CN116411062A - 基于78个snp位点评估阿达木单抗治疗银屑病有效性的试剂盒 - Google Patents
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Abstract
本发明公开了一种阿达木单抗药物作用的78个SNP位点，所提供的78个SNP位点更加适合亚洲人群，对亚洲人群具有指导意义；还提供了一种评估阿达木单抗在治疗银屑病有效性中的应用，当患者携带78个SNP位点中的一个或多个变异位点时，则说明其使用阿达木单抗有效；还提供了一种基于78个SNP位点评估阿达木单抗治疗银屑病有效性的检测试剂盒，含有用于检测银屑病患者是否携带78个SNP位点的成套单链DNA，成套单链DNA由序列表中SEQ ID No.1～234条单链组成。
Description
技术领域
本发明涉及生物技术领域，更具体地，涉及一种基于78个SNP位点评估阿达木单抗治疗银屑病有效性的试剂盒。
背景技术
银屑病是一种多基因遗传性疾病，为治疗银屑病，市场上出现了阿达木单抗药物，阿达木单抗是TNF-α的全人源IgG1抗体，阿达木单抗通过与游离的TNF-α结合，阻断TNF-α与细胞表面TNF-α受体的相互作用，从而调控TNF-α诱导或调节应答。
阿达木单抗在治疗银屑病的过程中，携带不同突变基因的患者表现出不同的应答率。为实现精准治疗，让患者在治疗中少走弯路，进而减轻患者的经济负担，本申请通过公共数据库查找，发现当前有多篇文章分析了携带不同突变基因的患者对阿达木单抗药物的应答率，但是都缺乏系统性的评估，对银屑病患者的指导意义较低，且这些研究主要针对的是欧美人群，对亚洲人群尚未有明确的指导。
发明内容
本发明的一个目的是解决至少上述问题，并提供至少后面将说明的优点。
本发明还有一个目的是提供一种阿达木单抗作用的78个SNP位点，所提供的78个SNP位点更加适合亚洲人群，对亚洲人群具有指导意义；
还提供了一种阿达木单抗作用的78个SNP位点在评估阿达木单抗在治疗银屑病有效性中的应用，当患者携带78个SNP位点中的一个或多个变异位点时，则说明其使用阿达木单抗有效；
还提供了一种基于78个SNP位点评估阿达木单抗治疗银屑病有效性的试剂盒，含有用于检测银屑病患者是否携带78个SNP位点的成套单链DNA，成套单链DNA由序列表中SEQID No.1～234条单链组成。
为了实现根据本发明的这些目的和其它优点，提供一种阿达木单抗作用的78个SNP位点，78个SNP位点包括：rs2071303位点、rs28371759位点、rs1801274位点、rs3761847位点、rs1800795位点、rs352139位点、rs2145623位点、rs33980500位点、rs4810485位点、rs3794271位点、rs396991位点、rs10903129位点、rs2546890位点、rs510432位点、rs1295686位点、rs885814位点、rs1043879位点、rs3735451位点、rs10210302位点、rs17301249位点、rs6427528位点、rs548234位点、rs27524位点、rs1061622位点、rs2736340位点、rs17716942位点、rs6920220位点、rs394581位点、rs9373839位点、rs2476601位点、rs1061624位点、rs2734440位点、rs6691117位点、rs10499194位点、rs2246709位点、rs35599367位点、rs2812378位点、rs1799852位点、rs7527798位点、rs11586238位点、rs11209026位点、rs3218253位点、rs767455位点、rs240993位点、rs20575位点、rs10512734位点、rs8049439位点、rs2104286位点、rs12081765位点、rs645544位点、rs13393173位点、rs3087243位点、rs12721622位点、rs2228145位点、rs1350948位点、rs1267067位点、rs7234029位点、rs4750316位点、rs7927894位点、rs2302489位点、rs1980422位点、rs7574865位点、rs9828223位点、rs1126535位点、rs10919563位点、rs3213094位点、rs9304742位点、rs2230926位点、rs610604位点rs6822844位点、rs13031237位点、rs3814057位点、rs6661932位点、rs4646437位点、rs2740574位点、rs1130864位点、rs12777960位点、rs25648位点。
一种阿达木单抗作用的78个SNP位点在评估阿达木单抗在治疗银屑病有效性中的应用。
一种基于78个SNP位点评估阿达木单抗治疗银屑病有效性的试剂盒，用于检测银屑病患者是否携带78个SNP位点的物质为含有成套单链DNA的试剂盒，其中，成套单链DNA由序列表中SEQ ID No.1～234条单链组成。
一种基于78个SNP位点评估阿达木单抗治疗银屑病有效性的试剂盒的使用方法，包括以下具体步骤：
S1、从银屑病患者的外周血中提取DNA，获得待测DNA；
S2、对待测DNA采用PCR技术进行扩增，获得PCR扩增产物；
S3、将PCR产物使用碱性磷酸酶处理，获得处理后的PCR产物；
S4、将获得的处理后的PCR产物进行单碱基延伸，获得延伸后产物；
