CN112126683A - 用于迟发型子痫前期诊断的标志物 - Google Patents
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Abstract
本发明公开了一组用于迟发型子痫前期诊断的标志物。本发明是基于基因芯片技术筛选迟发型子痫前期患者与正常孕妇外周血血细胞差异表达基因，通过共表达网络分析筛选在疾病发生中的枢纽基因，并采用荧光定量PCR验证这些标志物在实际应用中的诊断价值。所述标志物特异性高，可为迟发型子痫前期的鉴别诊断提供良好帮助，同时检测标本具有无创性与简易性的优势，可为临床疑似迟发型子痫前期孕妇的普遍筛查提供新的策略。
Description
技术领域
本发明涉及一组用于迟发型子痫前期诊断的标志物。
背景技术
子痫前期(preeclampsia)是指孕妇在妊娠20周后新发高血压、蛋白尿或其他终末器官损伤，其发病率为4-5％，是母亲妊娠期的主要并发症，全球每年有超过7万例孕妇和50万例胎儿因其死亡[1]。子痫前期是一种动态性疾病，病情呈持续性进展，可根据临床症状的发病时间将之分成早发型(≤34周，early-onset of preeclampsia；EOPE)和迟发型(>34周， late-onsetofpreeclampsia；LOPE)子痫前期两类。对于两种子痫前期是认为其是一类疾病跨越了较长的妊娠期还是两种不同的疾病尚未定论，但越来越多的研究表明两种子痫前期的发病机制完全不同：早发型子痫前期与胎盘的发育缺陷相关，而迟发型子痫前期与母亲自身的因素更息息相关，如微血管疾病，遗传因素[2-4]。对于疑似子痫前期的孕妇尽早做出诊断有助于患者的临床护理与监测，用药指导，同时也避免了对于正常孕妇或其他患有疾病孕妇的不必要护理，从而最大限度保障孕妇和胎儿的安全。
目前临床对于子痫前期的诊断主要是依靠咨询病史，临床表现以及一些常规辅助检查做出诊断，但由于该病临床表现的多样性，常需要注意有无多脏器的损害以及与其他妊娠期高血压疾病的区别。生物标志物的检测在大量疾病的早期诊断中发挥的重要作用。国内外也有一些报道评估了血清标志物如冠毛素2(PAPPA2)[5]、内皮素(ENG)[6]、胎盘生长因子(PlGF) [7]、Fms相关酪氨酸激酶1(FLT1)[7]在子痫前期中的诊断价值，但目前这些标志物在临床上的使用并不广泛，仍需要大量的临床随机试验进行验证与评估。同时，研究发现一些血清标志物对于早发型子痫前期的诊断价值显著大于迟发型子痫前期[8,9]。因此，对于迟发型子痫前期的标志物研究仍处于空白。
(1)采用结合病史，临床表现及辅助检查诊断子痫前期：病史：询问孕妇妊娠前是否有高血压、肾病、系统性红斑狼疮、血栓类疾病、糖尿病等病史，有无妊娠期高血压疾病家族史，咨询患者在此次妊娠后是否有视力模糊，头痛。上腹疼痛等症状的出现及严重程度。高血压：收缩压≥140mmHg和(或)舒张压≥90mmHg，若血压低于140/90mmHg，但较基础血压仍升高，不作为诊断依据，但需要严密观察。尿蛋白：尿蛋白≥0.3g/24h或尿蛋白定性≥(+)。辅助检查：一般还会结合血常规、尿常规、肝功能、肾功能、凝血功能、超声、心电图等检查进行辅助诊断。若孕妇出现下述任一表现可诊断为重度子痫前期：(1)血压持续升高：收缩压≥160mmHg和(或)舒张压≥110mmHg；(2)持续性头痛、视觉障碍或其他中枢神经系统异常表现；(3)持续性上腹部疼痛及肝包膜下血肿或肝破裂表现；(4)肝酶异常；(5)肾功能受损；(6)低蛋白血症伴腹水、胸水或心包积液；(7)血液系统异常：血小板计数呈持续性下降并低于100×109/L；微血管内溶血；(8)心功能衰竭；(9)肺水肿；(10)胎儿生长受限或羊水过少、胎死宫内、胎盘早剥等[10,11]。这种诊断方法对于疑似子痫前期的患者能够最大限度的减少漏诊，但其不足之处在于灵敏度不高，往往需要连续监测才能做出诊断。另外子痫前期临床表现比较多样，需要与妊娠期高血压，妊娠合并高血压，慢性肾炎相鉴别，往往会使的诊断延后，影响临床护理与治疗方案的选择。
