1 were determined. In patients with elevated VEGF values (&gt;183.6 pg/ml), PAI-1 gene polymorphism was detected, which reduces the fibrinolytic activity of the blood system and increases the risk of coronary disorders. This is especially important for patients in a hospital with a large number of risk factors for the development of VTEC due to prolonged immobilization of the limb. The study made it possible to determine that with VEGF values up to 183.6 pg/ml, a low probability of thromboembolic complications is predicted, and with values above 183.6 pg/ml — high.Conclusion. The course of DOA in athletes may be complicated by surgical intra-articular interventions of traumatological and orthopedic profile, which does not exclude the development of VTEO, significantly complicating drug therapy and the rehabilitation period. The presented data show that the determination of VEGF, 5G-675 4G polymorphism of the PAI 1 gene in blood serum can be used to assess the risk of venous thromboembolic complications (VTE), contributing to modern informative diagnostics, improving the quality of life of athletes and prolonging their sports career.

Association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and risk of Alzheimer's disease, metabolic syndrome, and female infertility: A meta-analysis.

Background:Plasminogen activator inhibitor-1 (PAI-1) is considered to be involved in the physiopathological mechanisms of Alzheimer's disease (AD), metabolic syndrome (MetS), and female infertility. Previous studies investigating the association between PAI-14G/5G (rs1799889) gene polymorphism and the risk of AD, MetS, and female infertility have reported inconsistent results. The aim of the present study was to investigate possible associations.Methods:Eligible studies were retrieved through PubMed, Medline, EMBASE, CNKI, and WANFANG databases. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the associations. Subgroup analyses by ethnicity and mean age, sensitivity analyses, and publication bias were performed.Results:Five studies (four articles) for AD, six studies (six articles) for MetS, and four studies (four articles) for female infertility were included in this meta-analysis. Our results showed no significant associations between the PAI-14G/5G polymorphism and the risk of AD and female infertility in five genetic models. For the risk of MetS, the PAI-1 4G/5G (rs1799889) polymorphism may be associated with the risk of MetS (4G vs 5G, OR = 1.31, 95%CI = 1.04–1.64, P = .021), especially in Asians (4G/4G vs 4G/5G+5G/5G, OR = 1.38, 95%CI = 1.01–1.87, P = .041) and patients with mean age > 50 years old (4G/4G vs 4G/5G+5G/5G, OR = 1.36, 95%CI = 1.03–1.78, P = .029).Conclusion:The present meta-analysis suggested that the PAI-1 4G/5G polymorphism might be associated with the risk of MetS, but no evidence was detected for AD and female infertility.

Inherited and acquired thrombophilia in adults with retinal vascular occlusion: A systematic review and meta‐analysis

BackgroundRetinal vascular occlusion is a leading cause of sight loss. Both retinal artery occlusion (RAO) and retinal vein occlusion (RVO) have been associated with hypercoagulable states; however, the burden of thrombophilia in these patients is unclear. ObjectivesThis study aims at estimating the prevalence of inherited and acquired thrombophilias in adults with RAO or RVO through a systematic review and meta‐analysis of the literature. Patients/MethodsPubMed and EMBASE were systematically searched from inception to 29 February 2020. All studies reporting prevalences of factor V Leiden (FVL) and prothrombin (F‐II) G20210A mutations, methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor (PAI) 4G polymorphisms, antithrombin III (AT‐III), protein C (PC) and protein S (PS) activity deficiencies, hyperhomocysteinemia, and antiphospholipid (APL) antibodies in adults with RAO or RVO were included. Pooled prevalences and 95% confidence intervals (CI) were calculated. ResultsNinety‐five studies were included; FVL and F‐II mutations were found in 6% (95% CI: 5‐8) and 3% (95% CI: 2‐4) of individuals with RVO, respectively, whereas AT‐III, PC, and PS activity deficiencies were found in <2%. The MTHFR C677T and PAI 4G homozygous polymorphism were observed in 13% (95% CI: 10‐17) and 23% (95% CI: 16‐31) of RVO, respectively; 8% presented APL antibodies. Similar findings were observed in individuals with RAO. ConclusionsCompared with healthy subjects, patients with retinal vascular occlusion showed similar prevalences of inherited and acquired thrombophilias. These findings do not support routine thrombophilia screening in individuals with RAO or RVO.

