Correlation between plasminogen activator inhibitor-1 4G/5G polymorphism and pre-eclampsia: an appraisal

Aim: Plasminogen activator inhibitor-1 (PAI-1) is an important inhibitor of the fibrinolytic system, so it is biologically plausible that elevated levels could suppress fibrinolysis and result in an increased risk of thrombosis. There is considerable controversy regarding the clinical role of PAI-1 4G/5G polymorphism as a risk factor of pre-eclampsia. Here, the author performs a summative analysis on the recent previous reports on the PAI-1 4G/5G and its correlation to pre-eclampsia. Method: The metanalysis was performed in order to assess the correlation between the pattern of PAI-1 4G/5G polymorphism and pre-eclampsia. From the available six case-control studies, 880 patients and 810 controls are evaluated. Results: The overall frequencies of 4G allele for the patients and controls are 49.9 and 44.4, respectively. According to this study, 54.9% of subjects with 4G allele have pre-eclampsia while 43.1% of subjects without 4G allele have pre-eclampsia. From overall risk estimation, the subjects with 4G alleles have 1.27 times higher risk to pre-eclampsia. Conclusion: According to this analysis, the author proposes that the pattern of PAI-1 4G/5G polymorphism might represent a useful marker of increased risk for pre-eclampsia. In addition, the lack of association between pattern of PAI-1 4G/5G and ethnicity of the patients can be demonstrated in this study.     

纤溶酶原激活物抑制因子1基因启动子区4G和5G多态基因型分布及其与多囊卵巢综合征的相关性研究

目的探讨纤溶酶原激活物抑制因子1（PAI-1）基因启动子区4G及5G的多态基因型分布,及其与多囊卵巢综合征（PCOS）发病的关系。方法应用聚合酶链反应-限制性片段长度多态性技术,检测101例PCOS患者（PCOS组）与42例因男性或单纯输卵管因素不孕患者（对照组）PAI-1基因启动子区4G基因型及5G多态基因型分布,测定并计算两组患者的体重指数、胰岛素抵抗指数、胰岛素敏感指数及自然流产数等临床指标。根据体重指数将PCOS患者分为肥胖者（48例）与非肥胖者（53例）。结果PCOS组PAI-1基因启动子区4G基因型频率为57％（58／101）,对照组为38％（16／42）;PCOS组5G基因型频率为43％（43／101）,对照组为62％（26／42）。两组4G及5G基因型频率分别比较,差异均有统计学意义（P〈0．05）。肥胖者胰岛素抵抗指数、胰岛素敏感指数与非肥胖者比较,差异均有统计学意义（P〈0．05,P〈0．01）。肥胖者4G基因型频率为48％（23／48）,非肥胖者为68％（36／53）;肥胖者5G基因型频率为52％（25／48）,非肥胖者为32％（17／53）。两者4G及5C基因型频率分别比较,差异均有统计学意义（P〈0．05）。27例有妊娠史的PCOS患者中,自然流产14例,4G基因型频率为79％（11／14）,5G基因型频率为21％（3／14）;无自然流产13例,4G基因型频率为38％（5／13）,5G基因型频率为62％（8／13）,两者4G与5G基因型频率分别比较,差异均有统计学意义（P〈0．05）。结论PAI-1基因启动子区4G基因型频率高,可能与PCOS的发病,尤其是与非肥胖者发生PCOS有关,并与PCOS患者的自然流产率高有关。     

Plasminogen activator/plasminogen activator inhibitor-1 and cytokine modulation by the PROACT System