(2)血浆标志物检测诊断子痫前期：Kleinrouweler[12]等发现sFLT1和sENG在子痫前期患者中表达明显升高，而PlGF的表达则明显低于正常组。Kate E Duhig[13]等进行了一项针对 PlGF在子痫前期诊断的随机临床研究，研究发现PlGF检测大大缩短了临床确诊子痫前期的时间，支持采用PlGF检测作为诊断子痫前期疑似患者的手段。Palomaki[14]等研究报道了联合 sFLT1/PlGF进行子痫前期诊断，灵敏度约为61.9％，特异性约为69.4％。虽然目前对于子痫前期的血浆标志物的检测报道很多，但在实际临床应用确是很少，一方面是目前的报道都是基于目前的研究都是患者与正常病人之间的表达对比，缺乏临床多中心随机对照试验验证这些血清标志物在实际临床诊断的应用准确度与特异性；另一方面，有研究发现在早发型子痫前期中有着良好诊断灵敏度与特异性的血清标志物在迟发型子痫前期中诊断价值显著下降[8,9]。因此对于迟发型子痫前期的标志物仍处于空白期。
采用以上策略对于疑似子痫前期孕妇进行临床诊断各有其优缺点，但还不能满足临床上迟发型子痫前期的诊断要求。因此，探索新的策略来辅助迟发型子痫前期的诊断仍有必要。
众所周知，通过将子痫前期胎盘组织和配对的正常组织差异基因表达芯片是筛选子痫前期血清标志物的一种常见策略之一。此策略通过芯片技术寻找高差异表达的基因，如果存在分泌蛋白，选择其中一个或者其中几个差异最显著的蛋白，然后进行血清检测，验证其能否作为子痫前期诊断标志物。但迟发型子痫前期与早发型子痫前期的发病机制不同，有研究表明，胎盘的功能紊乱主要引发早发型子痫前期的发生，而迟发型子痫前期的孕妇的胎盘发育更接近于正常孕妇[15]。这也解释了使用此种方法筛选的标志物在迟发型子痫前期的诊断价值不理想。迟发型子痫前期主要由母亲自身的因素引发，具体的发病机制仍需进一步研究。因此，迟发型子痫前期孕妇与正常孕妇外周血中的差异表达基因是筛选迟发型子痫前期标志物的一种良好潜在方法，但是现有技术中相关的研究较少。
发明内容
本发明的目的在于克服现有技术的不足，提供一组用于迟发型子痫前期诊断的标志物。
本发明所采取的技术方案是：
本发明的第一个方面，提供：
一组用于迟发型子痫前期诊断的标志物，所述标志物选自以下标志物中的至少一种：
重度迟发型子痫前期下调标志物：IGF2、ABHD9、CPLX2、EVX1、EXOC3L2、LYNX1、OR2H1、ORMDL3、THY1、GCS1；
重度迟发型子痫前期上调标志物：COMMD6、CD52、HMGB1、GZMA、XCL1；
非重度迟发型子痫前期下调标志物：RGS2、GCA、HHEX、LBR、LRRK2、NAMPT、 RAP2C、PTAR1、DEK、SPR9；以及
非重度迟发型子痫前期上调标志物：TBXA2R、ADAM33、ARSD、CLCNKA、ADRB3、INHBC、DNAL4、B3GNT6、GPR12、OR1L3。
在一些实例中，所述标志物选自所述重度迟发型子痫前期下调标志物、所述重度迟发型子痫前期上调标志物、所述非重度迟发型子痫前期下调标志物和所述非重度迟发型子痫前期上调标志物中的至少2种、3种、4种、5种、6种、7种至所有标志物总数之和。
在一些实例中，所述标志物为所述重度迟发型子痫前期下调标志物构成的标志物组。
在一些实例中，所述标志物为所述重度迟发型子痫前期上调标志物构成的标志物组。
在一些实例中，所述标志物为所述非重度迟发型子痫前期下调标志物构成的标志物组。
在一些实例中，所述标志物为所述非重度迟发型子痫前期上调标志物构成的标志物组。
在一些实例中，所述标志物为所述标志物选自所述重度迟发型子痫前期下调标志物、所述重度迟发型子痫前期上调标志物、所述非重度迟发型子痫前期下调标志物和所述非重度迟发型子痫前期上调标志物构成的标志物组中的至少2组。
在一些实例中，所述标志物为所述重度迟发型子痫前期下调标志物、所述重度迟发型子痫前期上调标志物、所述非重度迟发型子痫前期下调标志物和所述非重度迟发型子痫前期上调标志物的集合。
本发明的第二个方面，提供：
定量标志物表达量的试剂盒在制备迟发型子痫前期诊断试剂盒或辅助诊断试剂盒中的应用，所述标志物如本发明的第一个方面所述。
在一些实例中，所述迟发型子痫为重度迟发型子痫前期或非重度迟发型子痫前期。
在一些实例中，所述标志物来自孕妇外周血样本。
在一些实例中，所述试剂盒为mRNA定量试剂盒。
在一些实例中，所述mRNA定量试剂盒为荧光定量PCR试剂盒。
本发明的第三个方面，提供：