Полиморфизмы генов системы гемостаза у женщин с привычным невынашиванием беременности

The objective: to evaluate the prevalence of hemostasis and folate cycle gene polymorphisms in patients with a history of miscarriage. Materials and methods. A survey was conducted of 125 women with habitual miscarriage who were in the first, main, group. The criteria for inclusion of patients in the study were the presence of two or more pregnancy losses in the anamnesis up to 22 weeks. The exclusion criteria were anatomical, endocrine, infectious, immunological, social causes of miscarriage, and the presence of benign uterine tumors and antiphospholipid syndrome. Group II (control) included 40 somatically healthy women, without reproductive losses, with a history of at least one physiological pregnancy. All women underwent a molecular genetic study of 8 hemostatic system genes and 4 folate cycle genes by a multiplex allele-specific polymerase chain reaction in real time. Results. As a result of the analysis in women with habitual miscarriage, statistically significantly more often revealed: homozygous polymorphism for the gene FGB 455G&gt; A, ITGA2 (α2-integrin) C807T, both homo- and heterozygous forms, homozygous polymorphism 5GG75GG7575G &gt; 4G – homo- and heterozygous forms, as well as polymorphism of MTHFR 677C&gt; T and MTHFR 1298A&gt; C genes. A statistically significant association of ITGA2 807C&gt; T and PAI-1 675 5G&gt; 4G polymorphisms was confirmed with more than six and sevenfold increased odds of habitual miscarriage (p=0.0002 and 0.0001, respectively). Carrying the mutant allele of the FGB 455G&gt; A gene was associated with a 3.6-fold increase in the chances of reproductive loss. Multigenic forms of thrombophilia were detected in 109 (87.2%) women of the main group, which was 3.5 times higher than the corresponding indicators in the control group – 10 (25.0%); p &lt;0.05. Conclusion. In order to prevent recurrent reproductive losses in patients with a history of pregnancy miscarriage, with the exception of other causes, it is necessary to carry out an examination for the presence of clotting and folate cycle polymorphisms. Detection of the carrier of mutant alleles in patients with pregnancy miscarriage will help to properly study the activity of certain parts of the hemostasis system, to adequately select therapy and to realize the reproductive function of a woman. Key words: habitual miscarriage, pregnancy polymorphism of hemostasis genes, folate cycle.

Gene-gene interactions and prevalence of gene polymorphism associated with disorders of hemostasis and folate metabolism in patients with recurrent miscarriage

Aim. To assess the association between polymorphisms of FVL-1691G&gt;A, FII-20210G&gt;A, MTHFR-677C&gt;T, MTHFR-1298А&gt;C, РАІ-1-6755G&gt;4G and their combinations in patients with recurrent early pregnancy losses (RPL). Materials and methods. This study included two groups of women (age range 20-35 years): 50 currently non-pregnant women with a history of 2-5 unexplained recurrent early spontaneous abortion and unknown causes of miscarriages (RPL group), and 50 currently non-pregnant women with a history of having given birth to at least one live baby and without a history of spontaneous abortion, preterm labor, stillbirth, preeclampsia and other pregnancy complications (control group). Gene polymorphisms were detected by the technique of polymerase chain reaction-real time. We have analyzed the frequencies, Hardy-Weinberg equilibrium, V-Kramer test, χ2 test, odds ratio (OR) and its 95% confidence interval (95% CI). General (χ2 test, df=2) and multiplicative (χ2 test, df=1) models of inheritance have been used to assess the presence of gene polymorphisms. Results. Significant association between heterozygotes genotype PAI-1-5G4G (72% vs 32%, p=0.000; OR 5.46; 95% CI 2.32-12.87) and RPL was found. Heterozygous genotype FII-20210GA was detected only in RPL group (4% vs 0%). Combinations of genetic polymorphisms of FVL-1691G&gt;A, FII-20210G&gt;A, MTHFR-677C&gt;T, MTHFR-1298А&gt;C, РАІ-1-6755G&gt;4G increase the risk of RPL by 2.4 times (56% vs 20%; χ2=29.20, р=0.000; OR 3.69, 95% CI 1.52-8.97; strong V-Kramer association). The combination of two heterozygotes variants of minor alleles was found to be a risk factor for RPL (34% vs 10%; χ2=8.73, р=0.004; OR 4.64, 95% CI 1.55-3.84). Combined PAI-1-5G4G + FVL-1691GA genotypes was detected only in RPL group of women (2% vs 0%). No significant association between the combination of three heterozygotes variants of minor alleles and RPL. Conclusion. Our data suggest significant gene-gene interaction of the heterozygotes variants of minor alleles of FVL-1691G&gt;A, FII-20210G&gt;A, MTHFR-677C&gt;T, MTHFR-1298А&gt;C, РАІ-1-6755G&gt;4G polymorphisms in patients with recurrent miscarriage. Combined genotypes FVL-1691GA/PAI-1-5G4G can be considered as a genetic molecular predictor of recurrent early pregnancy losses.

