WO2022077538A1 - 基于hspa1b基因插入缺失多态性位点的心源性猝死易感性检测试剂盒 - Google Patents

基于hspa1b基因插入缺失多态性位点的心源性猝死易感性检测试剂盒 Download PDF

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WO2022077538A1
WO2022077538A1 PCT/CN2020/122328 CN2020122328W WO2022077538A1 WO 2022077538 A1 WO2022077538 A1 WO 2022077538A1 CN 2020122328 W CN2020122328 W CN 2020122328W WO 2022077538 A1 WO2022077538 A1 WO 2022077538A1
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sudden cardiac
cardiac death
detection kit
deletion
susceptibility
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何艳
于欢
张晴
高玉振
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苏州大学
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  • the invention relates to a detection kit for sudden cardiac death susceptibility based on the insertion and deletion polymorphism of HSPA1B gene, and belongs to the technical field of detection.
  • SCD Sudden cardiac death
  • 3'UTR plays an important role in regulating gene expression
  • the heat shock protein family A(Hsp70) member 1B, HSPA1B gene is located in the human histocompatibility complex III region, and because of the highly conserved gene sequence and the similarity of the encoded products, extracellular
  • the HSPA1B protein is recognized by the immune system in the body and causes an immune response, which initiates or exacerbates the atherosclerotic process and is a potential risk factor for sudden cardiac death.
  • the present invention provides a kit for detecting SCD susceptibility based on the polymorphism of the insertion deletion site rs3036297 on the HSPA1B gene, which can be used to evaluate the susceptibility of an individual to suffer from SCD.
  • the first object of the present invention is to provide a kit for detecting sudden cardiac death susceptibility based on the indel polymorphism of HSPA1B gene, which is used to detect the genotype of the rs3036297 site of HSPA1B gene.
  • the kit for detecting susceptibility to sudden cardiac death includes a specific primer pair for detecting the rs3036297 site of the HSPA1B gene, and components for PCR amplification and capillary electrophoresis.
  • the specific primer pair includes a sense primer and an antisense primer, the nucleotide sequence of the sense primer is as shown in SEQ ID NO.1, and the nucleotide sequence of the antisense primer is as shown in SEQ ID NO.2 Show:
  • SEQ ID No. 1 5'-ACTGTTGGGACTCAAGGACT-3';
  • SEQ ID No. 2 5'-TACAAAAATAATGAAGCCAGCTAAT-3'.
  • the Tm value of the nucleotide sequence of the sense primer is 58°C.
  • the Tm value of the nucleotide sequence of the antisense primer is 56°C.
  • the 5' end of the specific primer pair is provided with a fluorescent label.
  • the fluorescently labeled specific primer is designed for the indel site of rs3036297 on the HSPA1B gene, and can specifically amplify the fragment containing the indel, and the fluorescent dye is labeled on the oligonucleotide by fluorescent labeling technology.
  • the kit for detecting SCD includes a primer pair with the sequences shown in SEQ ID No. 1 and SEQ ID No. 2, but the primers of the present invention are not limited to this pair of primers.
  • PCR amplification and capillary electrophoresis include: Taq DNA polymerase, dNTP mixed solution, MgCl 2 solution, PCR reaction buffer and deionized water.
  • genotypes of PCR amplified products were analyzed by capillary electrophoresis.
  • the second object of the present invention is to provide the application of the susceptibility detection kit for sudden cardiac death in detecting the genotype of the rs3036297 site of the HSPA1B gene.
  • the application is to use fluorescently labeled PCR amplification to obtain PCR amplification products, and the amplification products are subjected to genotype analysis by capillary electrotyping.
  • the specific primer pair included in the kit of the present invention is designed for the insertion deletion site of rs3036297 on the HSPA1B gene, and can specifically amplify the DNA fragments containing this site and detect fragments of different lengths in capillary electrophoresis.
  • the migration rate was used to identify different genotypes.
  • the rs3036297 indel site on the HSPA1B gene of the tested DNA carries the deletion allele as the SCD susceptible type. Therefore, this technology can play a role in predicting the susceptibility of an individual to SCD by detecting the genotype of the rs3036297 indel site on the HSPA1B gene of the individual.
  • Figure 1 is a schematic diagram of gene sequencing and SDS-PAGE gel electrophoresis typing diagram.
  • Genomic DNA from peripheral blood was extracted using a blood genomic DNA extraction system (non-spin column type).
  • Step 2 PCR reaction - replication of the target fragment
  • SEQ ID No.1 5'-ACTGTTGGGACTCAAGGACT-3', Tm value is 58 °C;
  • SEQ ID No.2 5'-TACAAAAATAATGAAGCCAGCTAAT-3', Tm value is 56 °C;
  • the primer pair can specifically amplify the fragment containing the indel polymorphism of rs3036297 in the HSPA1B gene.
  • the total volume of the PCR reaction system is 10ul, including: 1 ⁇ l DNA template, 0.04 ⁇ l each of 50 ⁇ M specific primer pairs, 0.08 ⁇ l of 2.5U/ ⁇ l Taq DNA polymerase; 0.2 ⁇ l of 2.5mM dNTP mixture; 0.6 ⁇ l of 25mM MgCl 2 solution ⁇ l; 1 ⁇ l of 10 ⁇ PCR reaction buffer; deionized water to make up; the reaction was carried out on an Eppendorf Mastercycler nexus PCR amplicon, the reaction conditions were: 94°C for 3 min; then 30 PCR cycles were performed: 94°C for 30s, 57°C for 30s, 72°C for 1 min; final 72°C for 5 min.
  • the products are separated by capillary electrophoresis using ABI 3500 gene sequencer to obtain the genotype of the detected individual, and the interpretation will be provided by professionals.
  • FIG. 1A is an example of the sequencing result of the template strand, the underline corresponds to the five-base indel of the coding strand at rs3036297;
  • FIG. 1B is a schematic diagram of electrophoresis of the products obtained by using the PCR amplification system of the present invention for 14 DNA samples from different individuals, 1, 3, 4, 6, and 11 were homozygotes for deletion, 2 and 13 were homozygotes for insertion, and the rest were heterozygotes.

