CN112760372A - 心肌梗死差异表达基因及其应用 - Google Patents
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Abstract
本发明公开了心肌梗死差异表达基因及其应用，所述的生物标志物包括TEX30和/或ZNF420。本发明公开了相比正常人，TEX30、ZNF420在心肌梗死患者中呈现显著性差异，且ROC曲线显示具有较高的AUC值，提示TEX30和/或ZNF420可应用于心肌梗死诊断。本发明提供了一种诊断心肌梗死的产品。本发明还提供了一种用于治疗心肌梗死的药物组合物。
Description
技术领域
本发明涉及生物医药领域，具体涉及心肌梗死差异表达基因及其应用。
背景技术
根据流行病学的最新统计，心血管疾病目前是我国居民死亡的首位病因，其死亡人数占居民疾病死亡总数的40％以上，其中心肌梗死的发病率近年呈快速上升趋势，成为严重影响人民群众健康的病种之一。心肌梗死后的心肌逐渐坏死，进而形成心力衰竭、心肌破裂或心律失常等一系列临床事件。为预防心肌坏死，心肌缺血应早期治疗，如纤溶治疗、冠状动脉旁路移植术、PCU等会明显改善预后。尽管对于心血管疾病的研究在不断的发展，并且对于心肌梗死的诊断和治疗在过去的十年中获得了十分明显的改善，但是心肌梗死仍然是一类致死率很高的疾病。
分子标志物是可以定量测量的生物学参数，为健康和生理评估指数。它提供了疾病的风险和诊断信息。心肌梗死诊断目前依赖于心肌肌钙蛋白的上升或下降(其中至少有一个值超过参考值上限的第99百分位数)，且合并以下症状之一：(1)缺血症状；(2)心电图有新的缺血改变；(3)心电图出现新Q波；(4)影像学证据提示，新发存活心肌丢失；(5)血管造影或尸体解剖发现冠状动脉内血栓。虽然对于心肌梗死的相关调控靶点已有深入研究，如抑制生长因子配体、各类受体(血小板衍生生长因子受体、血管内皮生长因子受体、表皮生长因子受体)及多种酶类，但是，有效诊断、预防及治疗心肌梗死的分子靶标仍缺乏，因此寻找心肌梗死的分子标志物具有重要意义。
发明内容
本发明的目的在于提供用于诊断心肌梗死的分子标志物。
为了实现上述目的，本发明采用了如下技术方案：
本发明第一方面提供了一种诊断心肌梗死的产品，所述的产品包括检测TEX30和/或ZNF420基因表达水平的试剂。
在本发明中，TEX30(基因ID：93081)包括TEX30基因及其编码的蛋白及其同源物，突变，和同等型。该术语涵盖全长，未加工的TEX30，以及源自细胞中加工的任何形式的TEX30。该术语涵盖TEX30的天然发生变体(例如剪接变体或等位变体)。
在本发明中，ZNF420(基因ID：147923)包括ZNF420基因及其编码的蛋白及其同源物，突变，和同等型。该术语涵盖全长，未加工的ZNF420，以及源自细胞中加工的任何形式的ZNF420。该术语涵盖ZNF420的天然发生变体(例如剪接变体或等位变体)。
本发明的实用性并不局限于对本发明的靶标基因的任何特定变体的基因表达进行定量。本领域技术人员知道，进行生物信息学分析时，通常会将测序序列和已知的基因进行比对，只要有关序列可以比对到相关基因上，就可以看做是该基因的表达，因此，在提及差异表达的基因时，该基因的不同的转录本、突变型或其片段也包含在本发明中。
本领域技术人员应当理解，测定基因表达的手段不是本发明的重要方面。本发明可以利用本领域内已知的任何方法测定基因的表达水平。
进一步，所述的产品包括核酸膜条、芯片或试剂盒。
在本发明中，核酸膜条包括基底和固定于所述基底上的特异性识别TEX30和/或ZNF420的寡核苷酸探针；所述基底可以是任何适于固定寡核苷酸探针的基底，例如尼龙膜、硝酸纤维素膜、聚丙烯膜、玻璃片、硅胶晶片、微缩磁珠等。
进一步，所述的芯片包括基因芯片、蛋白质芯片，其中基因芯片包括针对TEX30和/或ZNF420的引物或寡核苷酸探针，蛋白质芯片包括特异性结合TEX30和/或ZNF420蛋白的结合剂。
进一步，所述的试剂盒包括基因检测试剂盒和蛋白检测试剂盒，所述的基因检测试剂盒包括特异性针对TEX30和/或ZNF420的引物、寡核苷酸探针或芯片；所述的蛋白检测试剂盒包括特异性结合TEX30和/或ZNF420蛋白的结合剂。