S5、将获得的延伸产物进行纯化，获得纯化产物；
S6、将纯化产物放置在检测仪上进行检测银屑病患者是否携带一个或多个阿达木单抗作用的78个SNP位点。
优选的是，步骤S6中的具体检测过程为，先将纯化产物放置在SpectroCHIP芯片上，将SpectroCHIP芯片使用MALDI-TOF进行分析，检测结果使用TYPER软件分型并输出结果。
优选的是，步骤S1中将采取的DNA的浓度调整至50ng/μL，-20℃存储备用。
本发明至少包括以下有益效果：
第一、提供了一种阿达木单抗作用的78个SNP位点，所提供的78个SNP位点更加适合亚洲人群，对亚洲人群具有指导意义；
第二、提供了一种阿达木单抗作用的78个SNP位点在评估阿达木单抗在治疗银屑病有效性中的应用，当患者携带78个SNP位点中的一个或多个变异位点时，则说明其使用阿达木单抗有效；
第三、提供了一种基于78个SNP位点评估阿达木单抗治疗银屑病有效性的试剂盒，含有用于检测银屑病患者是否携带78个SNP位点的成套单链DNA，成套单链DNA由序列表中SEQ ID No.1～234条单链组成。
本发明的其它优点、目标和特征将部分通过下面的说明体现，部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
具体实施方式
下面结合实施例对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
本发明提供了一种阿达木单抗作用的78个SNP位点，78个SNP位点包括：rs2071303位点、rs28371759位点、rs1801274位点、rs3761847位点、rs1800795位点、rs352139位点、rs2145623位点、rs33980500位点、rs4810485位点、rs3794271位点、rs396991位点、rs10903129位点、rs2546890位点、rs510432位点、rs1295686位点、rs885814位点、rs1043879位点、rs3735451位点、rs10210302位点、rs17301249位点、rs6427528位点、rs548234位点、rs27524位点、rs1061622位点、rs2736340位点、rs17716942位点、rs6920220位点、rs394581位点、rs9373839位点、rs2476601位点、rs1061624位点、rs2734440位点、rs6691117位点、rs10499194位点、rs2246709位点、rs35599367位点、rs2812378位点、rs1799852位点、rs7527798位点、rs11586238位点、rs11209026位点、rs3218253位点、rs767455位点、rs240993位点、rs20575位点、rs10512734位点、rs8049439位点、rs2104286位点、rs12081765位点、rs645544位点、rs13393173位点、rs3087243位点、rs12721622位点、rs2228145位点、rs1350948位点、rs1267067位点、rs7234029位点、rs4750316位点、rs7927894位点、rs2302489位点、rs1980422位点、rs7574865位点、rs9828223位点、rs1126535位点、rs10919563位点、rs3213094位点、rs9304742位点、rs2230926位点、rs610604位点rs6822844位点、rs13031237位点、rs3814057位点、rs6661932位点、rs4646437位点、rs2740574位点、rs1130864位点、rs12777960位点、rs25648位点。
上述的78个SNP位点对亚洲人群具有指导意义，其中，rs28371759位点、rs3735451位点、rs2246709位点、rs35599367位点、rs12721622位点、rs4646437位点、rs2740574位点为本发明找出的新的SNP位点，这些新的SNP位点更加适合亚洲人群。
本发明提供了一种阿达木单抗作用的78个SNP位点在评估阿达木单抗在治疗银屑病有效性中的应用，当患者携带78个SNP位点中的一个或多个变异位点时，则说明其使用阿达木单抗有效。
本发明提供了一种基于78个SNP位点评估阿达木单抗治疗银屑病有效性的试剂盒，用于检测银屑病患者是否携带78个SNP位点的物质为含有成套单链DNA的试剂盒，其中，成套单链DNA由序列表中SEQ ID No.1～234条单链组成，这234条单链包括用于扩增78个SNP位点基因片段的PCR引物对，以及特异性检测这78个SNP位点基因型的78条对应Sequenom MassARRAY单碱基延伸引物，具体如表1所示。
试剂盒的使用方法：
S1、从银屑病患者的身体上利用EDTA抗凝管采血2mL，利用商品化的试剂盒从采集的血液中提取基因组DNA，对于提取的DNA利用分光光度计定量、琼脂糖凝胶电泳质检DNA质量，质量合格的DNA将浓度调整到50ng/μL，-20℃存储备用，获得待测DNA；
S2、对待测DNA进行PCR扩增，其中，引物如表1所示，扩增技术在384孔板中进行，每个孔板中的液体总体积为5μL，每个孔板中含有20-50ng DNA、0.5pmol每条扩增引物、0.1μL的25mM dNTPs，PCR反应条件为：94℃4min；94℃20s，56℃30s，72℃1min，45个循环；72℃3min；4℃保持，获得PCR扩增产物；