Association of uPA and PAI-1 tumor levels and 4G/5G variants of PAI-1 gene with disease outcome in luminal HER2-negative node-negative breast cancer patients treated with adjuvant endocrine therapy

BackgroundThe aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated.Patients and methodsThis study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position − 675 of the PAI-1 gene was detected by PCR-RFLP analysis.ResultsOur research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS).We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, − 675 4G/5G and − 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (− 675 4G/4G).ConclusionOur study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy.

Impact of PAI-1 4G/5G and C > G polymorphisms in acute ST elevation myocardial infarction and stable angina patients: A single center Egyptian study

BackgroundMany genetic factors, including polymorphisms in the genes regulating blood coagulation and fibrinolysis have been proposed as risk factors for coronary artery disease (CAD). PAI-1 is the chief inhibitor of tissue plasminogen activator and urokinase plasminogen activator. PAI-1 has a crucial role in regulation of fibrinolysis. Aim of the studyIs to investigate the association between Plasminogen activator inhibitor-1 (PAI-1) 4G/5G, PAI-1C/G polymorphisms and CAD. In addition, studying the relation of these polymorphisms to the level of active PAI-1 in Egyptian patients presenting to a single tertiary center in Cairo. Subjects and methodsOne hundred and forty-four patients were included in this study: 42 STEMI (ST elevation myocardial infarction) patients, 63 stable angina patients, and 39 as a control group. Detection of PAI-1 4G/5G and C > G polymorphisms was done using allele specific polymerase chain reaction and restriction fragment length polymorphism (RFLP) respectively. Plasma plasminogen activator inhibitor-1 activity was detected using enzyme linked immunosorbent assay (ELISA). ResultsIn the studied CAD patients, PAI-14G/5G polymorphism showed 31.7%, and 68.3% for 5G/5G, and (4G/5G + 4G/4G) respectively; however for the control group, 5G/5G, and (4G/5G + 4G/4G) were detected in 21.6%, and 78.4% respectively (p value 0.59). The genotypic frequencies for PAI-1C/G in CAD patients accounted for 27% (CC), 73% (CG + GG); while in the control group these frequencies were 35.3%, and 64.7% respectively (p value 1.43). ConclusionNo significant association between PAI-1 4G/5G and C > G polymorphisms and the risk of coronary artery disease or the activity level of PAI-1 among the studied Egyptian population sample. However, STEMI patients showed significant presence of combined mutant allele of both genes more frequently.

Causes of Budd-Chiari Syndrome: A Review based on a Case Report

Budd-Chiari syndrome (BCS) is an obstruction of hepatic venous flow at any level, from small hepatic veins to the junction of the inferior cava vein and the right atrium. Studies report that BCS is associated with prothrombosis. The authors present a review of the topic based on a case report of BCS where several risk factors are involved. These factors were genetic, such as mutation of the plasminogen activator inhibitor with 4G polymorphism and acquired, such as ulcerative colitis and oral contraceptives.

A clinical case of congenital and acquired thrombophilia with pulmonary artery thrombosis

A clinical case of 48-year-old man with recurrent thrombosis of small pulmonary arteries (PA) has been described in the article. Hereditary and acquired thrombophilia associated with mutations of plasminogen activator inhibitor (heterozygote of the PAI-1 4G / 5G polymorphism) and platelet fibrinogen receptor (heterozygote of the ITGB3 Leu33Pro polymorphism), hyperhomocysteinemia, and hypercholesterolemia was diagnosed. The diagnosis was confirmed by measurement of blood homocysteine and cholesterol levels, and molecular investigation of gene polymorphism mentioned above. PA thrombosis and thrombus location were detected using contrast-enhanced chest computed tomography. Conservative treatment resulted in clinical and radiological improvement.

