CN117143996B - Brd3基因多态性对抗血栓药物治疗预测的生物标志物作用 - Google Patents
Brd3基因多态性对抗血栓药物治疗预测的生物标志物作用 Download PDFInfo
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Abstract
本发明属于生物技术领域、医药领域,具体涉及BRD3基因多态性对抗血栓药物治疗预测的生物标志物作用。具体提供了rs467387的检测试剂在制备预测抗血栓药物疗效、预测抗血栓药物血药浓度的产品中的应用。经健康人群验证,rs467387 AA基因型的患者服药后AUC和抗FXa活性高于GA和AA基因型的患者。
Description
技术领域
本发明属于生物技术领域、医药领域,具体涉及BRD3基因多态性对抗血栓药物治疗预测的生物标志物作用。
背景技术
血栓的形成是心肌梗死、卒中、深静脉血栓、肺栓塞等心血管疾病的重要致病因素,抗血栓治疗一直是这类疾病抢救措施及预防策略的核心,其中抗凝血是抗血栓治疗的重要方法之一。利伐沙班是全球第一个高选择性直接抑制因子Xa的口服抗凝药,Xa因子是外源性和内源性凝血途径的交汇点,是凝血过程中的关键点。该药即高选择性、直接抑制Xa因子活性,从而抑制凝血酶的生成和血栓的形成。与需要皮下给药的低分子肝素和戊达肝素以及需要定期监测国际标准化比值的维生素K拮抗剂相比,利伐沙班使用相对容易。
利伐沙班在大范围的个体(性别、年龄、种族、体重)中具有可预测的药代动力学特性。基于年龄、女性和较高的CHA2DS2-VASc评分,卒中和/或缺血性卒中风险较高的患者更有可能出现剂量不足,利伐沙班在抗凝治疗方面存在差异。但目前对于影响抗血栓其药效(PD)和药代动力学(PK)的遗传多态性研究较少。
溴结构域(Bromodomain,BRD)是一类进化高度保守、能够识别并结合组蛋白乙酰化赖氨酸残基的蛋白结构域,由大约110个氨基酸形成的四条反相平行的α螺旋(αZ、αA、αB、αC)和两条疏水环(ZA和BC)组成。BET家族蛋白包括BRD2(bromodomain-containingprotein 2)、BRD3、BRD4以及睾丸特异性的BRDT(Testis-specific bromodomain-containing protein),其结构具有相似性,包括N端的两个串联溴结构域(BD1和BD2)和一个超末端结构域(ET)。
在心血管疾病方面,已发现BET在生理和病理状态下均控制细胞分化、细胞身份和细胞状态转变。抑制BET可减少动脉粥样硬化、血管生成、内膜增生、肺动脉高压和心脏肥大。治疗动脉粥样硬化和2型糖尿病的BRD4选择性抑制剂阿帕他隆(RVX-208)已被FDA认定为突破性疗法。但目前关于BRD3与抗血栓治疗的相关性研究数据较少。
发明内容
为了探索可能影响利伐沙班治疗效果的生物标志物,本发明进行了一项多中心研究,检测药代动力学(PK)和药效学(PD)参数,并进行全外显子组测序和关联分析。研究结果发现,含溴结构域蛋白3(BRD3)在利伐沙班的PK和PD中均发挥重要作用。训练集中,BRD3rs467387 AA基因型的AUC和3h时的抗FXa活性最大(p=0.027,0.010)。同样,验证集中也证实,BRD3 rs467387 AA基因型的AUC和3h时候的抗FXa活性高于GA和AA(p=0.004,0.015)。这说明A基因突变者在服用利伐沙班后吸收能好、抗凝活性更高。
第一方面,本发明提供了rs467387的检测试剂在制备预测抗血栓药物疗效、预测抗血栓药物血药浓度的产品中的应用。
优选地,所述抗血栓药物包括溶栓药、抗凝药、抗血小板药,
具体地,所述溶栓药包括尿激酶、阿替普酶、瑞替普酶或链激酶,
具体地,所述抗凝药包括肝素、华法林、阿加曲班、磺达肝癸钠、利伐沙班、阿哌沙班、艾多沙班或达比加群酯,