术语“引物”指的是能够形成与模板链互补的碱基对(base pair)，并且起到用于复制模板链的起始点作用的7个～50个核酸序列。引物通常合成而得，但也可以使用自然生成的核酸。引物的序列并不一定需要与模板的序列完全相同，只要充分互补而能够与模板杂交即可。可以混入不改变引物的基本性质的追加特征。作为可以混入的追加特征的例子，有甲基化、带帽、一个以上的核酸被同系物取代和核酸间的修饰，但不限于此。
术语“杂交”指的是两个互补的核酸链在适当严格的条件下彼此退火结合。通常利用探针长度的核酸分子来进行杂交。核酸杂交技术在现有技术中是公知的。本领域的技术人员了解如何估计和调整杂交条件的严格度，使得具有至少所需程度的互补性的序列将稳定地杂交，而具有较低互补性的序列将不能稳定地杂交。
术语“探针”指的是能与另一分子的特定序列或亚序列或其它部分结合的分子。除非另有指出，术语“探针”通常指能通过互补碱基配对与另一多核苷酸(往往称为“靶多核苷酸”)结合的多核苷酸探针。根据杂交条件的严谨性，探针能和与该探针缺乏完全序列互补性的靶多核苷酸结合。探针可作直接或间接的标记，其范围包括引物。杂交方式包括，但不限于：溶液相、固相、混合相或原位杂交测定法。
术语“寡核苷酸”指的是由脱氧核糖核苷酸、核糖核苷酸或其任意组合构成的短聚合物。寡核苷酸的长度通常在大10个核苷酸和大约100个核苷酸之间。寡核苷酸优选地长度为15个核苷酸到70个核苷酸，最通常的是20个核苷酸到26个核苷酸。寡核苷酸可以用作引物或探针。
本发明第二方面提供了检测分子标志物的试剂在制备诊断心肌梗死的产品中的应用，所述的分子标志物包括TEX30和/或ZNF420。
进一步，所述的试剂包括通过测序技术、核酸杂交技术、核酸扩增技术、蛋白免疫技术检测样本中TEX30和/或ZNF420基因表达水平的试剂。
本发明可在检测前或与检测同时地对核酸进行扩增。核酸扩增技术的示例性非限制性实例包括但不限于：聚合酶链式反应(PCR)、逆转录聚合酶链式反应(RT-PCR)、转录介导的扩增(TMA)、连接酶链式反应(LCR)、链置换扩增(SDA)和基于核酸序列的扩增(NASBA)。本领域的普通技术人员将认识到，某些扩增技术(例如，PCR)需要在扩增前将RNA逆转录成DNA(例如，RT-PCR)，而其他扩增技术则直接扩增RNA(例如，TMA和NASBA)。
本发明中的核酸杂交技术包括但不限于原位杂交(ISH)、微阵列和Southern或Northern印迹。原位杂交(ISH)是一种使用标记的互补DNA或RNA链作为探针以定位组织一部分或切片(原位)或者如果组织足够小则为整个组织(全组织包埋ISH)中的特异性DNA或RNA序列的杂交。DNA ISH可用于确定染色体的结构。RNA ISH用于测量和定位组织切片或全组织包埋内的mRNA和其他转录本(例如，ncRNA)。通常对样本细胞和组织进行处理以原位固定靶转录本，并增加探针的进入。探针在高温下与靶序列杂交，然后将多余的探针洗掉。分别使用放射自显影、荧光显微术或免疫组织化学，对组织中用放射、荧光或抗原标记的碱基标记的探针进行定位和定量。ISH也可使用两种或更多种通过放射性或其他非放射性标记物标记的探针，以同时检测两种或更多种转录本。
将Southern和Northern印迹分别用于检测特异性DNA或RNA序列。使从样本中提取的DNA或RNA断裂，在基质凝胶上通过电泳分离，然后转移到膜滤器上。使滤器结合的DNA或RNA与和所关注的序列互补的标记探针杂交。检测结合到滤器的杂交探针。该程序的一种变化形式是反向Northern印迹，其中固定到膜的底物核酸为分离的DNA片段的集合，而探针是从组织提取并进行了标记的RNA。
蛋白免疫技术包括夹心免疫测定，例如夹心ELISA，其中使用识别生物标志物上不同表位的两种抗体进行该生物标志物的检测；放射免疫测定(RIA)、直接、间接或对比酶联免疫吸附测定(ELISA)、酶免疫测定(EIA)、荧光免疫测定(FIA)、蛋白质印迹法、免疫沉淀法和基于任何颗粒的免疫测定(如使用金颗粒、银颗粒或乳胶颗粒、磁性颗粒或量子点)。可例如在微量滴定板或条的形式中实施免疫法。
进一步，所述的试剂包括：
特异性识别TEX30和/或ZNF420基因的寡核苷酸探针；或
特异性扩增TEX30和/或ZNF420基因的引物；或
特异性结合TEX30和/或ZNF420基因编码的蛋白的结合剂。