OBJECTIVE: To examine the effects of the PROACT treatment on the fibrinolytic system and inflammatory cytokines in human peritoneum. DESIGN: Controlled clinical study. SETTING: University hospital. PATIENT(S): Nine subjects undergoing laparotomy had peritoneal samples taken at the incision. INTERVENTION(S): The PROACT applicator was inserted through the peritoneal incision, and treatment of peritoneum was performed twice. A peritoneal sample was taken from one treated area. At closure, the second treated sample and an additional control sample were taken. All four samples were snap frozen in liquid nitrogen. Samples were homogenized and protein content extracted. MAIN OUTCOME MEASURE(S): Concentrations of total and active transforming growth factor-beta 1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor 1 (PAI-1) were obtained. RESULT(S): Total TGF-beta1 at opening was 30% less in treated samples. At closure, active TGF-beta1 increased significantly (163%) in control samples and not in treated samples. Tumor necrosis factor alpha was detectable only in control samples at closure. During surgery, tPA levels showed a marked decrease in control samples vs. a small increase in treated samples. Levels of uPA increased significantly only in the control samples. In control samples, tPA/PAI-1 ratio was two thirds of treated sample ratio. CONCLUSION(S): Heating of the peritoneum with the PROACT System modulates the biologic tissue response to induce effects that would be consistent with inhibition of postoperative adhesion development.     

Effect of the cessation of long-term hormone replacement therapy on plasma plasminogen activator inhibitor-1 and fibrinogen

OBJECTIVE: Hormone replacement therapy (HRT) has generally been documented to reduce plasminogen activator inhibitor-1 (PAI-1) and fibrinogen levels in plasma of postmenopausal women. We used a wash out protocol to study whether stopping long-term HRT with estrogen alone or a combination of estrogen-progestin have different effects on these markers of hemostasis. STUDY DESIGN: Thirty healthy postmenopausal women on HRT participated. Fifteen had estradiol valerate, and 15 had estradiol valerate and levonorgestrel. Each was studied after long-term HRT (period 1), four weeks after cessation of the treatment (period 2, wash out), and three weeks after reintroducing the therapy (period 3). RESULTS: In the estrogen group, PAI-1 increased by 18% during the wash out period (P=0.013) and decreased by 22% after reintroduction of therapy (P=0.001). In the combined therapy group, there was a trend of PAI-1 to increase by 18% when therapy was discontinued (P=0.17), and it decreased by 25% after reintroduction of hormone replacement therapy (P=0.036). Fibrinogen was initially lower in the estrogen group compared with the combined therapy group (p=0.014), and did not change during wash out. CONCLUSION: This wash out study shows that cessation of long-term HRT unfavorably increases PAI-1, but appears to have no adverse effect on fibrinogen.     

PAI-1基因4G/5G多态性与PCOS糖代谢、肥胖的相关性研究

目的:探讨纤溶酶原激活物抑制因子-1(PAI-1)基因启动子4G/5G多态性与多囊卵巢综合征(PCOS)糖代谢、肥胖的关系。方法:PCR-RFLP法检测42例正常育龄妇女,101例PCOS患者[根据糖代谢情况分为A、B、C组;根据体重指数(BMI)分为肥胖、非肥胖组]PAI-1基因启动子4G/5G位点插入或缺失多态性,比较组间多态基因型分布及体重指数(BMI)、胰岛素抵抗指数(Homa-IR)、胰岛素敏感指数(ISI)。结果:①BMI、Homa-IR指标PCOS糖代谢C组>B组>A组、肥胖PCOS组>非肥胖PCOS组,ISI则相反,差异均有显著性(P<0.05)。②PCOS组不同糖代谢组PAI-1基因4G/5G多态基因型分布无差异,但PCOS组、PCOS糖代谢异常C组与对照组、PCOS非肥胖组与肥胖组之间比较有统计学差异(χ2=4.439、4.018、4.151;P均<0.05);4G型(4G/4G基因型)PCOS组、PCOS糖代谢异常C组与非肥胖PCOS组分布显著高于相应对照组与肥胖PCOS组;5G型(4G/5G+5G/5G基因型)分布相反。结论:①PCOS患者高PAI-1 4G/4G多态基因型,可能是其高PAI-1活性现象的重要遗传基础。②PAI-1基因启动子4G/5G多态性可能与PCOS患者糖代谢异常、非肥胖PCOS发病、病情进展有关。     

