本文選題：PAPP-A + 子癇前期�。� 參考：《南方醫(yī)科大學(xué)》2017年碩士論文

【摘要】：[背景]子癇前期是妊娠期特發(fā)的產(chǎn)科重癥,可造成全身各系統(tǒng)各臟器灌流減少,導(dǎo)致孕婦全身臟器損傷及胎兒宮內(nèi)生長受限、死胎等一系列不良妊娠結(jié)局,是引起孕產(chǎn)婦及胎兒死亡的主要原因之一。子癇前期病情重,對(duì)母兒影響大,并發(fā)癥多,孕產(chǎn)婦及胎兒結(jié)局差。目前關(guān)于子癇前期的病因及機(jī)制尚不清楚,且缺乏有效的評(píng)估手段和治療方法。因此,明確病因、尋找預(yù)測(cè)指標(biāo)和治療手段顯得尤為重要,并成為目前醫(yī)學(xué)研究熱點(diǎn)。妊娠相關(guān)蛋白 A(pregnancy-associated plasma protein-A,PAPP-A)是鋅指超家族中的一種金屬螯合蛋白酶,孕期主要由合體滋養(yǎng)細(xì)胞分泌,并在外周血和胎盤中維持著高濃度。PAPP-A的水平降低與染色體數(shù)目異常(非整倍體)和不良妊娠結(jié)局相關(guān)。早孕期PAPP-A水平的下降會(huì)造成自發(fā)性流產(chǎn)、早產(chǎn)、胎兒宮內(nèi)生長受限、胎盤早剝等風(fēng)險(xiǎn)增加。PAPP-A可以通過水解胰島素樣生長因子結(jié)合蛋白(insulin-like growth factor binding proteins,IGFBPs),降低其與胰島素樣生長因子(insulin growth factor 1,IGF-1)的結(jié)合力,最終導(dǎo)致游離的IGF-1釋放,而IGF-1能增加細(xì)胞外基質(zhì)的黏性,刺激滋養(yǎng)細(xì)胞侵入子宮蛻膜。因此,PAPP-A水平的降低會(huì)導(dǎo)致IGF-1水平的降低,使滋養(yǎng)細(xì)胞侵入異常造成胎盤淺著床是子癇前期可能的發(fā)病機(jī)制之一�；诖�,本研究旨在探討PAPP-A與子癇前期的關(guān)系。具體從蛋白和基因多態(tài)性兩個(gè)層面,共分為三個(gè)部分分析兩者的關(guān)系:1.通過研究PAPP-A在子癇前期患者早孕期外周血中的表達(dá)情況,分析兩者的關(guān)系,評(píng)估PAPP-A對(duì)子癇前期的預(yù)測(cè)價(jià)值。2.通過研究PAPP-A在中晚孕期子癇前期患者外周血中的表達(dá)情況,分析PAPP-A與子癇前期的相關(guān)性;3.分析PAPP-A基因多態(tài)性在子癇前期患者與正常孕婦間的分布差異,尋找子癇前期的易感基因。第一章早孕期母體外周血中PAPP-A水平與子癇前期的相關(guān)性及其預(yù)測(cè)價(jià)值研究[目的]分析早孕期母體外周血中PAPP-A與子癇前期的關(guān)系,探究PAPP-A對(duì)子癇前期的預(yù)測(cè)價(jià)值;[方法]收集2015年1月至2016年12月在南方醫(yī)科大學(xué)附屬深圳市婦幼保健院完成產(chǎn)前檢查并分娩的48例子癇前期孕婦和50例健康孕婦的臨床資料進(jìn)行回顧性分析。比較兩組孕婦早孕期血清中PAPP-A水平的差異,采用二分類Logistic回歸分析PAPP-A與子癇前期的相關(guān)性,采用受試者工作特征(receiver operating characteristic,ROC)曲線分析PAPP-A對(duì)子癇前期的預(yù)測(cè)價(jià)值。[結(jié)果](1)一般資料:子癇前期組年齡、孕前BMI高于正常組,差異具有統(tǒng)計(jì)學(xué)意義(P0.01);子癇前期組高血壓家族史、多次懷孕、經(jīng)產(chǎn)婦的比例均高于正常組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05);子癇前期組分娩孕周早于正常組,剖宮產(chǎn)的比例高于正常組及新生兒出生體重低于正常組,差異均有統(tǒng)計(jì)學(xué)意義(P＜0.001);兩組新生兒性別分布差異無統(tǒng)計(jì)學(xué)意義(P0.05);(2)PAPP-A水平:早孕期子癇前期組PAPP-A MoM值為0.57(0.44～0.96),低于正常組的0.87(0.64～1.43),差異有統(tǒng)計(jì)學(xué)意義(P0.001);(3)Logistic回歸分析:PAPP-A與子癇前期的發(fā)生呈負(fù)相關(guān),比值比(OR)值為 0.316(95%CI:0.117～0.854);(4)ROC曲線下面積(ROC-AUC):PAPP-AMoM預(yù)測(cè)子癇前期的ROC-AUC 為 0.717(95%CI0.614～0.820),PAPP-AMoM 聯(lián)合年齡的預(yù)測(cè)子癇前期的 ROC-AUC 為 0.755(95%CI:0.659～0.851)。[結(jié)論]妊娠早期,子癇前期孕婦外周血中PAPP-A水平是明顯低于健康孕婦的,兩者(?)呈負(fù)相關(guān)。