一种治疗或预防迟发型子痫前期药物的筛选方法，包括将待筛选的化合物与细胞作用，检测其对标志物表达量的影响，根据所述标志物表达量的变化情况，确定待筛选的化合物是否入选，所述标志物如本发明的第一个方面所述。
在一些实例中，所述迟发型子痫为重度迟发型子痫前期或非重度迟发型子痫前期。
本发明的第四个方面，提供：
一种确定迟发型子痫前期风险的系统，包括：
数据存储装置：用于存储样本的标志物表达量信息；
数据分析装置：对标志物表达量信息进行分析，确定迟发型子痫前期风险；
结果展示装置：展示数据分析装置的分析结果；
其中，所述标志物如本发明的第一个方面所述。
在一些实例中，所述迟发型子痫为重度迟发型子痫前期或非重度迟发型子痫前期。
本发明的有益效果是：
本发明一些实例，基于基因芯片技术筛选迟发型子痫前期孕妇外周血血细胞的差异表达基因。通过共表达网络分析筛选出在迟发型子痫前期发病中的枢纽基因，这些枢纽基因为迟发型子痫前期的鉴别诊断提供了新的途径。
本发明一些实例，通过荧光定量PCR这种检测技术对筛选的枢纽基因进行疾病预测和诊断价值的验证，该方法具有灵敏度高，特异性强的优势，确立了筛选的枢纽基因对于迟发型子痫前期的诊断具有很高的应用价值。
本发明一些实例，检测样本是孕妇的外周血细胞，取材方便且属于无创性操作，易于对疑似迟发型子痫前期的孕妇进行大规模的筛查，避免不必要的医疗浪费。
附图说明
图1是不同类型的子痫前期外周血血细胞与对照组的差异表达基因的筛选火山结果图； EOPE_S，重度早发型子痫前期；LOPE_S，重度迟发型子痫前期；LOPE_NS，非重度子痫前期；EO_N，早发型子痫前期对应的正常组；LO_N，迟发型子痫前期对应的正常组。
图2是不同类型的子痫前期外周血血细胞的差异表达基因聚类热图。
图3是基因表达检测芯片数据中高变异基因的相关性分析。
图4是不同模块的高变异基因与不同类型的子痫前期的相关性分析。
图5是差异表达基因与不同模块的高变异基因的相关性分析。
图6是重度迟发型子痫前期对应模块内差异表达基因的共表达分析；模块turquoise(左)；模块yellow(右)。
图7是非重度迟发型子痫前期对应模块内差异表达基因的共表达分析；模块turquoise(左)；模块blue(中)；模块black(右)。
图8是部分潜在的标志物在迟发型子痫前期孕妇外周血血细胞表达分析；基因表达芯片数据(上)；实验验证数据(下)。
具体实施方式
下面结合具体的实验方法，进一步说明本发明的技术方案。以下实施例应仅举例说明本发明。它们无论如何不应解释为限制本发明的范围。
实施例1：新型诊断标志物的筛选
在Gene Expression Omnibus(GEO)中检索一个子痫前期外周血血细胞表达芯片数据库 (GSE48424)[16],分别将不同类型的子痫前期与对应的对照组进行比较筛选差异表达基因 ((Fold Change≥2；P-value<0.01)，如图1，早发型子痫前期的差异表达基因的数目显著低于迟发型子痫前期，同时病情严重程度不同的迟发型子痫前期之间也存在异质性，如图2。
为了进一步筛选在子痫前期发病中发挥枢纽作用的基因，我们对芯片数据中的基因进行高变异基因筛选并进行相关性分析，将之划分为18个不同的模块，如图3，主要有salmon， red，yellow，green，magenta，turquoise，black，blue等模块。
通过对不同模块与不同类型的子痫前期之间的相关性分析，筛选促进疾病发生发展的基因模块，如图4，重度迟发型子痫前期主要集中于yellow，turquoise模块，非重度迟发型子痫前期主要集中在turquoise，blue，black模块。
将不同类型子痫前期的差异表达基因与不同模块的高变异基因进行对比分析，判断筛选的差异表达基因是否对应在相对子痫前期模块中，如图5。除了早发型子痫前期，其他差异表达基因基本都对应在相关模块中。因此也反映了迟发型子痫前期孕妇的外周血检测能够反映疾病的状态。
对于模块中的差异表达基因进行共表达分析筛选出在不同类型子痫前期中驱动疾病发生的枢纽基因；如图6，图7。通过基因与疾病的相关程度和PubMed文献检索联合检索潜在的迟发型子痫前期标志物用于后续的荧光定量PCR验证，如表1。
实施例2：标志物的检测
1)采用EDTA抗凝管静脉采血2ml，颠倒混匀。
2)将2mL外周血分装到2个2mL的EP管中各1mL，1500×g,5min，4℃；