具体地,所述抗血小板药包括血栓素A2抑制剂、二磷酸腺苷P2Y12受体拮抗剂、凝血酶受体拮抗剂、5-羟色胺受体拮抗剂、血小板糖蛋白、磷酸二酯酶抑制剂。
优选地,所述抗血栓药物是利伐沙班。
优选地,所述血栓包括白色血栓、混合血栓、红色血栓、透明血栓,所述白色血栓包括延续性血栓,所述混合血栓包括红细胞为主的血栓、球形血栓或层状血栓。
在本发明中,针对所述rs467387所做检测的样本包括获自或衍生自目标受试者的组合物,其包含有待例如基于物理、生物化学、化学和/或生理学特征表征和/或鉴定的细胞实体和/或其他分子实体。该样本可以获自受试者的血液和生物来源的其他流体样本及组织样本,如活检组织样本或从其衍生的组织培养物或细胞。组织样本的来源可以是实体组织,如来自新鲜、冷冻和/或保藏的器官或组织样本、活检组织或吸出物;血液或任意血液组分;体液;来自个体妊娠或发育的任何时间的细胞;或血浆。术语样本包括在其获得后以任何方式处理过的生物样本,如经试剂处理、稳定化、或针对某些成分(如蛋白质或多核苷酸)富集、或包埋在用于切片目的的半固体或固体基质中。
进一步,所述样本包括但不限于:血液、血清、血浆、组织、血液来源的细胞、淋巴液、滑膜液、脑脊髓液、胸膜液、支气管灌洗、痰、腹腔液、膀胱冲洗液、分泌物(例如,乳腺分泌物)、口腔冲洗液、拭子(例如,口腔拭子)、触碰准备物、细针穿刺物、细胞提取物及其组合。
在本发明的具体实施方案中,所述样本优选为受试者来源的血液或组织,更优选为受试者来源的血液。
更具体地,所述检测是通过提取样本DNA后进行检测,所述提取DNA可以采用本领域技术人员所熟知的任何方式,也可以提取RNA后反转录得到DNA。
优选地,所述产品包括试剂盒、芯片、试纸、高通量测序、系统、设备、装置。
优选地,所述rs467387的检测试剂具体可以是指检测rs467387具体基因型的试剂,或者,所述rs467387的检测试剂也可以称为检测受试者是否在rs467387处发生A突变的试剂,当检测结果为A突变时,代表受试者在服用利伐沙班后吸收能好、抗凝活性更高。
优选地,所述rs467387的检测试剂包括以下方法中使用的试剂:TaqMan探针法、测序法、芯片法、飞行质谱仪(MALDI-TOFMS)检测、限制性片段长度多态性法(PCR-RFLP)、单链构象多态性法(PCR-SSCP)、等位基因特异性PCR(AS-PCR)、SNaPshot法、SNPlex法、变性高效液相色谱法(DHPLC)、变性梯度凝胶电泳法(DGGE)。
优选地,所述利用TaqMan探针法确定SNP的多态性或基因型所需的试剂和/或仪器包括TaqMan探针、PCR引物对、定量PCR仪、进行基因分型的模块、TaqMan探针法所需要的其他试剂中的至少一种。
优选地,所述芯片法中可以使用的芯片包括基于核酸杂交反应的芯片、基于单碱基延伸反应的芯片、基于等位基因特异性引物延伸反应的芯片、基于“一步法”反应的芯片、基于引物连接反应的芯片、基于限制性内切酶反应的芯片、基于蛋白DNA结合反应的芯片、基于荧光分子DNA结合反应的芯片中的至少一种。进一步,所述芯片也称为阵列,指包含连接的核酸或肽探针的固体支持物。阵列通常包含按照不同的已知位置连接至基底表面的多种不同的核酸或肽探针。
优选地,所述利用飞行质谱仪(MALDI-TOFMS)检测法确定SNP的多态性或基因型所需的试剂和/或仪器包括PCR引物对、基于单碱基延伸反应的延伸引物、磷酸酶、树脂、芯片、MALDI-TOF(matrix-assisted laser desorption/ionization–time of fligh,基质辅助激光解吸附电离飞行时间质谱)、Sequenom MassArray技术所需要的其他试剂和仪器中的至少一种。
优选地,所述测序法包括但不限于第一代测序、第二代测序、第三代测序。
优选地,所述第一代测序方法包括但不限于Sanger法、焦磷酸测序法、连接酶法。