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Abstract

公开了一种基于HSPA1B基因插入缺失多态性位点的心源性猝死易感性检测试剂盒。试剂盒中包含的特异性引物对是针对HSPA1B基因上的rs3036297号插入缺失位点而设计，能特异性扩增出包含该位点的DNA片段并通过检测不同长度片段在毛细管电泳中的迁移率来识别不同基因型，结合病例对照研究发现，可认为被检测DNA的HSPA1B基因上的rs3036297号插入缺失位点携带有缺失型等位基因者为SCD易感型。该技术通过检测个体的HSPA1B基因上的rs3036297号插入缺失位点的基因型，可以起到预测个体SCD的易感性的作用。证实位于HSPA1B基因的3'UTR中的一个五碱基（AAGTT）插入缺失多态（rs3036297）与患SCD风险性存在显著性关联；该多态在亚洲人群中的频率分布为插入型0.655，缺失型0.355。

Description

基于HSPA1B基因插入缺失多态性位点的心源性猝死易感性检测试剂盒 技术领域
本发明涉及一种基于HSPA1B基因插入缺失多态性位点的心源性猝死易感性检测试剂盒，属于检测技术领域。
背景技术
心源性猝死(sudden cardiac death，SCD)是指由心脏原因引起的突发性的非预料死亡，表现为短期内发生的突发意识丧失及循环、呼吸骤停。“短期”规定为有目击者情况下小于1小时内，无目击者时则为24小时。流行病学表明，中国每年每10万人中有40.7人死于SCD，考虑到我国庞大的人口基数，SCD病例数量十分庞大。以往大量研究表明，SCD的死因多为冠状动脉粥样硬化性心脏病或致命性心律失常。前者多见于高龄人群，后者则多见于年轻人。考虑到死后的尸体解剖和组织学检查难以找到准确的死因，为了能准确诊断SCD，揭开SCD发生的分子机制、寻找SCD的遗传标记迫在眉睫。
过去针对SCD诊断领域的研究主要集中于对重要蛋白编码基因的编码区突变与猝死的关联性分析，然而相关的突变不仅数量有限，普通群体极低的基因频率难以完全解释相对而言较高的猝死发生率。随着全基因组关联研究及二代测序技术的发展，越来越多的遗传标记被发现参与SCD的调控。SCD遗传标记的识别能够进一步深入了解其潜在机制，优化SCD的风险分层，并为分子诊断和预防提供强有力的理论依据。考虑到3'UTR对基因表达起到重要的调控作用，我们把目光投向了这片区域内的遗传多态，通过病例对照研究分析相关基因中3'UTR的遗传多态性与SCD的易感性之间的关联，为建立可用于SCD 风险评估的基因多态性检测体系提供了可能。
热休克70家族成员1B(heat shock protein family A(Hsp70)member 1B,HSPA1B)基因位于人类组织相容性复合体III区域，同时因其基因序列的高度保守及编码产物的相似性，细胞外的HSPA1B蛋白被体内的免疫系统识别并引起免疫应答，启动或加剧动脉粥样硬化过程，是心源性猝死的潜在危险因素。
现有技术中，并没有对rs3036297插入缺失多态与SCD相关性的研究报道，也没有通过检测HSPA1B基因3'UTR的插入缺失多态位点来预测SCD的易感性的相关报道。
发明内容
为解决上述问题，本发明基于HSPA1B基因上的rs3036297号插入缺失位点的多态性可用于评估个体患SCD的易感性，提供一种检测SCD易感性的试剂盒。
本发明的第一个目的是提供一种基于HSPA1B基因插入缺失多态性位点的心源性猝死易感性检测试剂盒，所述的试剂盒用于检测HSPA1B基因的rs3036297位点的基因型。
进一步地，所述的心源性猝死易感性检测试剂盒包括用于检测HSPA1B基因的rs3036297位点的特异性引物对，以及用于PCR扩增和毛细管电泳的组件。
进一步地，所述特异性引物对包括有义引物和反义引物，有义引物的核苷酸序列如SEQ ID NO.1所示，反义引物的核苷酸序列如SEQ ID NO.2所示：
SEQ ID No.1：5’-ACTGTTGGGACTCAAGGACT-3’；
SEQ ID No.2：5’-TACAAAAATAATGAAGCCAGCTAAT-3’。
进一步地，所述的有义引物的核苷酸序列的Tm值为58℃。
进一步地，所述的反义引物的核苷酸序列的Tm值为56℃。
进一步地，所述的特异性引物对的5’端设有荧光标记。
本发明中，荧光标记的特异性引物是针对HSPA1B基因上的rs3036297号插入缺失位点而设计，能特异性扩增出包含该插入缺失的片段，通过荧光标记技术将荧光染料标记在寡核苷酸引物的5’端，PCR扩增后产物的一条链均携带标记引物的荧光染料。实验原理本领域技术人员能理解，特异性引物对可用常规的合成技术合成。优选的技术方案中，所述检测SCD的试剂盒包含有SEQ ID No.1和SEQ ID No.2所示序列的引物对，但本发明的引物不限于这对引物。
