妊娠相关蛋白A的表达及其基因多态性与子痫前期的相关性研究

发布时间：2018-07-05 05:45

本文选题：PAPP-A + 子痫前期　；参考：《南方医科大学》2017年硕士论文

【摘要】：[背景]子痫前期是妊娠期特发的产科重症,可造成全身各系统各脏器灌流减少,导致孕妇全身脏器损伤及胎儿宫内生长受限、死胎等一系列不良妊娠结局,是引起孕产妇及胎儿死亡的主要原因之一。子痫前期病情重,对母儿影响大,并发症多,孕产妇及胎儿结局差。目前关于子痫前期的病因及机制尚不清楚,且缺乏有效的评估手段和治疗方法。因此,明确病因、寻找预测指标和治疗手段显得尤为重要,并成为目前医学研究热点。妊娠相关蛋白 A(pregnancy-associated plasma protein-A,PAPP-A)是锌指超家族中的一种金属螯合蛋白酶,孕期主要由合体滋养细胞分泌,并在外周血和胎盘中维持着高浓度。PAPP-A的水平降低与染色体数目异常(非整倍体)和不良妊娠结局相关。早孕期PAPP-A水平的下降会造成自发性流产、早产、胎儿宫内生长受限、胎盘早剥等风险增加。PAPP-A可以通过水解胰岛素样生长因子结合蛋白(insulin-like growth factor binding proteins,IGFBPs),降低其与胰岛素样生长因子(insulin growth factor 1,IGF-1)的结合力,最终导致游离的IGF-1释放,而IGF-1能增加细胞外基质的黏性,刺激滋养细胞侵入子宫蜕膜。因此,PAPP-A水平的降低会导致IGF-1水平的降低,使滋养细胞侵入异常造成胎盘浅着床是子痫前期可能的发病机制之一。基于此,本研究旨在探讨PAPP-A与子痫前期的关系。具体从蛋白和基因多态性两个层面,共分为三个部分分析两者的关系:1.通过研究PAPP-A在子痫前期患者早孕期外周血中的表达情况,分析两者的关系,评估PAPP-A对子痫前期的预测价值。2.通过研究PAPP-A在中晚孕期子痫前期患者外周血中的表达情况,分析PAPP-A与子痫前期的相关性;3.分析PAPP-A基因多态性在子痫前期患者与正常孕妇间的分布差异,寻找子痫前期的易感基因。第一章早孕期母体外周血中PAPP-A水平与子痫前期的相关性及其预测价值研究[目的]分析早孕期母体外周血中PAPP-A与子痫前期的关系,探究PAPP-A对子痫前期的预测价值;[方法]收集2015年1月至2016年12月在南方医科大学附属深圳市妇幼保健院完成产前检查并分娩的48例子痫前期孕妇和50例健康孕妇的临床资料进行回顾性分析。比较两组孕妇早孕期血清中PAPP-A水平的差异,采用二分类Logistic回归分析PAPP-A与子痫前期的相关性,采用受试者工作特征(receiver operating characteristic,ROC)曲线分析PAPP-A对子痫前期的预测价值。[结果](1)一般资料:子痫前期组年龄、孕前BMI高于正常组,差异具有统计学意义(P0.01);子痫前期组高血压家族史、多次怀孕、经产妇的比例均高于正常组,差异具有统计学意义(P0.05);子痫前期组分娩孕周早于正常组,剖宫产的比例高于正常组及新生儿出生体重低于正常组,差异均有统计学意义(P＜0.001);两组新生儿性别分布差异无统计学意义(P0.05);(2)PAPP-A水平:早孕期子痫前期组PAPP-A MoM值为0.57(0.44～0.96),低于正常组的0.87(0.64～1.43),差异有统计学意义(P0.001);(3)Logistic回归分析:PAPP-A与子痫前期的发生呈负相关,比值比(OR)值为 0.316(95%CI:0.117～0.854);(4)ROC曲线下面积(ROC-AUC):PAPP-AMoM预测子痫前期的ROC-AUC 为 0.717(95%CI0.614～0.820),PAPP-AMoM 联合年龄的预测子痫前期的 ROC-AUC 为 0.755(95%CI:0.659～0.851)。[结论]妊娠早期,子痫前期孕妇外周血中PAPP-A水平是明显低于健康孕妇的,两者(?)呈负相关。妊娠早期母体外周血中PAPP-A水平对子痫前期发生的预测有一定的价值。第二章中晚孕期母体外周血中PAPP-A的表达与子痫前期的相关性研究[目的]探讨妊娠中晚孕期子痫前期患者与正常孕妇外周血清中PAPP-A表达的差异,分析两者的相关性。[方法]选取2014年7月至2016年12月在南方医科大学附属深圳市妇幼保健院产科住院的子痫前期患者132例和同期住院分娩的正常妊娠孕妇158例。在上述对象中随机选择子痫前期患者50例和正常晚期妊娠患者40例,采用酶联免疫吸附试验(ELISA)检测外周血中PAPP-A的表达情况,采用二分类Logistic回归分析中晚孕期PAPP-A浓度与子痫前期的相关性。[结果](1)一般资料:子痫前期组年龄、孕前BMI、收缩压和舒张压均高于正常组,差异具有统计学意义(P0.05);子痫前期组高血压家族史和剖宫产比例均高于正常组,差异具有统计学意义(P0.05);子痫前期组分娩孕周早于正常组,新生儿出生体重明显低于对照组的新生儿出生体重,差异均有统计学意义(P0.001)。(2)PAPP-A的表达水平:子痫前期组PAPP-A浓度值为12.48(11.26～14.49)mIU/L,高于对照组的 10.36(8.75～11.62)mIU/L,差异有统计学意义(P=0.003);将子痫前期组分为轻度子痫前期组和重度子痫前期组,两组血清中PAPP-A水平相比较:轻度子痫前期组PAPP-A浓度值为12.35(11.58～14.74)mIU/L,重度子痫前期组PAPP-A浓度值为12.71(10.79～14.49)mIU/L,差异无统计学意义(P=0.705)。(3)Logistic相关分析:妊娠中晚期母体外周血中PAPP-A浓度与子痫前期的发生呈正相关,OR值为 1.892(95%CI:1.401～2.553)(P0.001)。[结论]妊娠中晚期,子痫前期孕妇外周血中PAPP-A浓度明显高于健康孕妇,两者呈正相关,提示PAPP-A可能参与子痫前期的发生发展。第三章PAPP-A基因多态性与子痫前期的相关性研究[目的]通过研究PAPP-A基因多态性与子痫前期的关系,从而筛查出子痫前期的易感人群,为子痫前期的风险评估和产前筛查提供帮助。[方法]选取2014年7月至2016年12月在南方医科大学附属深圳市妇幼保健院产科住院的子痫前期患者132例和同期住院分娩的正常妊娠孕妇158例。采用SNaPshot技术进行PAPP-A基因rs7020782位点和rs12375498位点分型检测。[结果](1)一般资料:子痫前期组年龄、孕前BMI、收缩压与舒张压均高于正常组,差异具有统计学意义(P0.01);子痫前期组分娩孕周早于正常组,新生儿出生体重低于正常组,差异均有统计学意义(P0.001)。(2)子痫前期组孕妇PAPP-Ars7020782位点的基因型为AA、AC和CC的基因型频率分别为48.85%、9.16%和34.35%;对照组孕妇分别为60.96%、8.22%和37.67%。等位基因方面,子痫前期组孕妇A等位基因频率和C等位基因频率分别是53.44%和46.56%,对照组孕妇A等位基因频率和C等位基因频率分别是65.07%和34.93%。共显性模型结果显示子痫前期组中AC基因型频率明显高于对照组,差异有统计学意义(P=0.040)。(3)PAPP-A rs12375498基因型分布不符合Hardy-Weinberg平衡检验(P0.05),未作后续分析。[结论]PAPP-A基因Ser1224Tyr(rs7020782)位点AC基因型可能增加了子痫前期的发生风险;而PAPP-A Cys327Cys(rs12375498)位点由于未满足Hardy-Weinberg平衡检验,未能进行后续探讨,还需进一步增加样本量继续研究
