CN117110617A - 一组与慢阻肺频繁急性加重表型相关的标志物及其应用 - Google Patents
一组与慢阻肺频繁急性加重表型相关的标志物及其应用 Download PDFInfo
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- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本发明公开了一组与慢性阻塞性肺病(chronicobstructivepulmonarydisease,慢阻肺)频繁急性加重表型相关的标志物及其应用。所述标志物包括间α‑胰蛋白酶抑制因子重链H3、淋巴管内皮透明质酸受体1、对氧磷酶1、丙氨酸乙醛酸转氨酶、免疫球蛋白κ可变区3D‑11、胞裂蛋白2、载脂蛋白F、多巴胺β‑羟化酶、肌肉肌酸激酶、FAM20C高尔基体相关分泌途径激酶或脂肪储存诱导跨膜蛋白1中任意一种或至少两种的组合。本发明挖掘全新的、可用于慢阻肺稳定期检出与鉴定频繁急性加重与非频繁急性加重表型患者人群的一组核酸/蛋白质生物标志物,能鉴别诊断慢阻肺两个不同表型患者人群,并进行精准治疗和早期预警。
Description
技术领域
本发明属于生物技术领域,涉及一组与慢阻肺频繁急性加重表型相关的标志物及其应用。
背景技术
慢阻肺是一种常见的、渐进性呼吸道气流受阻的重大慢性疾病。根据患者每年急性加重的发作频率,慢阻肺患者可分为两种临床表型人群,即频繁急性加重和非频繁急性加重。频繁急性加重是慢阻肺的一种预后更差的独特表型,与非频繁急性加重患者相比,呼吸道病变更重,肺功能恶化更快,住院风险更高,患者因缺氧导致的其它严重并发症,使得生活质量更差和家庭经济负荷更大。这一亚型状态意味着存在许多复杂的潜在因素,可调节慢阻肺不同亚型的病理生理过程,正是这些因素可以决定患者对慢阻肺反复急性发作的易感性,并导致慢阻肺病变的严重程度和预后转归。
目前慢阻肺频繁急性加重表型依靠临床评估,根据患者对先前治疗事件的回忆来预测,不仅耗时而且标准难以统一,尚缺少一个快速、便捷、统一、实用的诊断标准和检测手段,需要通过发现具有特异性、功能性的和简单易行、适用于临床的生物标志物来指导临床上对慢阻肺频繁急性加重患者的早期诊断、精准干预和个性化治疗,如CN114410772A公开了检测待测对象易感基因是否发生突变的物质在制备预测或辅助预测待测对象是否易感慢阻肺急性加重表型产品中的应用,所述易感基因为ITK,ROCK1,ADCY9,ITGA2B,PDGFRB,FGFR3,SERPINA3,ITPR1,CFTR,USP24,SAA1,TEK,SPTBN2,PLXNA4,SPTA1,PLG,MAPKAPK2,LAMA3,P4HB和/或MRC2基因。
综上所述,开发新型的、与慢阻肺频繁急性加重表型相关的标志物,丰富检测指标和手段,对于慢阻肺治疗领域具有重要意义。
发明内容
针对现有技术的不足和实际需求,本发明提供一组与慢阻肺频繁急性加重表型相关的标志物及其应用,挖掘新型的、高特异性和高灵敏性的核酸/蛋白质标志物,可用于检测与诊断慢阻肺频繁急性加重与非频繁急性加重患者。
为达上述目的,本发明采用以下技术方案:
第一方面,本发明提供一组与慢阻肺频繁急性加重表型相关的标志物,其特征在于,所述标志物包括间α-胰蛋白酶抑制因子重链H3(ITIH3)、淋巴管内皮透明质酸受体1(LYVE1)、对氧磷酶1(PON1)、丙氨酸乙醛酸转氨酶(AGXT)、免疫球蛋白κ可变区3D-11、胞裂蛋白2(SEPTIN2)、载脂蛋白F(APOF)、多巴胺β-羟化酶(DBH)、肌肉肌酸激酶(CKM)、FAM20C高尔基体相关分泌途径激酶(FAM20C)或脂肪储存诱导跨膜蛋白1(FITM1)中任意一种或至少两种的组合。