PAI-1基因启动子区4G/5G基因多态性与多囊卵巢综合征

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是育龄期女性最常见的生殖内分泌疾病,病因迄今不明,具有高度的家族聚集性,提示遗传因素在其发病中起重要作用。纤溶酶原激活物抑制剂1(plasminogen activator inhibitor-1,PAI-1)是纤溶系统的主要生理抑制剂,大量研究表明PAI-1基因启动子区4G/5G基因多态性可通过升高血浆PAI-1水平及活性影响胰岛素的敏感性,参与胰岛素抵抗(insulin resistance,IR)的形成。IR是PCOS主要的病理生理机制,与PCOS患者肥胖、自然流产等的发生密切相关,提示PAI-1基因启动子区4G/5G基因多态性与PCOS的发生、发展可能有着密切的关系。因此,PAI-1基因启动子区4G/5G基因多态性与PCOS的相关研究也成为近年研究热点,主要涉及PCOS的发病、肥胖、IR、自然流产及远期并发心血管疾病等,但相关结论尚存争议。     

子宫内膜癌患者血清uPA和PAI-1的含量变化及临床意义

目的:探讨子宫内膜癌患者血清尿激酶型纤溶酶原激活物(uPA)及纤溶酶原激活物抑制物-1(PAI-1)含量的变化及其临床意义。方法:用ELISA法测定35例子宫内膜癌(内膜癌组)、18例子宫内膜增生(内膜增生组)和16例正常子宫内膜患者(正常对照组)血清uPA和PAI-1含量及计算两者的比值。结果:内膜癌组患者血清uPA和PAI-1含量及uPA/PAI-1值均显著高于内膜增生组及正常对照组,差异有极显著性(P均<0.01)。内膜增生组及正常对照组,差异无统计学意义(P>0.05)。内膜癌组Ⅲ~Ⅳ期患者血清uPA和PAI-1含量与Ⅰ期相比差异有极显著性(P<0.01),Ⅲ~Ⅳ期患者血清uPA和PAI-1含量高于Ⅱ期(P<0.05),Ⅱ期患者血清uPA、PAI-1含量高于Ⅰ期(P<0.05)。内膜癌组患者血清uPA、PAI-1含量及uPA/PAI-1值随着手术病理分期及组织学分级的增高、肌层浸润深度的增加及淋巴结的转移而升高,差异有显著性(P均<0.05),而与患者病理类型无关(P>0.05)。结论:子宫内膜癌患者血清uPA和PAI-1含量及uPA/PAI-1值明显升高,并与其手术病理分期、浸润转移有关,提示其可能在内膜癌的发生、发展及浸润过程中起重要作用。     

uPA系统在子宫内膜异位症中的表达及意义

目的:研究尿激酶型纤溶酶原激活剂(uPA)及其受体(uPAR)和纤溶酶原激活剂抑制剂(PAI-1)在子宫内膜异位症中的表达和意义。方法:采用免疫组化链霉菌抗生物素蛋白-过氧化物酶连接法(S-P法)分别检测30例子宫内膜异位症患者的异位内膜及其相应的在位内膜(研究组)以及30例正常子宫内膜(对照组)中uPA、uPAR、PAI-1的表达。结果:异位内膜和在位内膜及对照组子宫内膜组织中,uPA的表达分别为0.198、0.112、0.079;uPAR的表达分别为0.162、0.119、0.076;PAI-1的表达分别为0.230、0.158、0.080;异位内膜组织中uPA、uPAR、PAI-1与在位内膜及对照组相比,差异均有统计学意义(P<0.05,P<0.01);在位内膜组织中uPA、uPAR、PAI-1与对照组比较,差异亦有统计学意义(P<0.05)。无论是增殖期还是分泌期,异位内膜组织中uPA、uPAR、PAI-1的表达均高于在位内膜及对照组(P<0.05,P<0.01),在位内膜中uPA、uPAR、PAI-1的表达高于对照组(P<0.05)。结论:异位和在位子宫内膜组织中uPA、uPAR、PAI-1表达的变化可能与子宫内膜异位症的发生、发展有关。     

The V109G polymorphism in the p27 gene is associated with endometriosis

Objective

To investigate the prevalence of the p27 gene polymorphism in women with endometriosis.