Global Fibrinolytic Activity, PAI-1 Level, and 4G/5G Polymorphism in Thai Children with Arterial Ischemic Stroke

Prolonged euglobulin clot lysis time (ECLT) and increased level of plasminogen activator inhibitor-1 (PAI-1) were reported to be risk factors of arterial ischemic stroke (AIS) by some studies; however, these findings were not supported by other studies. The objective of this study was to determine the association of ECLT, PAI-1 level, and polymorphisms of 4G and 5G of PAI-1 gene to the development of AIS in Thai children. This study included patients aged 1-18 years old. Diagnosis of AIS was confirmed by imaging study. The control group was age- and sex-matched healthy subjects. Demographic data were recorded, and blood was tested for ECLT, PAI-1 level, lipid profiles, fasting blood sugar (FBS), and 4G and 5G polymorphisms of PAI-1 gene. There were 70 subjects participating in this study, consisting of 30 patients and 40 controls. Demographic data, lipid profiles, and FBS were similar between the 2 groups. Furthermore, ECLT and PAI-1 level did not differ between patient and control groups; however, both showed significant correlation (r = .352, P = .006). The 4G/5G polymorphism was the most common genotype in both patient and control groups (69.0% vs. 80.0%). However, 4G and 5G polymorphisms of PAI-1 gene did not correlate with PAI-1 level in this study (P = .797). The PAI-1 level and 4G/5G polymorphism may not be a risk factor of AIS in this population. It was also found that the 4G/5G polymorphism was the most common PAI-1 genotype in this study.

Central nervous system bleeding in pediatric patients with factor XIII deficiency: A study on 23 new cases

BackgroundFactor XIII (FXIII) deficiency is an extremely rare bleeding disorder, which has the highest incidence in Sistan and Baluchistan Province in Iran, compared to its overall incidence around the world. This disorder has different clinical manifestations ranging from mild bleeding tendency to lethal bleeding episodes including central nervous system (CNS) hemorrhage. The aim of this study was to evaluate the demographic data, pattern of CNS bleeding, and the role of plasminogen activator inhibitor-1 (PAI-1) (PAI-1) 4G/5G and thrombin activatable fibrinolysis inhibitor (TAFI) Thr325Ile polymorphisms in intracranial and extracranial hemorrhages in 23 new cases of FXIII-deficient subjects.MethodsThis case–control study was conducted on 23 FXIII-deficient patients with CNS bleeding episodes and 23 patients as the control group with FXIII deficiency but without any history of CNS bleeding. Initially, to confirm the molecular defect, both groups were evaluated for the most frequently reported mutation of FXIII (Trp187Arg mutation) in a previous study in Sistan and Baluchistan Province. Then, demographic data, clinical manifestations, and pattern of CNS bleeding were determined. Eventually, the patients were assessed for PAI-14G/5G and TAFI Thr325Ile polymorphisms.ResultsThe results of this study revealed that all the subjects (including the case and control groups) were homozygous for Trp187Arg mutation. Nineteen patients (82.6%) had intracranial hemorrhage (ICH) and four patients (17.4%) had extracranial hemorrhage (ECH). Intraparenchymal hemorrhage was the most common form of ICH (89.5%), and epidural hemorrhage was observed in two patients (10.5%). Anatomic regions in patients with intraparenchymal hemorrhage were temporal in six (35.3%), occipital in four (23.5%), diffused intraparenchymal in four (23.5%), temporal-occipital in two (11.8%), and subdural with temporal in one (5.9%) patient.We found that in the case group, 14 patients (60.8%) were homozygous for TAFI Thr325Ile polymorphism and 8 cases (34.7%) were heterozygous. In the control group, 4 (17.4%) and 13 (56.5%) patients were homozygous and heterozygous, respectively (P < 0.001 vs. P < 0.01).We also found that an equal number of patients (two individuals) in the case and control groups (8.7% in each group) were heterozygous for PAI-14G/5G polymorphism.ConclusionIt seems that PAI-14G/5G polymorphism does not have any effect on occurrence of ICH and ECH in patients with FXIII deficiency, while TAFI Thr325Ile is a strong genetic risk factor (odds ratio:14.9, 95% confidence interval: 7.4–31.1).