本发明第三方面提供了分子标志物在构建预测心肌梗死的计算模型中的应用，所述的分子标志物包括TEX30和/或ZNF420。
在本发明中，可以以不同方式实施和实现将标志物水平与某种可能性或风险关联起来的步骤。优选地，在数学上组合基因和一种或多种其它标志物的测定浓度，并将组合值与根本的诊断问题关联起来。可以通过任何适宜的现有技术数学方法将标志物值的测定组合。
优选地，在标志物组合中应用的数学算法是一种对数函数。优选地，应用此类数学算法或此类对数函数的结果是单一值。根据根本的诊断问题，能容易地将此类值与例如个体关于心肌梗死的风险或与有助于评估心肌梗死患者的其它有意诊断用途关联起来。以一种优选的方式，此类对数函数是如下获得的：a)将个体分类入组，例如正常人、有心肌梗死风险的个体、具有心肌梗死的患者等等，b)通过单变量分析来鉴定在这些组之间差异显著的标志物，c)对数回归分析以评估标志物的可用于评估这些不同组的独立差别值，并d)构建对数函数来组合独立差别值。在这种类型的分析中，标志物不再是独立的，而是代表一个标志物组合。
用于将标志物组合与疾病关联起来的对数函数优选采用通过应用统计方法开发和获得的算法。例如，适宜的统计方法是判别分析(DA)(即线性、二次、规则DA)、Kernel方法(即SVM)、非参数方法(即k-最近邻居分类器)、PLS(部分最小二乘)、基于树的方法(即逻辑回归、CART、随机森林方法、助推/装袋方法)、广义线性模型(即对数回归)、基于主分量的方法(即SIMCA)、广义叠加模型、基于模糊逻辑的方法、基于神经网络和遗传算法的方法。熟练技术人员在选择适宜的统计方法来评估本发明的标志物组合并由此获得适宜的数学算法方面不会有问题。在一个实施方案中，用于获得评估心肌梗死中使用的数学算法的统计方法选自DA(即线性、二次、规则判别分析)、Kernel方法(即SVM)、非参数方法(即k-最近邻居分类器)、PLS(部分最小二乘)、基于树的方法(即逻辑回归、CART、随机森林方法、助推方法)、或广义线性模型(即对数回归)。
本发明第四方面提供了一种用于治疗心肌梗死的药物组合物，所述的药物组合物包括抑制TEX30基因表达的试剂和/或促进ZNF420基因表达的试剂。
本发明第五方面提供了TEX30和/或ZNF420在制备治疗心肌梗死的药物组合物中的应用。
进一步，所述的药物组合物包括抑制TEX30基因表达的试剂和/或促进ZNF420基因表达的试剂。
本发明的优点和有益效果：
本发明公开了一种可用于诊断心肌梗死的产品，为诊断心肌梗死提供了新方法。
本发明还公开了一种用于治疗心肌梗死的药物组合物。
附图说明
图1是TEX30差异表达箱线图；
图2是TEX30诊断急性心肌梗死的ROC曲线图；
图3是TEX30和ZNF420联合诊断急性心肌梗死的ROC曲线图。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案，具体实施例不代表对本发明保护范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。
实施例1筛选急性心肌梗死差异表达基因
1、数据来源
从GEO数据库下载急性心肌梗死(AIM)数据集GSE66360，样本量为control：AIM＝50:49。
2、差异表达分析
使用R软件中的“limma”包进行差异表达分析，差异基因的筛选标准为adj.Pvalue<0.05。
3、实验结果
分析结果显示，本发明涉及的生物标志物TEX30在急性心肌梗死患者样本中表达上调，ZNF420在急性心肌梗死患者样本中表达下调，如表1和图1所示。
表1、TEX30、ZNF420的差异表达情况
| 基因 | AveExpr | t | P.Value |
| TEX30 | 7.61 | 4.28 | 0.00 |
| ZNF420 | 7.26 | -5.69 | 0.00 |
实施例2诊断效能验证
1、实验方法
使用R包“pROC”(版本1.15.0)绘制受试者工作曲线(ROC)，分析AUC值、敏感性和特异性，判断指标单独或者联合的诊断效能。在判断指标联合的诊断效能时，对各基因的表达水平进行logistics回归，通过拟合出的回归曲线计算出每个个体患癌与否的概率，确定不同的概率划分阈值，根据确定的概率划分阈值，计算得出联合检测方案的灵敏度、特异性以及准确性等。