Study design

Transversal case–control study. Genomic DNA was extracted from cells collected from buccal swabs. The p27 V109G polymorphism was investigated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Brazilian population.

Results

We analysed the 104 patients and 109 control subjects. The distribution of genotype and allele frequencies of p27 V109G polymorphism was significantly different between the endometriosis cases and healthy women (p = 0.016 and 0.002). Women who had at least one mutated allele presented twofold chances for endometriosis development (OR = 1.9; 95% CI, 1.120–3.343).

Conclusion

The polymorphic variant at codon 109 of the p27 gene seems to be associated with higher risk of endometriosis development.     

ACE和AGT基因多态性与子宫内膜异位症相关性的研究

目的:探讨ACE基因A240*T和AGT基因M235*T多态性与中国河北省汉族孕龄妇女Ⅲ、Ⅳ期EMs遗传易感性的关系。方法:用病例对照研究法,78例Ⅲ、Ⅳ期EMs患者与82例对照组的外周血白细胞为样本,用PCR-RFLP技术分析ACE基因A240*T和AGT基因M235*T多态性分布频率。结果:ACE基因的3种基因型AA、AT、TT在EMs组和对照组的分布频率分别为:41.0%、43.6%、15.4%;56.1%、39%、4.9%。A/T等位基因在两组的分布频率分别为62.8%、37.2%;75.6%、24.4%,两组差异有统计学意义(P<0.05)。AGT基因3种基因型MM、MT、TT在EMs和对照组的分布频率分别为6.4%、37.2%、56.4%;8.5%、35.4%、56.1%。M/T等位基因在两组的分布频率分别为25%、75%;26.2%、73.8%,两组差异无统计学意义。结论:携带ACE240*T等位基因增加患Ⅲ、Ⅳ期子宫内膜异位症的危险。AGT基因M235*TM/T等位基因在EMs组和对照组的分布无显著差异。     

Correlation between plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G polymorphism and metabolic/proinflammatory factors in polycystic ovary syndrome

Abstract

Polycystic Ovary Syndrome (PCOS) is the most common cause of subfertility associated to metabolic disorders. The aim of this study was to correlate metabolic and proinflammatory factors in women with PCOS. The frequency of Plasminogen Activator Inhibitor-1 (PAI-1) promoter 4?G/5?G polymorphism was also compared to healthy controls. We evaluated 79 PCOS and 79 healthy women. PAI-1 levels are positively correlated with proinflammatory factors in PCOS group. 4?G allele in PAI-1 gene was more frequent in PCOS and the 4G/4?G genotype was associated with increased PAI-1 levels. A correlation between insulin resistance and proinflammatory and overweight was also observed. C-reactive protein, serum levels of vascular cell adhesion molecule-1 (sVCAM-1), Lipid Accumulation Product (LAP) and vitamin D are good tools to evaluated factors associated to cardiovascular risk in women with PCOS.     

Plasminogen Activator Inhibitor-1 -675 4G/5G Polymorphism and Polycystic Ovary Syndrome Risk: A Meta Analysis

Purpose

Several studies have reported that excessive amounts of plasminogen activator inhibitor-1(PAI-1) might increase the incidence of polycystic ovary syndrome(PCOS), but so far the published results were inconsistent. The aim of this study was to further investigate the association between PAI-1 gene polymorphism and the susceptibility to PCOS by performing a meta-analysis.

Methods

A comprehensive literature search for relevant studies was conducted on google scholar, PubMed, the Chinese National Knowledge Infrastructure (CNKI) and the Chinese Biomedical Literature Database (CBM). This meta-analysis was performed using the STATA 11.0 software and the pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated.