优选地,所述第二代测序的应用包括靶向区域测序、全外显子测序、全基因组测序、线粒体DNA测序等。
本发明所述“第三代测序”是指单分子测序技术。DNA测序时,不需要经过PCR扩增,实现了对每一条DNA分子的单独测序。三代测序技术是未来主要发展方向,第三代测序技术应用包括但不限于在基因组测序、甲基化研究、突变鉴定(SNP检测)这三个方面上。
最优选地,所述测序法是全外显子组测序。
另一方面,本发明提供了一种预测抗血栓药物疗效的系统,所述系统包括根据rs467387的分型结果判断抗血栓药物疗效的计算装置(模块)。
具体地,所述药物疗效体现在患者服用药物后的血药浓度。更具体地体现在AUC(AUC0-t)、Anti-Xa活性;优选地,3h的Anti-Xa活性。
优选地,所述系统包括用于输入rs467387的分型结果的输入装置。
优选地,所述系统还可以包括用于输出预测结果的输出装置。
优选地,所述系统还可以包括rs467387的分型的检测装置。
优选地,所述系统还包括预测结果发送装置,所述预测结果发送装置可以将受试者的预测结果发送到受试者(患者)或医护人员可以查阅的信息通信终端装置。
另一方面,本发明提供了一种预测抗血栓药物疗效的计算机可读存储介质,所述计算机可读存储介质上存储有计算机程序,所述计算机程序被处理器执行时根据rs467387的分型结果判断抗血栓药物疗效。
优选地,可以采用一个或多个计算机可读的介质的任意组合。计算机可读介质可以是计算机可读信号介质或者计算机可读存储介质。计算机可读存储介质例如可以是但不限于电、磁、光、电磁、红外线、或半导体的系统、装置或器件,或者任意以上的组合。在本发明中,所述计算机可读存储介质可以是任何包含或存储程序的有形介质,该程序可以被指令执行系统、装置或者器件使用或者与其结合使用。
优选地,计算机可读存储介质的更具体的例子包括但不限于:具有一个或多个导线的电连接、便携式计算机磁盘、硬盘、随机存取存储器(RAM)、只读存储器(ROM)、可擦式可编程只读存储器(EPROM或闪存)、光纤、便携式紧凑磁盘只读存储器(CD-ROM)、光存储器件、磁存储器件,或者上述的任意合适的组合。
具体地,所述系统/计算机可读存储介质是用于区分不同级别的不同组件、元件、部件、部分或装配的一种方法。然而,如果其他词语可实现相同的目的,则可通过其他表达来替换所述词语。本领域所属技术领域的技术人员熟知,本发明可以实现为设备、方法或计算机程序产品。因此,本发明公开的内容可以具体实现为以下形式,即可以是完全的硬件、也可以是完全的软件(包括固件、驻留软件、微代码等),还可以是硬件和软件结合的形式。此外,在一些具体实施例中,本发明还可以实现为在一个或多个计算机可读介质中的计算机程序产品的形式,该计算机可读介质中包含计算机可读的程序代码。
附图说明
图1是本发明的研究设计。
图2是训练集中BRD3上的rs467387基因多态性对PD结果的影响。
图3是训练集中BRD3上的rs467387基因多态性对PK结果的影响。
图4是训练集中BRD3上的rs467387基因多态性对PK/PD结果预测的ROC曲线。
图5是验证集中BRD3上的rs467387基因多态性对PD结果的影响。
图6是验证集中BRD3上的rs467387基因多态性对PK结果的影响。
图7是验证集中BRD3上的rs467387基因多态性对PK/PD结果预测的ROC曲线。
具体实施方式
下面结合实施例对本发明做进一步的说明,以下所述,仅是对本发明的较佳实施例而已,并非对本发明做其他形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更为同等变化的等效实施例。凡是未脱离本发明方案内容,依据本发明的技术实质对以下实施例所做的任何简单修改或等同变化,均落在本发明的保护范围内。
研究人群及分组