进一步地，所述的PCR扩增和毛细管电泳的组件包括：Taq DNA聚合酶、dNTP混合液、MgCl 2溶液、PCR反应缓冲液和去离子水。
进一步地，PCR扩增产物通过毛细管电泳对基因型进行分析。
本发明的第二个目的是提供所述的心源性猝死易感性检测试剂盒在检测HSPA1B基因的rs3036297位点基因型中的应用。
进一步地，所述的应用是采用荧光标记PCR扩增获得PCR扩增产物，扩增产物通过毛细管电分型法进行基因型分析。
通过分子生物学研究发现HSPA1B基因的3'UTR中的一个插入缺失多态rs3036297的不同等位基因型可影响HSPA1B基因转录活性，携带插入型等位基因的个体HSPA1B的转录活性相对较低；此外，通过一定规模人群的SCD病例对照研究发现，该插入缺失多态的插入型等位基因与SCD发生呈负相关，即使在调整年龄、性别等因素后，这种相关性仍然存在。因此认为这个插入缺失多态可用于评估个体患SCD的易感性。
本发明的有益效果：
本发明的试剂盒中包含的特异性引物对是针对HSPA1B基因上的rs3036297号插入缺失位点而设计，能特异性扩增出包含该位点的DNA片段并通过检测不同长度片段在毛细管电泳中的迁移率来识别不同基因型，结合我们的病例对照研究发现，可认为被检测DNA的HSPA1B基因上的rs3036297号插入缺失位点携带有缺失型等位基因者为SCD易感型。因此，该技术通过检测个 体的HSPA1B基因上的rs3036297号插入缺失位点的基因型，可以起到预测个体SCD的易感性的作用。本课题组首次证实位于HSPA1B基因的3'UTR中的一个五碱基(AAGTT)插入缺失多态(rs3036297)与患SCD风险性存在显著性关联；该多态在亚洲人群中的频率分布为插入型0.655，缺失型0.355。
附图说明
图1为基因测序图示和SDS-PAGE凝胶电泳分型图示。
具体实施方式
下面结合具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实施例1：检测试剂盒的使用
步骤1：DNA模板的抽取
使用血液基因组DNA提取系统(非离心柱型)提取外周血的基因组DNA.
步骤2：PCR反应-目的片段的复制
使用可检测SCD易感性的PCR检测试剂盒，其中，含有下列引物：
SEQ ID No.1：5’-ACTGTTGGGACTCAAGGACT-3’，Tm值为58℃；
SEQ ID No.2：5’-TACAAAAATAATGAAGCCAGCTAAT-3’，Tm值为56℃；
该引物对可特异性地扩增HSPA1B基因中包含rs3036297号插入缺失位点多态性的片段。
PCR反应体系总体积为10ul，中包括：1μl DNA模板，50μM特异性引物对两条各0.04μl，2.5U/μl Taq DNA聚合酶0.08μl；2.5mM dNTP混合液0.2μl；25mM MgCl 2溶液0.6μl；10×PCR反应缓冲液1μl；去离子水补足；在Eppendorf Mastercycler nexus PCR扩增仪上进行反应，反应条件是：94℃3min；再进行 30个PCR循环：94℃30s，57℃30s，72℃1min；最后72℃5min。
步骤3：插入缺失基因型分析
扩增结束后产物采用ABI 3500基因测序仪进行毛细管电泳分离从而得到检测个体的基因型，并由专业人员提供解释。
对照组与SCD病例组在该位点的基因频率差异与患病风险OR值见表1。
基因测序图示和SDS-PAGE凝胶电泳分型图示见图1。其中图1A为模板链测序结果示例，下划线处对应编码链在rs3036297处的五碱基插入缺失；图1B为对14个来自不同个体的DNA样本使用本发明的PCR扩增体系得到产物电泳示意图，1、3、4、6、11为缺失型纯合子，2、13为插入型纯合子，其余为杂合子。
表1多态位点rs3036297和SCD风险性之间的关联
Figure PCTCN2020122328-appb-000001
注： a根据年龄性别校正.OR:似然比(风险率)；CI：置信区间
如表1所示，在共显性模型中，在95％置信区间内，相比于基因型为缺失/缺失型的个体，插入/插入型的个体发生SCD的风险减少了69％，插入/缺失型的个体发生SCD的风险则减少了45％；显性模型中，相比于基因型为缺失/缺失型的个体，基因型为插入/插入或插入/缺失型的个体发生SCD的风险减少了49％；最后，加性模型分析显示，相比于携带插入型等位基因个体，携带缺失型等位基因的个体发生SCD的风险减少了42％。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。

