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。     

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。     

妊娠期糖尿病PAI-1 4G/5G基因多态性与胰岛素抵抗的相关性

目的:探讨纤溶酶原激活物抑制剂-1(PAI-1)4G/5G基因多态性与天津及河北地区汉族人群中妊娠期糖尿病(GDM)发病及胰岛素抵抗(IR)的相关性。方法:用PCR方法检测GDM组和正常妊娠对照组(每组75例)PAI-1 4G/5G基因型,并分析相关临床资料。结果:GDM组4G/4G基因型频率及4G等位基因频率均高于正常对照组(P<0.05)。GDM组4G/4G基因型孕妇空腹胰岛素、胰岛素抵抗指数均高于5G/5G组(P<0.05)。结论:PAI-1 4G/5G基因多态性与GDM发病相关,4G/4G基因型可能是GDM的易感基因;PAI-1 4G/4G基因型与GDM患者IR的发生有关。     

血清性激素结合球蛋白与多囊卵巢综合征糖代谢的相关研究

目的:探讨血清性激素结合球蛋白(SHBG)与多囊卵巢综合征(PCOS)患者糖代谢的关系及干预治疗对其影响。方法:以16例正常育龄妇女为对照组,69例PCOS患者分为3组:非胰岛素抵抗(NIR)组、高胰岛素血症(HI)组、异常糖代谢(AMG)组,其中6例患者接受12周二甲双胍联合体育锻炼干预治疗,免放法测定血清SHBG水平。分别比较4组SHBG水平,分析SHBG与BMI、腰围、血压、Homa-IR、胰岛素敏感指数(ISI)等因素的相关性。结果:SHBG水平:HI、AMG>NIR>对照组;BMI、Homa-IR:AMG>HI>NIR组(P<0.01);ISI:AMG相似文献   

PAI-1、TGFβ1基因多态性与子宫内膜异位症相关性的研究

目的:探讨PAI-1基因启动子区4G/5G和TGFβ1基因-509C/T基因多态性与中国河北省汉族育龄妇女Ⅲ、Ⅳ期EMs遗传易感性的关系。方法:用病例对照研究法,75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PAI-1基因启动子区4G/5G和TGFβ1基因-509C/T基因多态性分布频率。结果:PAI-1基因-6754G/5G的3种基因型:4G/4G、4G/5G、5G/5G在EMs组和对照组的分布频率分别为:69.3%,28.0%,2.7%;12.2%,31.7%,56.1%。4G/5G等位基因在两组的分布频率为83.3%,16.7%;28.1%,71.9%。两组差异有统计学意义(P0.05)。TGFβ1基因-509C/T3种基因型:CC/CT/TT在EMs和对照组的分布频率分别为:10.7%,58.7%,30.7%;57.3%,41.5%,1.2%。C/T等位基因在两组的分布频率为40%,60%;78%,22%。两组差异有统计学意义(P0.05)。结论:携带PAI-1基因启动子区-6754G等位基因增加了患Ⅲ、Ⅳ期EMs的危险性。携带TGFβ1基因-509T等位基因患Ⅲ、Ⅳ期EMs的危险性增加。     

纤溶酶原激活物抑制物 1基因启动子区4G/5G多态性与川崎病冠状动脉损伤的关系

目的探讨纤溶酶原激活物抑制物 1(PAI 1)基因启动子区4G/5G多态性与中国汉族儿童川崎病(KD)的关系。 方法对2001—2003在深圳市儿童医院就诊的KD患儿126例，用等位基因特异性聚合酶链反应(AS PCR)检测126例患儿和120名健康儿童PAI 1基因启动子区4G/5G多态性；用发色底物法检测各组PAI 1血浆活性。 结果(1)KDⅠ组(合并冠状动脉损伤)和KDⅡ组(无冠状动脉损伤)患儿PAI 1血浆活性均高于健康对照组，差异有显著性(P均<005)。KDⅠ组PAI 1血浆活性高于KDⅡ组，差异有显著性(t=978，P<005)。(2)KDⅠ组和KDⅡ组中4G/4G基因型PAI 1血浆活性明显高于4G/5G基因型和5G/5G基因型，差异有显著性(均P<005)。(3)KDⅠ组4G/4G基因型频率显著高于KDⅡ组(P<005)和健康对照组(P<005)。与非4G/4G纯合子基因型相比，4G/4G纯合子基因型对KD冠状动脉并发症的比值比(OR)为280(95%置信区间：125~629，P<005)。 结论PAI 1基因启动子区4G/5G多态性与KD冠状动脉损伤密切相关，PAI 1基因启动子区4G/4G基因型可作为KD冠状动脉损伤高危人群的基因标志。     