研究设计如图1所示,本发明基于全国多中心的临床生物等效性试验,纳入18-45岁、身体质量指数(BMI)在18-26 kg/m2之间的中国健康受试者。受试者在空腹和餐后条件下接受单剂量的利伐沙班,包括10、15和20 mg。所有受试者均在利伐沙班给药48 h或72 h后出院。除利伐沙班15 mg剂量组和10 mg剂量组的年龄外,各剂量组健康受试者的人口统计学特征无差异(表1)。
表1、空腹和餐后服用10、15、20 mg利伐沙班健康受试者的人口学特征
所有健康受试者在研究开始前至少4周没有服用任何药物。受试者在服药前一天进入研究,他们被随机分配到测试剂组或参照组。服用10mg利伐沙班剂量组的为训练集,15mg和20mg剂量组的为验证集。
本发明在健康人群开展研究,与临床患者相比,健康受试者的基线数据干净,不受疾病、合并用药等因素的影响,有利于明确探索遗传因素对药物代谢的影响,为发现新靶点奠定数据基础。
通用方法
1、药代动力学(PK)
1.1 血样采集
PK参数来源于连续采血获得的利伐沙班血药浓度-时间曲线。给药前和给药后16-19个时间点(0.5、16、14、1.5、2、2.5、3、3.5、5、5、6、8、10、48h)采集静脉血(6mL)。在采血后的120min内,4度,3000g离心10min。药效学(PD)参数的检测采样时间分别为给药后0、3、8、12h。在2.7mL柠檬酸钠(3.2% v/v)试管中采集血液样本,在采样60分钟内,室温下2500g离心15min。血浆样本在取样后6个月内转移到-70℃低温保存,等待进行检测分析。
1.2 PK指标与检测
采用高效液相色谱串联质谱(HPLC-MS/MS)或液相色谱串联质谱(LC-MS/MS)检测利伐沙班浓度。PK参数采用标准的非房室法确定,使用Phoenix WinNonlin 7.0(PharsightCorporation,Sunnyvale,CA,USA)或电子化临床数据管理系统(DAS for EDC V5.0)(Medbanks,Beijing,China)。从数据中获得峰浓度(Cmax)、半衰期(t1/2)和达峰时间(tmax)。0-t h药时曲线下面积(AUC0-t)通过线性梯形规则计算。
2、药效学(PD)
2.1 血样采集
药效学(PD)参数的检测采样时间分别为给药后0、3、8、12 h。在2.7 mL柠檬酸钠(3.2% v/v)试管中采集血液样本,在采样60分钟内,室温下2500 g离心15min。血浆样本在取样后6个月内转移到-70℃低温保存,等待进行检测分析。
2.2 PD指标与检测
使用Sysmex ® CS-2100i全自动多参数止血分析仪(Sysmex,日本)检测PD参数(APTT、PT、抗FXa活性)。采用经验证的凝血法检测试剂盒(Thromborel-S ®和Actin ®,西门子医疗诊断产品有限公司,德国)测定PT和APTT。采用验证过的显色法抗FXa试剂盒(BIOPHEN DiXaI®,HYPHEN BioMed,Neuville sur Oise,France)检测抗FXa活性。检测开始前对利伐沙班进行校准和质控(BIOPHEN Rivaroxaban® Calibrator and Control,HYPHEN BioMed,Neuville sur Oise,France)。抗FXa活性的检测限为利伐沙班0-494 ng/mL。质控样本浓度为31 ng/mL。利伐沙班的精密度为相对标准偏差<6.44%,日内和日间平均准确度分别为112.12%和119.92%。
3、数据统计分析
所有的统计分析均使用SPSS软件(SPSS version 24.0,SPSS Inc.,Chicago,IL,USA)完成。连续变量和分类变量分别以平均值±标准差,频率和百分比表示。采用Pearson相关分析对变量间的相关性进行检验。P<0.05被认为有统计学意义。在Plink软件中采用加性模型对表型SNP进行关联分析,对连续变量采用线性回归模型。采用皮尔逊相关分析来检验变量之间的相关性。双侧p值<0.05被认为有统计学意义。