S3、将PCR扩增产物用虾碱性磷酸酶(SAP)处理，去除反应体系中游离的dNTPs，SAP反应体系为7μL，其包括PCR产物5μL，SAP混合液2μL(SAP 0.5U，缓冲液0.17μL)。利用PCR仪器进行虾碱性磷酸酶处理，PCR反应条件：37℃40min，85℃5min，4℃维持，获得处理后的PCR产物；
S4、将获得的处理后的PCR产物进行单碱基延伸，反应体系的总体积为9μL，其包括处理后的PCR产物7μL，EXTEND Mix 2μL(引物0.94μL，iPLEX酶0.04μL，延伸混合物0.2μL)，PCR反应条件为：Ⅰ94℃30s；Ⅱ94℃5s；Ⅲ52℃5s；Ⅳ80℃5s；Ⅴgo toⅢ4more times；ⅥgotoⅡ39more times；Ⅶ72℃3min，4℃forever，获得延伸后产物；
S5、将Clean Resin树脂平铺到6mg的树脂板中，再将延伸产物放置在树脂板的孔内，向含有延伸产物的孔内加入16μL的水，最后加入干燥后的树脂到含有延伸产物的孔内，封膜，将树脂板低速垂直旋转30min，使孔内的树脂和延伸产物充分接触，然后离心使竖树脂沉入孔底部，得到的纯化后的纯化产物浮在上层；
S6、先将纯化产物放置在SpectroCHIP芯片上，将SpectroCHIP芯片使用MALDI-TOF进行分析，检测结果使用TYPER软件分型并输出结果。
<实施例>
1、利用本发明对19例中重度银屑病患者进行基因检测，这些患者的基因变异情况详见表1。
表1
注：ID为SNP位点，REF为参考基因组信息，PSA为银屑病患者编号，0为未发生SNP突变，1为发生SNP突变。
2、根据检测结果，上述患者分别检测处的突变位点数量如表2所示；
表2患者突变位点数量
3、我们对银屑病患者给予了阿达木单抗治疗的建议，给药方案为40mg皮下注射，每两周一次，分别在治疗前(PASI-0)，治疗3个月(PASI-3)，利用PSAI(银屑病面积与严重性指数)评分对银屑病患者的皮损进行评估，进而衡量阿达木单抗治疗银屑病的疗效，结果详见表3.银屑病患者治疗前后PASI评分。
银屑病疗效判定标准:按照银屑病皮损面积及严重程度指数(psoriasis areaand severity index，PASI)评分标准，记录治疗前后的PASI评分，根据PASI评分下降率进行疗效判定。PASI评分下降率＝(治疗前PASI评分-治疗后PASI评分)/治疗前PASI评分x100％。
表3.银屑病患者治疗前后PASI评分
通过分析银屑病患者在治疗三个月后的PASI评分下降率，我们发现这些患者的皮损均发生了好转(PASI评分降低)。
4、利用GWAS研究常用的ASA(Asian Screening Array)全基因组芯片对10,000例中国汉族人银屑病和10,000例对照人群进行了基因组DNA的测序分析，随后重点分析了与阿达木单抗相关的基因组变异位点，其中有差异的位点，见表4：中国汉族人银屑病阿达木相关基因组变异
表4中国汉族人银屑病阿达木相关基因组变异
注：CHR染色体号；BP物理位置；A1参考等位基因；Allele参考等为基因频率；F_A:Allere中前面碱基的频率；F_U:Allere中后面前面碱基的频率。
通过表4总结出：本发明中涉及的78SNP与中国汉族人银屑病的发生具有明显的相关性,P_value＜0.01。
5、从表1中可以看出，上述19名患者中具有关于rs28371759位点、rs3735451位点、rs2246709位点、rs35599367位点、rs12721622位点、rs4646437位点、rs2740574位点这七个位点的突变，为了进一步证明仅携带此7个突变位点的银屑病患者，在进行阿达木单抗治疗时也会具有很好的效果，做了如下实验：
通过检测大量的患有银屑病患者的基因，从中找到了具有这七个位点中的一个或多个位点突变的案例，见下表5银屑病患者基因分型：
表5银屑病患者基因分型
5、针对表5中的患者进行用药，治疗方法同实施例3，结果见表6：
表6银屑病患者治疗前后PASI评分
从表6可以看出，阿达木单抗对具有表4中展示的具有rs28371759位点、rs3735451位点、rs2246709位点、rs35599367位点、rs12721622位点、rs4646437位点、rs2740574位点中一个或多个位点突变的患者，具有良好的治疗效果。
尽管本发明的实施方案已公开如上，但其并不仅仅限于说明书和实施方式中所列运用，它完全可以被适用于各种适合本发明的领域，对于熟悉本领域的人员而言，可容易地实现另外的修改，因此在不背离权利要求及等同范围所限定的一般概念下，本发明并不限于特定的细节和这里示出与描述的图例。
Claims (1)
1.评估阿达木单抗治疗银屑病有效性的试剂盒，其特征在于，用于检测银屑病患者是否携带78个SNP位点的物质为含有成套单链DNA的试剂盒，其中，成套单链DNA由序列表中SEQ ID No.1～234条单链组成；
其中，所述SNP位点包括：rs28371759位点、rs3735451位点、rs2246709位点、rs35599367位点、rs12721622位点、rs4646437位点、rs2740574位点。
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