白细胞介素1与多囊卵巢综合征肥胖的相关性

目的 探讨炎症细胞因子——白细胞介素1(IL-1)β亚型(IL-1β)和IL-1受体拮抗剂(IL-1ra)与多囊卵巢综合征(PCOS)患者肥胖发生的关系.方法(1)2006年10月至2007年1月,选择在北京大学第三医院生殖医学中心就诊的PCOS患者118例,根据WHO国际肥胖特别工作组2000年提出的亚太地区肥胖标准[体质指数(BMI)≥25 kg/m2]分为PCOS肥胖组56例,PCOS非肥胖组62例.采用PCR技术检测IL-1β基因-511位点、第5外显子位点和IL-1 ra基因第2内含子的基因多态性.(2)随机抽取PCOS肥胖组患者29例和PCOS非肥胖组患者31例,采用ELISA法检测血清IL-1β、IL-1ra水平,并测定空腹血糖(FBG)、空腹胰岛素(FINS)、超敏C反应蛋白水平和白细胞计数.结果(1)基因型和等位基因频率:PCOS肥胖组患者IL-1β基因-511位点T/T基因型频率及T等位基因频率分别44.6％和63.4％,PCOS非肥胖组患者分别为11.3％和39.5％,两组分别比较,差异均有统计学意义(P＜0.05);PCOS肥胖组患者IL-1 ra基因Ⅰ/Ⅴ基因型频率及Ⅴ等位基因频率分别为19.6％和9.8％,PCOS非肥胖组分别为3.2％和1.6％,两组分别比较,差异也均有统计学意义(P＜0.05).(2)血清学检测结果:PCOS肥胖组患者血清IL-1β水平为(149±36)ng/L,高于PCOS非肥胖组患者的(96±42)ng/L,PCOS肥胖组患者IL-1 ra水平为(284±97)ng/L,高于PCOS非肥胖组患者的(208±84)ng/L,两组分别比较,差异均有统计学意义(P＜0.05).PCOS肥胖组患者FBG、FINS、超敏C反应蛋白水平和白细胞计数分别为(5.1±0.7)mmol/L、(17±9)mU/L、(1.5±0.6)mg/L、(7.0±2.3)×109/L,PCOS非肥胖组患者分别为(4.9±0.5)mmol/L、(11 ±8)mU/L、(0.9 ±0.4)mg/L、(5.9±1.3)×109/L,两组间各项指标分别比较,差异均有统计学意义(P＜0.05).(3)IL与BMI的相关性:PCOS患者血清IL-1β(r=0.673)、IL-1ra(r =0.557)与BMI呈线性正相关(P均＜0.05).结论 炎症因子IL-1β和IL-1ra与PCOS患者肥胖的发生明显相关,IL-1β基因-511位点携带T等位基因和IL-1ra基因携带等位基因Ⅴ的PCOS患者更有发生肥胖的倾向.     

抗苗勒管激素及其Ⅱ型受体基因多态性在多囊卵巢综合征患者表达的研究

目的:研究抗苗勒管激素(AMH)及抗苗勒管激素Ⅱ型受体(AMHRⅡ)基因多态性在多囊卵巢综合征( PCOS)患者的表达情况;同时分析PCOS不同AMH基因型患者体重指数(BMI)、性激素水平之间是否存在差异,从基因水平探讨PCOS的发病机制.方法:采用聚合酶链反应(PCR)及DNA正、反向测序方法,检测94例PCOS患者(PCOS组)及94例正常排卵患者(对照组)AMH和AMHRⅡ基因型,同时将两组AMH、AMHRⅡ不同基因型患者的年龄、BMI及性激素水平分别进行比较.结果:①两组AMH基因型分布比较,差异有统计学意义(P＜0.05),而AMH等位基因频率、AMHRⅡ基因型分布及等位基因频率分布比较,差异均无统计学意义(P＞0.05).②在PCOS组不同AMH基因型患者中,BMI、LH、T间差异有统计学意义(P＜0.05),基因型分布类型与BMI、LH、T有关(P＜0.05),而与年龄、FSH、E2、PRL无关(P＞0.05);对照组年龄、BMI、性激素水平与AMH基因型分布无关(P＞0.05).③对照组和PCOS组年龄、BMI、性激素水平与AMHRⅡ基因型分布无关(P＞0.05).结论:AMH基因的多态性可能与PCOS的发病相关;PCOS患者AMH基因型中G/T表型可能是引起患者肥胖、高雄激素血症的原因.     