4、基因多态性分析
采用盐析法从外周血中提取基因组DNA,进行全外显子组测序。测序库是通过对KAPA库制备试剂盒(KAPA Biosystems Inc.,美国)的修改构建而成。使用Bioruptor(Diagenode,Lie'ge,Belgium)将1μg的基因组DNA剪切到平均200 bp的片段大小。片段用amprexp珠(Beckman Coulter Inc.,美国)纯化。测序库进行最小PCR循环,并使用量子比特2.0荧光计(Thermo Fisher Scientific,美国)进行定量。使用Roche NimbleGen SeqCapEZ外显子组扩增试剂盒V3(Roche NimbleGen Inc.,瑞士)将测序库合并为池进行溶液相杂交。捕获的测序库使用安捷伦2100生物分析仪(安捷伦科技公司,美国)进行分析,使用量子比特2.0荧光仪(Thermo Fisher Scientific,美国)测量DNA浓度,然后发送测序,使用HiSeq 3000平台(Illumina,Inc.,美国)生成2×150 bp的对端解读。基于质量控制后获得的高质量数据,采用PLINK 1.09中进行的主成分分析进行分层总体评估,剔除离群样本。采用差异基因的超几何分布检验来计算p值,并使用Benjamini-Hochberg多重检验来计算误检率。对芯片数据进行质量控制,将分型缺失率<10%,最小等位基因频率(Minor allelefrequency,MAF)>5%,Hardy-Weinberg平衡(Hardy-Weinberg equilibrium,HWE)检验P>10–6的SNP纳入进一步分析。
在366746个SNP中,525个SNPs缺失率>10%,2888183个SNPs MAF<5%,2842个SNPsHWE P<10–6,故被排除在最终分析之外。
实施例1、通过10mg利伐沙班使用人群中研究rs467387基因多态性的预测作用(训
练集)
在10mg利伐沙班使用人群进行数据统计分析发现,位于BRD3上的 rs467387基因多态性会影响利伐沙班的AUC0-t、3h的Anti-Xa活性;通过年龄、饮食等影响因素的校正后,发现不同基因型对AUC和Anti-Xa活性有显著影响,其对应ROC曲线面积分别为0.791和0.725(表2、图2~4)。
表2、rs467387基因多态性对10mg利伐沙班PK\PD指标的影响
实施例2、通过15mg和20mg利伐沙班使用人群中验证rs467387基因多态性的预测
作用(验证集)
表3、rs467387基因多态性对15mg和20mg利伐沙班PK/PD指标的影响
在15mg和20mg利伐沙班使用人群进行上述结果验证,分析发现,位于BRD3上的rs467387基因多态性依旧对利伐沙班的AUC0-t、3h的Anti-Xa活性有显著影响;同样,数据校正后的ROC曲线面积分别为0.712和0.709(表3、图5-7)。
Claims (4)
1.rs467387的检测试剂在制备预测抗血栓药物疗效、预测服用抗血栓药物后血药浓度的产品中的应用,所述抗血栓药物是利伐沙班。
2.如权利要求1所述应用,针对所述rs467387所做检测是针对血液进行的。
3.如权利要求1所述应用,所述rs467387的检测试剂包括以下方法中使用的试剂:TaqMan探针法、测序法、芯片法、飞行质谱仪检测、限制性片段长度多态性法、单链构象多态性法、等位基因特异性PCR、SNaPshot法、SNPlex法、变性高效液相色谱法或变性梯度凝胶电泳法。
4.如权利要求1所述应用,所述药物疗效体现在患者服用药物后的血药浓度。
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