Claims (10)

  1. 一种基于HSPA1B基因插入缺失多态性位点的心源性猝死易感性检测试剂盒，其特征在于，所述的试剂盒用于检测HSPA1B基因的rs3036297位点的基因型。
  2. 根据权利要求1所述的心源性猝死易感性检测试剂盒，其特征在于，所述的心源性猝死易感性检测试剂盒包括用于检测HSPA1B基因的rs3036297位点的特异性引物对，以及用于PCR扩增和毛细管电泳的组件。
  3. 根据权利要求2所述的心源性猝死易感性检测试剂盒，其特征在于，所述特异性引物对包括有义引物和反义引物，有义引物的核苷酸序列如SEQ ID NO.1所示，反义引物的核苷酸序列如SEQ ID NO.2所示：
    SEQ ID No.1：5’-ACTGTTGGGACTCAAGGACT-3’；
    SEQ ID No.2：5’-TACAAAAATAATGAAGCCAGCTAAT-3’。
  4. 根据权利要求3所述的心源性猝死易感性检测试剂盒，其特征在于，所述的有义引物的核苷酸序列的Tm值为58℃，反义引物的核苷酸序列的Tm值为56℃。
  5. 根据权利要求2所述的心源性猝死易感性检测试剂盒，其特征在于，所述的特异性引物对的5’端设有荧光标记。
  6. 根据权利要求2所述的心源性猝死易感性检测试剂盒，其特征在于，所述的PCR扩增和毛细管电泳的组件包括：Taq DNA聚合酶、dNTP混合液、MgCl 2溶液、PCR反应缓冲液和去离子水。
  7. 根据权利要求2所述的心源性猝死易感性检测试剂盒，其特征在于，所述的心源性猝死易感性检测试剂盒具体包括50μM特异性引物对，2.5U/μl Taq DNA聚合酶；2.5mM dNTP混合液；25 mM MgCl 2溶液；10×PCR反应缓冲液；去离子水。
  8. 根据权利要求2所述的心源性猝死易感性检测试剂盒，其特征在于，PCR扩增产物通过毛细管电泳对基因型进行分析。
  9. 权利要求1-8任一项所述的心源性猝死易感性检测试剂盒在检测HSPA1B基因的rs3036297位点基因型中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述的应用是采用荧光标记PCR扩增获得PCR扩增产物，扩增产物通过毛细管电分型法进行基因型分析。
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