[Abstract]:[background] preeclampsia is a severe obstetric severe pregnancy, which can cause a decrease in the perfusion of various organs of the whole body, resulting in a series of bad pregnancy outcomes, such as the injury of the body organs of the pregnant women, the confinement of fetal intrauterine growth, and the death of the fetus. It is one of the main causes of the death of pregnant and lying in women and the fetus. The etiology and mechanism of preeclampsia are still unclear and lack of effective methods and treatment methods. Therefore, it is particularly important to identify the etiology, to find predictors and treatment methods, and to become a hot topic in medical research. Pregnancy induced pregnancy related protein A (pregnancy-associated plasma protein-) A, PAPP-A) is a metal chelating protease in the zinc finger superfamily. The pregnancy is mainly secreted by syncytio cells, and the decrease in the level of high concentration of.PAPP-A in peripheral blood and placenta is associated with abnormal number of chromosomes (aneuploidy) and bad pregnancy outcomes. The decrease of PAPP-A levels in early pregnancy can cause spontaneous abortion, premature birth, and fetal birth. The risk of intrauterine growth restriction, placental abruption and other risks increases.PAPP-A by hydrolyzing the insulin like growth factor binding protein (insulin-like growth factor binding proteins, IGFBPs), reducing its binding force with the insulin-like growth factor (insulin growth factor 1, IGF-1), and ultimately leading to free IGF-1 release, which can increase cells. The viscosity of the external matrix stimulates the intruding of the trophoblast in the decidua. Therefore, the decrease of the PAPP-A level leads to a decrease in the level of IGF-1 and the abnormal intruding of the trophoblastic cells, which is one of the possible mechanisms of preeclampsia. Based on this, the aim of this study is to explore the relationship between PAPP-A and preeclampsia. The two levels of sex are divided into three parts to analyze the relationship between the two. 1. by studying the expression of PAPP-A in the peripheral blood of preeclampsia patients, the relationship between the two is analyzed, and the predictive value of PAPP-A on preeclampsia is evaluated by the study of the expression of PAPP-A in the peripheral blood of the preeclampsia patients during the middle and late pregnancy, and the analysis of PAPP-A and the analysis of PAPP-A. The correlation between preeclampsia and preeclampsia; 3. analysis of the difference in the distribution of PAPP-A gene polymorphism between preeclampsia and normal pregnant women and to find the susceptibility genes in preeclampsia. Chapter 1 the correlation and predictive value of PAPP-A level in preeclampsia and preeclampsia and the predictive value of preeclampsia during early pregnancy [Objective] to analyze PAPP-A and eclampsia in the maternal peripheral blood of early pregnancy The preeclampsia value of preeclampsia was investigated by PAPP-A. [Methods] the clinical data of 48 preeclampsia pregnant women and 50 healthy pregnant women who completed prenatal examination and childbirth in Shenzhen maternal and child health care hospital affiliated to Southern Medical University from January 2015 to December 2016 were retrospectively analyzed. The serum PAP in the two groups of pregnant women in the early pregnancy period was compared. The