The PAI-I Gene 4G/5G Polymorphism and Central Nervous System Bleeding In Factor XIII Deficiency

Background FXIII deficiency is one of the rare bleeding disorder (RBD) that has a highest incidence in Sistan and Baluchistan province around the world. This disorder represents with different clinical manifestations ranging from mild to severe bleeding tendency including CNS bleeding. The aim of this study is to evaluate the role of PAI-14G/5Gpolymorphism in central nervous bleeding (intra and extracranial hemorrhage) system in factor XIII deficiency. Methods In this case control study was studied 32 FXIII deficient patients with CNS bleeding and also 32 patients with factor XIII deficiency without history of CNS bleeding as control group. Initially both groups were evaluated for the previously reported polymorphism of factor XIII (Trp187Argpolymorphism) in order to confirm their disorder. Then all patients were assessed for PAI-14G/5G polymorphism. Eventually obtained data was analyzed by SPSS software. Results The result of this study revealed that all study patients were homozygote for Trp187Arg polymorphism. We also found that the equal numbers of patients (4 individuals) in case and control groups were heterozygote for PAI-14G/5G polymorphism and none of patients were homozygote for this polymorphism. All heterozygote patients had intracranial hemorrhage and patients with extracranial hemorrhage had no mutation of PAI-14G/5G. Intraparenchymal was the most common site of hemorrhage and was observed in 26 patients (92.8%).We also observed subdural and epidural hemorrhage in two patients (7.1%).Anatomic regions in patients with intraparenchymal hemorrhage, were temporal in nine (32.2%), occipital in eight (28.6%), diffused intraparenchymal hemorrhage in seven (25%), tempro-occipital in two (7.1%) and subdural with temporal in two (7.1%) patients. Conclusion: It seems that PAI-14G/5G polymorphism did not any effect on occurrence of intra and extracranial hemorrhage in patients with factor XIII deficiency. Disclosures: No relevant conflicts of interest to declare.

The PAI‐1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women

Plasminogen activator inhibitor type 1 (PAI-1) is an important regulator of fibrinolysis. A common deletion polymorphism that results in a sequence of 4G instead of 5G in the promoter region of the gene is associated with a small increase in the risk of venous thromboembolism. Its potential association with adverse pregnancy events remains controversial. We aimed to assess the impact of the 4G PAI-1 polymorphism on pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. This study represents a secondary investigation of a prior prospective cohort study investigating the association between inherited thrombophilias and adverse pregnancy events in Australian women. Healthy nulliparous women were recruited to this study prior to 22 weeks gestation. Genotyping for the 4G/5G PAI-1 gene was performed using Taqman assays in an ABI prism 7700 Sequencer several years after the pregnancy was completed. Pregnancy outcome data were extracted from the medical record. The primary outcome was a composite comprising development of severe pre-eclampsia, fetal growth restriction, major placental abruption, stillbirth or neonatal death. Pregnancy outcome data were available in 1733 women who were successfully genotyped for this polymorphism. The primary composite outcome was experienced by 139 women (8% of the cohort). Four hundred and fifty-nine women (26.5%) were homozygous for the 4G deletion polymorphism, while 890 (51.4%) were heterozygous. Neither homozygosity nor heterozygosity for the PAI-1 4G polymorphism was associated with the primary composite outcome (homozygous OR = 1.30, 95% CI = 0.81-2.09, P = 0.28, heterozygous OR = 0.84, 95% CI = 0.53-1.31, P = 0.44) or with the individual pregnancy complications. The PAI-1 4G polymorphism is not associated with an increase in the risk of serious adverse pregnancy events in asymptomatic nulliparous women.

Nitric oxide synthase3 VNTR (intron 4 a/b) polymorphism association with diabetic retinopathy