PAI-1基因多态性与孕早期糖化血红蛋白交互作用对妊娠期糖尿病发病的影响

目的:分析纤溶酶原激活物抑制物-1(PAI-1)基因多态性与孕早期糖化血红蛋白(HbA1c)水平交互作用,以期找出其对妊娠期糖尿病发病的影响。方法:选择2021年10月至2022年6月在新乡市中心医院早孕检查异常且孕期诊断为妊娠期糖尿病的30例孕妇作为妊娠期糖尿病组,另选取同时期早孕检查正常且孕期未被诊断为妊娠期糖尿病的45例孕妇作为对照组。Logistic回归模型分析影响妊娠期糖尿病发病的危险因素;受试者工作特征曲线(ROC)和校准曲线对模型进行评价。结果:妊娠期糖尿病组孕妇孕前体质量指数(BMI)、糖尿病家族史、空腹血糖、同型半胱氨酸(Hcy)、总胆红素水平(T-BIL)、低密度脂蛋白胆固醇(LDL-C)、空腹胰岛素(FINS)、HbA1c、PAI-1活性与对照组相比,差异有统计学意义(P<0.05)。两组孕妇PAI-1基因等位基因的分布比较,差异有统计学意义(P<0.05)。Logistic回归分析,空腹血糖高(OR 2.583)、FINS高(OR 1.984)、HbA1c高(OR 4.258)和PAI-1基因型(4G/4G)(OR 5.987)是妊娠期糖尿病发病的独立危险因素(P<0.05),T-BIL高(OR 0.429)为保护性因素(P<0.05)。ROC曲线和校准曲线显示该模型区分度和校准度良好;PAI-1基因型(4G/5G)和HbA1c≥8.0%、PAI-1基因型(4G/4G)和6.0%≤HbA1c<8.0%、PAI-1基因型(4G/4G)和HbA1c≥8.0%均存在正向交互作用(γ>1)。结论:携带PAI-1基因多态性与孕早期HbA1c水平具有协同交互作用,能够促进妊娠期糖尿病发病。在临床工作中应重视孕妇PAI-1基因型以及HbA1c水平升高的现象,有助于预测妊娠期糖尿病的发生。     

多囊卵巢综合征患者胰岛素受体基因外显子17的多态性研究

目的　探讨胰岛素受体基因外显子17与多囊卵巢综合征(PCOS)发病的关系。方法对33例PCOS患者(PCOS组)和28例因单纯输卵管原因或男性不育的不孕妇女(对照组)的胰岛素受体基因外显子17进行PCR扩增、单链构型多态性电泳分析,及等位基因分布频率比较。同时对各基因型患者进行内分泌检测。结果　两组胰岛素受体基因外显子17的1008bp处,均有T基因型向C基因型(T→C)的突变,均发现了3种基因型,即T/T、C/T、C/C基因型。PCOS组C/C基因型为39%,对照组为11%,两组比较,差异有统计学意义(P<0 .05 );PCOS组C/C基因型肥胖患者为47%,非肥胖患者为33%,两者比较,差异无统计学意义(P>0 .05)。PCOS组合并胰岛素抵抗患者为50%,无合并胰岛素抵抗患者为36%,两者比较,差异无统计学意义(P>0 .05)。PCOS组患者胰岛素敏感指数,T/T基因型患者为0 .038±0 .016,C/C基因型患者为0 .024±0 .010,C/T基因型患者为0 .028±0 .014,C/T基因型及C/C基因型与T/T基因型患者比较,差异有统计学意义(P<0 .05);T/T基因型与C/C基因型患者比较,差异无统计学意义(P>0 .05)。胰岛素受体β亚基表达及血清黄体生成素、睾酮水平, 3种基因型患者比较,差异均无统计学意义(P>0 .05)。结论　PCOS患者胰岛素受体基因外显子17多态性在1008bp发生T→C的突变频率高于     

G蛋白耦联雌激素受体-1与卵巢癌

G蛋白耦联雌激素受体-1(G protein-coupled estrogen receptor l,GPER-1)是一种新型的雌激素受体,能够介导雌激素的快速非基因组效应.GPER-1与雌激素具有高亲和力,能与天然雌激素和人工合成雌激素结合,快速激活细胞内第二信使或级联信号通路,间接调节转录活动,从而介导雌激素的生物学效应.GPER-1的亚细胞定位存在争议,因其亚细胞定位可能取决于不同的细胞类型.另外,性别、年龄等内在因素以及细胞外刺激、损伤等外在因素也影响GPER-1在质膜的相对丰度.近年来研究表明GPER-1的表达与女性生殖系统肿瘤的发生、发展密切相关,在卵巢癌组织中高表达,参与卵巢癌的发生发展,并可能作为评价卵巢癌患者预后的指标,有望成为卵巢癌重要的治疗靶点.     