difference of P-A level, the correlation between PAPP-A and preeclampsia was analyzed by two classification Logistic regression, and the predictive value of PAPP-A to preeclampsia was analyzed by receiver operating characteristic, ROC curve. [results] general data: the age of preeclampsia and pre pregnancy BMI were higher than that of the normal group, and the difference was statistically significant P0.01; the family history of hypertension in preeclampsia group and multiple pregnancies, the proportion of pregnant women was higher than that of the normal group, the difference was statistically significant (P0.05); the birth weight of the preeclampsia group was earlier than the normal group, the proportion of cesarean section was higher than the normal group and the birth weight of the newborn was lower than the normal group, the difference was statistically significant (P < 0.001); the two groups were new. There was no significant difference in gender distribution (P0.05); (2) PAPP-A level: the PAPP-A MoM value of preeclampsia group was 0.57 (0.44 ~ 0.96), lower than 0.87 (0.64 to 1.43) of normal group, and the difference was statistically significant (P0.001); (3) Logistic regression analysis: PAPP-A was negatively correlated with preeclampsia, and the ratio Ratio (OR) was 0.316 (95%CI:0.117 to 0.). 854) (4) area under ROC curve (ROC-AUC): PAPP-AMoM predicted that ROC-AUC of preeclampsia was 0.717 (95%CI0.614 ~ 0.820), ROC-AUC in preeclampsia was 0.755 (95%CI:0.659 to 0.851) in preeclampsia. [Conclusion] in early pregnancy, the level of PAPP-A in peripheral blood of preeclampsia pregnant women was significantly lower than that of healthy pregnant women, and both were negative. Correlation. The prediction of PAPP-A levels in maternal peripheral blood in the early pregnancy is of value to preeclampsia. Second the correlation between the expression of PAPP-A in the maternal peripheral blood and preeclampsia in the middle and late pregnant women [Objective] to explore the difference in the expression of PAPP-A in the peripheral serum of the preeclampsia and the normal pregnant women during the middle and late pregnancy. [Methods] 132 cases of preeclampsia and 158 normal pregnant women who were hospitalized during the period of July 2014 to December 2016 in obstetrics and Gynecology, affiliated to the maternity and child health care hospital of Southern Medical University, Southern Medical University, were selected to select 50 cases of preeclampsia and 40 cases of normal late pregnancy, and the enzyme linked immunosorbent assay was used. A test (ELISA) was used to detect the expression of PAPP-A in peripheral blood. The correlation of PAPP-A concentration in the middle and late pregnancy with preeclampsia was analyzed by two classification Logistic regression. [results] general data: age of preeclampsia, BMI, systolic pressure and diastolic pressure in pre eclampsia were higher than those of normal group, and the difference was statistically significant (P0.05); hypertension in preeclampsia group was high blood pressure. The proportion of family history and cesarean section was higher than that of the normal group (P0.05); the birth weight of the preeclampsia group was earlier than that of the normal group, the birth weight of the newborn was significantly lower than that of the control group (P0.001). (2) the expression level of PAPP-A: the concentration of PAPP-A in preeclampsia group was 12.48 (11.26 ~ 2). 