Our aim was to study the association of donor genetic features with long-term graft function as well as the impact of donor age, gender compatibility, cold ischemia time (CIT), and delayed graft function (DGF). We observed the outcomes of 125 kidney recipients for a minimum of 12 months (mean, 30.9 ± 13.0 months). Grafts were obtained from 89 donors who underwent profiling for AHSG 1/2, MMP9 -1562C/T, IL6 -174G/C, IL1β 3954C/T, MTHFR 677C/T, MTHFR 1298A/C, NOS3 -786C/T, and PAI1 4G/5G single-nucleotide polymorphisms (SNPs) using sequence-specific probe (SSP) polymerase chain reaction (PCR) and MPO -463G/A and CRP -390C/T/A with restriction fragment length polymorphism (RFLP) analysis. NOS3 IVa/b VNTR polymorphism was genotyped by gel electrophoresis of the respective PCR-generated DNA fragment. The presence of the aa eNOS genotype was connected with worse graft function. The aa genotype was also linked to acute rejection episodes. The lowest values of glomerular filtration rate (GFR) were displayed by recipients of grafts from donors with homozygotic PAI1 gene 5G polymorphism, linking paradoxically with lower PAI-1 synthesis suggesting that the intensity of proteolysis led to increased alloantigen specificity stimulating alloresponses. Graft function depended significantly on donor age with an influence of gender matching. GFR showed a significant dependence on DGF. Genetic features of the donor influenced long-term graft function. Variant eNOS gene polymorphism, which produced decreased eNOS activity, was linked to worse remote graft function. A similar negative impact was observed in the case of donor PAI1 polymorphism, with the functional consequence of lower gene product synthesis.

Association of plasminogen activator inhibitor-type 1 (−675 4G) polymorphism with pre-eclampsia: systematic review

BackgroundPlasma levels of plasminogen activator inhibitor-type 1 (PAI-1) are higher in women with severe pre-eclampsia/eclampsia (PE/E) than in gestation-matched non-hypertensive pregnant women. The PAI-1 (−675 4G) promoter polymorphism increases transcriptional...

Failure to Lyse Venous Thrombi Because of Elevated Plasminogen Activator Inhibitor 1 (PAI-1) and 4G Polymorphism of Its Promotor Genome (The PAI-1/4G Syndrome)

Plasminogen activator Inhibitor 1 (PAI-1) inhibits plasminogen activators leading to decreased fibrinolysis and increased risk of thromboembolic disease (TED). Shifts in PAI-1 promoter genome from normal 5G>5G to 4G>5G or 4G>4G alleles are associated with overexpression of PAI-1. In this study patients with residual venous thrombi were observed to have increased PAI-1 levels and more frequent shifts to 4G alleles. Of the 26, 20 (76.9%) patients with unresolved thrombus had elevated PAI-1 values. 4G genomic shifts were found in 92.9% patients studied. Normal PAI-1 levels were found in 5 patients with 4G polymorphisms. Thus, PAI-1 is often elevated among patients with residual thrombus, with an unexpectedly high prevalence of the 4G polymorphism of the promoter genome. Patients with persistent thrombus should be considered at risk of having constituently increased PAI-1 due to genomic changes in the PAI-1 promoter genome. Hypotheses are proposed to explain those with normal PAI-1, despite having 4G polymorphisms.

Impact of Donor-Dependent Genetic Factors on Long-Term Renal Graft Function

Our aim was to study the association of donor genetic features with long-term graft function as well as the impact of donor age, gender compatibility, cold ischemia time (CIT), and delayed graft function (DGF). We observed the outcomes of 125 kidney recipients for a minimum of 12 months (mean, 30.9 ± 13.0 months). Grafts were obtained from 89 donors who underwent profiling for AHSG 1/2, MMP9 -1562C/T, IL6 -174G/C, IL1β 3954C/T, MTHFR 677C/T, MTHFR 1298A/C, NOS3 -786C/T, and PAI1 4G/5G single-nucleotide polymorphisms (SNPs) using sequence-specific probe ( SSP) polymerase chain reaction (PCR) and MPO -463G/A and CRP -390C/T/A with restriction fragment length polymorphism (RFLP) analysis. NOS3 IVa/b VNTR polymorphism was genotyped by gel electrophoresis of the respective PCR-generated DNA fragment. The presence of the aa eNOS genotype was connected with worse graft function. The aa genotype was also linked to acute rejection episodes. The lowest values of glomerular filtration rate (GFR) were displayed by recipients of grafts from donors with homozygotic PAI1 gene 5G polymorphism, linking paradoxically with lower PAI-1 synthesis suggesting that the intensity of proteolysis led to increased alloantigen specificity stimulating alloresponses. Graft function depended significantly on donor age with an influence of gender matching. GFR showed a significant dependence on DGF. Genetic features of the donor influenced long-term graft function. Variant eNOS gene polymorphism, which produced decreased eNOS activity, was linked to worse remote graft function. A similar negative impact was observed in the case of donor PAI1 polymorphism, with the functional consequence of lower gene product synthesis.