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.     

Plasminogen activator inhibitor-1 4G/5G polymorphism and susceptibility to endometriosis in the Italian population

Objectives

Some controversy exists for the potential association of the plasminogen activator inhibitor-1 (PAI-1) gene polymorphism 4G/5G and susceptibility to endometriosis. To clarify this issue, we have examined the prevalence of this polymorphism in a case–control study in the Italian population.

Study design

The PAI-1 4G/5G polymorphism was evaluated in n = 368 reproductive year aged Caucasian women who underwent gynaecological laparoscopy for chronic pelvic pain, infertility, ovarian cysts and myomas. A second group of controls included n = 329 normal subjects.

Results

The 697 women enrolled were divided as follows: the endometriosis group (n = 204), the gynaecological control group (n = 164) and the general population control group (n = 329). No statistical significant differences emerged between endometriosis patients and gynaecological controls with regard to the allele frequencies and co-dominant and dominant models of genotype distribution. A borderline statistical difference was only observed for the recessive model of inheritance in which, contrary to previous findings, the PAI-1 4G/4G genotype seems to be less linked to the disease development.

Conclusion

The findings reported herein do not support the previously reported data indicating a greater susceptibility to endometriosis in patients harbouring the PAI-1 4G/5G and 4G/4G genotypes and exclude a significant role of polymorphism in endometriosis development.     

自然流产患者绒毛组织PAI-14G/5G多态性和uPA基因的表达及其意义

目的:探讨纤溶酶原激活物抑制剂-1(PAI-1)4G/5G多态性和纤溶酶原激活剂(uPA)与自然流产的关系及其在妊娠中的作用。方法:正常早孕(对照组)人工流产和自然流产(实验组)稽留流产的绒毛组织各30例,应用免疫组织化学PV法检测绒毛组织中PAI-1和uPA蛋白表达情况,等位基因特异性-PCR(AS-PCR)法检测PAI-1 4G/5G多态性的表达情况,RT-PCR法检测uPA mRNA表达情况。结果:①PAI-1蛋白主要在绒毛组织的滋养细胞质中表达,其表达对照组低于实验组(P<0.05)。uPA与PAI-1蛋白在细胞中分布一致,其表达水平对照组高于实验组(P<0.05)。②PAI-1 4G/4G基因型和4G等位基因表达水平对照组低于实验组(P<0.05),uPA mRNA表达水平对照组高于实验组(P<0.05)。③PAI-1和uPA蛋白在自然流产患者绒毛组织中的表达呈负相关(r=-0.639)。结论:PAI-1 4G/5G多态性和uPA异常表达可能与自然流产的发生有关。     

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.     

Neonatal hyperbilirubinemia and G71R mutation of the UGT1A1 gene in Turkish patients

Objective.?Nonphysiologic hyperbilirubinemia of unexplained cause is prevalent among Turkish newborns, suggesting that there might be genetic risk factors in this population. Mutation of the UGT1A1 gene, glycine to arginine at codon 71 (G71R), is related to the development of neonatal jaundice in East Asian populations but the frequency of this mutation is rare among Caucasian populations. There are insufficient data on the G71R mutation in Turkish newborns with hyperbilirubinemia. The aim of this study was to investigate the genotypic distribution of the G71R mutation and its relationship with nonphysiologic hyperbilirubinemia of unexplained cause in Turkish newborns.

Methods.?Polymerase chain reaction, restriction fragment length polymorphism and agarose gel electrophoresis techniques were used for detection of G71R mutation in 109 newborn infants: 39 with hyperbilirubinemia and 70 without hyperbilirubinemia.

Results.?The genotypic distribution for the mutation was 70 G/G, 32 A/G, 7 A/A genotypes and the mutated allele frequency was 0.22. The frequency of G71R mutation was 33.3 % (n?=?13) A/G, 7.7% (n?=?3) A/A in the hyperbilirubinemia group and 27.1% (n?=?19) A/R, 5% (n?=?4) A/A in the nonhyperbilirubinemia group. The difference between the groups was not statistically significant.

Conclusions.?Our results suggest that G71R mutation of UGT1A1 is not rare; however, an association between G71R mutation and hyperbilirubinemia of unexplained cause has not been shown in Turkish newborns.     

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.