14.49) mIU/L, higher than 10.36 (8.75 ~ 11.62) mIU/L of the control group, the difference was statistically significant (P=0.003); the pre eclampsia group was divided into mild preeclampsia group and severe preeclampsia group, and the level of PAPP-A in the two groups was compared: the PAPP-A concentration in the mild preeclampsia group was 12.35 (11.58 to 14.74) mIU/L, and the PAPP-A concentration in the severe preeclampsia group was of the concentration value. The difference was not statistically significant (P=0.705) for 12.71 (10.79 to 14.49) mIU/L. (3) Logistic correlation analysis: the concentration of PAPP-A in the maternal peripheral blood in the middle and late pregnancy was positively correlated with the occurrence of preeclampsia, OR was 1.892 (95%CI:1.401 2.553) (P0.001). [Conclusion] the concentration of PAPP-A in the peripheral blood of preeclampsia pregnant women was significantly higher than that of health. There is a positive correlation between pregnant women and pregnant women, suggesting that PAPP-A may be involved in the development of preeclampsia. Third the correlation between the polymorphism of PAPP-A gene and preeclampsia is studied [Objective] through the study of the relationship between PAPP-A gene polymorphism and preeclampsia, thus screening preeclampsia susceptible population for preeclampsia risk assessment and prenatal screening. For help. [Methods] 132 cases of preeclampsia and 158 normal pregnant women who were hospitalized in obstetrics and Gynecology of Shenzhen maternal and child health care hospital affiliated to Southern Medical University from July 2014 to December 2016 were selected. The PAPP-A gene rs7020782 loci and rs12375498 loci were detected by SNaPshot technique. [results] (1) general data: The age of preeclampsia, pre pregnancy BMI, systolic pressure and diastolic pressure were higher than that of the normal group, the difference was statistically significant (P0.01); the birth weight of the preeclampsia group was earlier than the normal group, the birth weight of the newborn was lower than the normal group (P0.001). (2) the genotype of PAPP-Ars7020782 loci in the preeclampsia group was AA, AC and CC base. The frequency of the genotype was 48.85%, 9.16%, and 34.35%, respectively. The frequencies of A allele and C allele of pregnant women in preeclampsia group were 53.44% and 46.56% respectively in the control group of 60.96%, 8.22%, and 37.67%. alleles respectively. The frequency of A allele and the C allele frequency in the control group were 65.07% and 34.93%. co dominant models, respectively. The frequency of AC genotypes in the preeclampsia group was significantly higher than that in the control group (P=0.040). (3) the distribution of PAPP-A rs12375498 genotype was not consistent with Hardy-Weinberg balance test (P0.05), and no subsequent analysis. [conclusion]PAPP-A gene Ser1224Tyr (rs7020782) site AC genotype may increase the risk of preeclampsia; and P The APP-A Cys327Cys (rs12375498) loci failed to follow up because they did not meet the Hardy-Weinberg equilibrium test, and the sample size should be further increased.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R714.244

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