3)余下的血细胞中加入1mL的PBS，充分混匀以洗涤细胞，1500×g,5min，4℃；
4)弃掉上清，于剩下的血细胞中加入1mL的TRIZOL(Invitrogen,15596026),充分混匀；
5)颠倒混匀后于室温放置10min，加200ul氯仿，震荡充分混匀，于冰上放置5min；15000×r，15min，4℃；
6)小心吸取上清于一个新的1.5mL的EP管中，加入等量的异丙醇混匀，于-20℃放置 30min+；
7)15000×r，5min，4℃，倾倒上清，加1mL提前预冷的75％的乙醇，充分吹打混匀；
8)15000×r，5min，4℃，重复步骤7一次；
9)倾倒上清，待酒精挥发完全后加入20ul DEPC水溶解RNA；
10)Nanodrop One(Thermo)测量RNA浓度以及质量；
11)采用PrimeScript RT Master Mix逆转录试剂盒(TaKaRa,RR036A)进行逆转录： 10ul体系：2ul Mix+1ul RNA+7ul DEPC水；
12)Nanodrop One(Thermo)测量cDNA浓度以及质量；
13)Lightcycler 480SYBR Green maste试剂盒(Roche,4887352001-1)进行荧光定量PCR 检测筛选出来的标志物表达量：
20ul体系：2ul PCR Primer+10ul Mix+7ul DEPC水+1ul cDNA
cDNA量不超过100ng；
14)采用实时荧光定量PCR系统(Roche,LightCycle480 II))进行荧光定量检测标志物的表达。
实验结果如图8，IGF2,ORMDL3在重度迟发型子痫前期中表达下降，RGS2,HHEX在非重度迟发型子痫前期中表达下降，TBXA2R在非重度迟发型子痫前期中表达上升，因此，我们筛选的标志物具有很高的特异性，有着良好的临床应用价值。
表1用于迟发型子痫前期筛选的标志物
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Claims (10)
1.一组用于迟发型子痫前期诊断的标志物，所述标志物选自以下标志物中的至少一种：
重度迟发型子痫前期下调标志物：IGF2、ABHD9、CPLX2、EVX1、EXOC3L2、LYNX1、OR2H1、ORMDL3、THY1、GCS1；
重度迟发型子痫前期上调标志物：COMMD6、CD52、HMGB1、GZMA、XCL1；
非重度迟发型子痫前期下调标志物：RGS2、GCA、HHEX、LBR、LRRK2、NAMPT、RAP2C、PTAR1、DEK、SPR9；以及
非重度迟发型子痫前期上调标志物：TBXA2R、ADAM33、ARSD、CLCNKA、ADRB3、INHBC、DNAL4、B3GNT6、GPR12、OR1L3。
2.定量标志物表达量的试剂盒在制备迟发型子痫前期诊断试剂盒或辅助诊断试剂盒中的应用，其特征在于：所述标志物如权利要求1所述。
3.根据权利要求2所述的应用，其特征在于：所述迟发型子痫为重度迟发型子痫前期或非重度迟发型子痫前期。
4.根据权利要求2或3所述的应用，其特征在于：所述标志物来自孕妇外周血样本。
5.根据权利要求2或3所述的应用，其特征在于：所述试剂盒为mRNA定量试剂盒。
6.根据权利要求5所述的应用，其特征在于：所述mRNA定量试剂盒为荧光定量PCR试剂盒。
7.一种治疗或预防迟发型子痫前期药物的筛选方法，包括将待筛选的化合物与细胞作用，检测其对标志物表达量的影响，根据所述标志物表达量的变化情况，确定待筛选的化合物是否入选，所述标志物如权利要求1所述。
8.根据权利要求7所述的筛选方法，其特征在于：所述迟发型子痫为重度迟发型子痫前期或非重度迟发型子痫前期。
9.一种确定迟发型子痫前期风险的系统，包括：
数据存储装置：用于存储样本的标志物表达量信息；
数据分析装置：对标志物表达量信息进行分析，确定迟发型子痫前期风险；
结果展示装置：展示数据分析装置的分析结果；
其中，所述标志物如权利要求1所述。
10.根据权利要求9所述的系统，其特征在于：所述迟发型子痫为重度迟发型子痫前期或非重度迟发型子痫前期。
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