Results

Ten case–control studies were included in this meta-analysis with a total of 2,079 cases and 1,556 controls. The results showed that PAI-1 -675 4G/5G polymorphism may increase the risk of PCOS, especially among Asian populations. However, there was no statistically significant association between the polymorphism and PCOS risk in Caucasians.

Conclusion

Our meta-analysis suggests that PAI-1 -675 4G/5G polymorphism may contribute to increasing susceptibility to PCOS in Asians. Detection of the PAI-1 gene polymorphism might be a promising biomarker for the susceptibility of PCOS.     

The G(-2518)A polymorphism of monocyte chemotactic protein-1 (MCP-1) and its serum and peritoneal fluid levels in Korean women with endometriosis

OBJECTIVES: To investigate the associations between endometriosis and the G(-2518)A polymorphism of monocyte chemotactic protein-1 (MCP-1), and serum and peritoneal fluid MCP-1 levels in Korean women. STUDY DESIGN: The G(-2518)A polymorphism of MCP-1 was analyzed by restriction fragment length polymorphism in 105 women with and in 101 women without endometriosis. Serum and peritoneal fluid MCP-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The genotype frequencies of the MCP-1 G (-2518)A polymorphism were GG 36.9%, AG 52.9%, and AA 10.2%. MCP-1 genotype frequencies and serum and peritoneal fluid MCP-1 levels were similar in those with or without endometriosis and were not dependent on disease stage. A significant correlation was found between serum and peritoneal fluid levels of MCP-1. However, no differences were found between MCP-1 genotypes in terms of serum and peritoneal fluid MCP-1 levels. CONCLUSIONS: Serum and peritoneal fluid MCP-1 levels and the G (-2518)A MCP-1 polymorphism were found not to be associated with endometriosis in Korean women.     

基质金属蛋白酶基因启动子区基因多态性与子宫内膜异位症遗传易感性的相关性研究

目的探讨基质金属蛋白酶（MMP）1、3启动子区基因多态性与子宫内膜异位症和子宫腺肌病遗传易感性的相关性。方法采用聚合酶链反应限制性片段长度多态性（PCR—RFLP）方法,分析1（30例子宫内膜异位症患者（内异症组）、80例子宫腺肌病组患者（腺肌病组）和150例健康妇女（对照组）MMP-1和MMP-3基因型及等位基因频率分布。结果（1）MMP-1中2G等位基因频率在内异症组和腺肌病组患者中分别为79．0％（158／200）和79．4％（127／160）,明显高于对照组（67．0％,201／300）,差异有统计学意义（P〈0．01）;3组中1G／1G、1G／2G、2G／2G3种基因型频率分布比较,差异也有统计学意义（P〈0．05）。2G／2G基因型或2G／2G＋1G／2G基因型均能增加内异症的患病风险,经年龄校正的风险值分别为3．65（95％CI=1．41—9．43）和3．25（95％CI=1．29～8．23）;2G／2G基因型可显著增加腺肌病的患病风险,经年龄校正的风险值为2．55（95％CI=1．03—6．33）。（2）MMP-3中5A、6A等位基因频率在内异症和腺肌病组患者中分别为14．0％（28／200）、86．0％（172／200）和15．6％（25／160）、83．4％（135／160）,与对照组（20．3％、79．7％）比较,差异无统计学意义（P〉0．05）;5A／5A、5A／6A、6A／6A基因型频率分布在3组中比较,差异也无统计学意义（P〉0．05）;与6A／6A基因型相比,5A／5A＋5A／6A基因型不增加内异症和腺肌病的患病风险。（3）MMP-1和MMP-3基因单体型分析结果显示,2G／6A基因单体型明显增加内异症的患病风险,但不增加腺肌病的患病风险。结论MMP-1基因启动子区2G等位基因的存在,可明显增加异位症和腺肌病的患病风险;MMP-3基因启动子区基因多态性与这两种疾病的患病风险无关,但2G／6A单体型可作为异位症患病风险的分层标记。