2、实验结果
(1)TEX30的ROC曲线分析
TEX30的诊断效能参见表2和图2，通过实验结果可知TEX30对于急性心肌梗死具有很好的诊断效果。
表2、TEX30的诊断效能
| 基因 | AUC | 敏感性 | 特异性 |
| TEX30 | 0.74 | 0.64 | 0.78 |
(2)TEX30+ZNF420联合诊断的ROC曲线分析
TEX30、ZNF420基因的AUC值参见表3，TEX30+ZNF420联合诊断的ROC曲线参见图3。
表3、基因的AUC值
| 基因 | AUC |
| TEX30 | 0.74 |
| ZNF420 | 0.79 |
| TEX30+ZNF420 | 0.92 |
通过实验结果可知，TEX30+ZNF420组合对于急性心肌梗死的诊断效果好于单个标志物，具有更好的诊断效能。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (10)
1.一种诊断心肌梗死的产品，其特征在于，所述的产品包括检测TEX30和/或ZNF420基因表达水平的试剂。
2.根据权利要求1所述的产品，其特征在于，所述的产品包括核酸膜条、芯片或试剂盒。
3.根据权利要求2所述的产品，其特征在于，所述的芯片包括基因芯片、蛋白质芯片，其中基因芯片包括针对TEX30和/或ZNF420的引物或寡核苷酸探针，蛋白质芯片包括特异性结合TEX30和/或ZNF420蛋白的结合剂。
4.根据权利要求2所述的产品，其特征在于，所述的试剂盒包括基因检测试剂盒和蛋白检测试剂盒，所述的基因检测试剂盒包括特异性针对TEX30和/或ZNF420的引物、寡核苷酸探针或芯片；所述的蛋白检测试剂盒包括特异性结合TEX30和/或ZNF420蛋白的结合剂。
5.检测分子标志物的试剂在制备诊断心肌梗死的产品中的应用，其特征在于，所述的分子标志物包括TEX30和/或ZNF420。
6.根据权利要求5所述的应用，其特征在于，所述的试剂包括通过测序技术、核酸杂交技术、核酸扩增技术、蛋白免疫技术检测样本中TEX30和/或ZNF420基因表达水平的试剂。
7.根据权利要求5或6所述的应用，其特征在于，所述的试剂包括：
特异性识别TEX30和/或ZNF420基因的寡核苷酸探针；或
特异性扩增TEX30和/或ZNF420基因的引物；或
特异性结合TEX30和/或ZNF420基因编码的蛋白的结合剂。
8.分子标志物在构建预测心肌梗死的计算模型中的应用，其特征在于，所述的分子标志物包括TEX30和/或ZNF420。
9.一种用于治疗心肌梗死的药物组合物，其特征在于，所述的药物组合物包括抑制TEX30基因表达的试剂和/或促进ZNF420基因表达的试剂。
10.TEX30和/或ZNF420在制备治疗心肌梗死的药物组合物中的应用，优选的，所述的药物组合物包括抑制TEX30基因表达的试剂和/或促进ZNF420基因表达的试剂。
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| CN108624680A (zh) * | 2018-07-03 | 2018-10-09 | 北京泱深生物信息技术有限公司 | Rae1基因或蛋白作为诊断心肌梗死的生物标志物的应用 |
| CN108913769A (zh) * | 2018-07-26 | 2018-11-30 | 泰山医学院 | 早期诊断心肌梗死的分子标志物 |
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| CN105400880A (zh) * | 2015-12-11 | 2016-03-16 | 天津市人民医院 | 急性心肌梗死早期诊断标志物 |
| CN108624680A (zh) * | 2018-07-03 | 2018-10-09 | 北京泱深生物信息技术有限公司 | Rae1基因或蛋白作为诊断心肌梗死的生物标志物的应用 |
| CN108913769A (zh) * | 2018-07-26 | 2018-11-30 | 泰山医学院 | 早期诊断心肌梗死的分子标志物 |
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