妊娠早期母體外周血中PAPP-A水平對(duì)子癇前期發(fā)生的預(yù)測(cè)有一定的價(jià)值。第二章中晚孕期母體外周血中PAPP-A的表達(dá)與子癇前期的相關(guān)性研究[目的]探討妊娠中晚孕期子癇前期患者與正常孕婦外周血清中PAPP-A表達(dá)的差異,分析兩者的相關(guān)性。[方法]選取2014年7月至2016年12月在南方醫(yī)科大學(xué)附屬深圳市婦幼保健院產(chǎn)科住院的子癇前期患者132例和同期住院分娩的正常妊娠孕婦158例。在上述對(duì)象中隨機(jī)選擇子癇前期患者50例和正常晚期妊娠患者40例,采用酶聯(lián)免疫吸附試驗(yàn)(ELISA)檢測(cè)外周血中PAPP-A的表達(dá)情況,采用二分類Logistic回歸分析中晚孕期PAPP-A濃度與子癇前期的相關(guān)性。[結(jié)果](1)一般資料:子癇前期組年齡、孕前BMI、收縮壓和舒張壓均高于正常組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05);子癇前期組高血壓家族史和剖宮產(chǎn)比例均高于正常組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05);子癇前期組分娩孕周早于正常組,新生兒出生體重明顯低于對(duì)照組的新生兒出生體重,差異均有統(tǒng)計(jì)學(xué)意義(P0.001)。(2)PAPP-A的表達(dá)水平:子癇前期組PAPP-A濃度值為12.48(11.26～14.49)mIU/L,高于對(duì)照組的 10.36(8.75～11.62)mIU/L,差異有統(tǒng)計(jì)學(xué)意義(P=0.003);將子癇前期組分為輕度子癇前期組和重度子癇前期組,兩組血清中PAPP-A水平相比較:輕度子癇前期組PAPP-A濃度值為12.35(11.58～14.74)mIU/L,重度子癇前期組PAPP-A濃度值為12.71(10.79～14.49)mIU/L,差異無統(tǒng)計(jì)學(xué)意義(P=0.705)。(3)Logistic相關(guān)分析:妊娠中晚期母體外周血中PAPP-A濃度與子癇前期的發(fā)生呈正相關(guān),OR值為 1.892(95%CI:1.401～2.553)(P0.001)。[結(jié)論]妊娠中晚期,子癇前期孕婦外周血中PAPP-A濃度明顯高于健康孕婦,兩者呈正相關(guān),提示PAPP-A可能參與子癇前期的發(fā)生發(fā)展。第三章PAPP-A基因多態(tài)性與子癇前期的相關(guān)性研究[目的]通過研究PAPP-A基因多態(tài)性與子癇前期的關(guān)系,從而篩查出子癇前期的易感人群,為子癇前期的風(fēng)險(xiǎn)評(píng)估和產(chǎn)前篩查提供幫助。[方法]選取2014年7月至2016年12月在南方醫(yī)科大學(xué)附屬深圳市婦幼保健院產(chǎn)科住院的子癇前期患者132例和同期住院分娩的正常妊娠孕婦158例。采用SNaPshot技術(shù)進(jìn)行PAPP-A基因rs7020782位點(diǎn)和rs12375498位點(diǎn)分型檢測(cè)。[結(jié)果](1)一般資料:子癇前期組年齡、孕前BMI、收縮壓與舒張壓均高于正常組,差異具有統(tǒng)計(jì)學(xué)意義(P0.01);子癇前期組分娩孕周早于正常組,新生兒出生體重低于正常組,差異均有統(tǒng)計(jì)學(xué)意義(P0.001)。(2)子癇前期組孕婦PAPP-Ars7020782位點(diǎn)的基因型為AA、AC和CC的基因型頻率分別為48.85%、9.16%和34.35%;對(duì)照組孕婦分別為60.96%、8.22%和37.67%。等位基因方面,子癇前期組孕婦A等位基因頻率和C等位基因頻率分別是53.44%和46.56%,對(duì)照組孕婦A等位基因頻率和C等位基因頻率分別是65.07%和34.93%。共顯性模型結(jié)果顯示子癇前期組中AC基因型頻率明顯高于對(duì)照組,差異有統(tǒng)計(jì)學(xué)意義(P=0.040)。(3)PAPP-A rs12375498基因型分布不符合Hardy-Weinberg平衡檢驗(yàn)(P0.05),未作后續(xù)分析。[結(jié)論]PAPP-A基因Ser1224Tyr(rs7020782)位點(diǎn)AC基因型可能增加了子癇前期的發(fā)生風(fēng)險(xiǎn);而PAPP-A Cys327Cys(rs12375498)位點(diǎn)由于未滿足Hardy-Weinberg平衡檢驗(yàn),未能進(jìn)行后續(xù)探討,還需進(jìn)一步增加樣本量繼續(xù)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.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R714.244

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