本发明中,间α-胰蛋白酶抑制因子重链H3,与透明质酸共价结合,对稳定细胞外基质起重要作用;淋巴管内皮透明质酸受体1,参与淋巴透明质酸的转运;对氧磷酶1,一种抗氧化酶,抑制脂多糖诱导的巨噬细胞炎性细胞因子的分泌和肺成纤维细胞的增殖;丙氨酸乙醛酸转氨酶,主要定位于过氧化物酶体,参与乙醛酸解毒;免疫球蛋白κ可变区3D-11,参与抗原识别;胞裂蛋白2,通过改变皮层肌动蛋白的表达,调节气道上皮屏障功能;载脂蛋白F,参与胆固醇的运输和/或酯化;多巴胺β-羟化酶,一种氧化还原酶,催化多巴胺向去甲肾上腺素转化;肌肉肌酸激酶,参与能量稳态的细胞质酶在能量需求波动较大的组织中,如骨骼肌的能量转导中起着重要作用;FAM20C高尔基体相关分泌途径激酶,在脂质稳态、伤口愈合和细胞迁移和粘附中发挥作用;脂肪储存诱导跨膜蛋白1参与肌肉发育。
本发明中,采用高灵敏、高通量蛋白组学检测方法,通过对慢阻肺频繁急性加重与慢阻肺非频繁急性加重两组患者血浆标本进行队列检测、统计学比较和生物信息学分析,捕获慢阻肺频繁急性加重与非频繁急性加重两组间、与各自疾病表型特征相关的血浆表达蛋白质47个。经过GO富集分析、KEGG信号通路富集分析和ROC曲线分析,又从其中挑选出11个AUC>0.7的蛋白质(包括间α-胰蛋白酶抑制因子重链H3、淋巴管内皮透明质酸受体1、对氧磷酶1、丙氨酸乙醛酸转氨酶、免疫球蛋白κ可变区3D-11、胞裂蛋白2、载脂蛋白F、多巴胺β-羟化酶、肌肉肌酸激酶、FAM20C高尔基体相关分泌途径激酶或脂肪储存诱导跨膜蛋白1),11个差异蛋白质的ROC分析结果显示AUC为0.985(95%CI:0.966~1.000),灵敏度为90.9%,特异性为100%。可在慢阻肺疾病稳定期用作于临床早期诊断/鉴别诊断频繁急性加重与非频繁急性加重表型患者人群的检测标志物,预警和干预慢阻肺频繁急性加重的发生,以及做好对慢阻肺频繁急性加重的预防和有效治疗。
第二方面,本发明提供如第一方面所述的与慢阻肺频繁急性加重表型相关的标志物和/或检测其的物质在制备预测或辅助预测慢阻肺频繁急性加重表型的产品中的应用。
第三方面,本发明提供一种预测或辅助预测慢阻肺频繁急性加重表型的产品,所述产品包括检测第一方面所述的与慢阻肺频繁急性加重表型相关的标志物的表达水平的试剂和/或设备。
第四方面,本发明提供如第一方面所述的与慢阻肺频繁急性加重表型相关的标志物在构建慢阻肺频繁急性加重表型预测模型或/和制备慢阻肺频繁急性加重表型预测装置中的应用。
第五方面,本发明提供一种慢阻肺频繁急性加重表型预测模型,所述预测模型用于执行包括:
输入第一方面所述的与慢阻肺频繁急性加重表型相关的标志物的表达水平,拟合二元logistic回归模型;
利用拟合的二元logistic回归模型,计算Nomogram结果,根据模型中各个蛋白质对结局变量的贡献程度,给每个蛋白质的表达水平进行赋分,然后再将各个评分相加得到总评分,最后通过总评分与结局事件发生概率之间的函数转换关系,从而计算出该患者是慢阻肺频繁急性加重表型的预测值,如图1所示。
本发明中,纳入11个筛选得到的蛋白:ITIH3+LYVE1+PON1+AGXT+IGKV3D+Septin-2+APOF+DBH+CKM+FAM20C+FITM1拟合的模型得到ROC曲线,AUC=0.985,具有较高的诊断预测效果。
第六方面,本发明提供一种慢阻肺频繁急性加重表型预测装置,所述装置包括检测单元和评估单元。
所述检测单元用于执行包括:
检测受试者的待测体液样品中第一方面所述的与慢阻肺频繁急性加重表型相关的标志物的表达水平。
所述评估单元用于执行包括:
将分析单元检测到的与慢阻肺频繁急性加重表型相关的标志物的表达水平输入第五方面所述的慢阻肺频繁急性加重表型预测模型中进行计算,并判断是否为慢阻肺稳定期频繁急性加重患者。
优选地,所述体液待测样品包括外周循环血、尿液、唾液、痰液、灌洗液、汗液或体液胞外囊泡中任意一种。
优选地,所述检测的方法包括蛋白质谱法、酶联免疫法或蛋白芯片法。
第七方面,本发明提供第一方面所述的与慢阻肺频繁急性加重表型相关的标志物作为靶点在筛选预防或治疗慢阻肺频繁急性加重表型的药物中的应用。
优选地,所述筛选包括基于候选药物使用前和使用后对所述与慢阻肺频繁急性加重表型相关的标志物的影响,从而确定候选药物是否可以用于预防或治疗慢阻肺频繁急性加重表型。
与现有技术相比,本发明具有以下有益效果:
本发明挖掘全新的、可用于慢阻肺稳定期检出与鉴定频繁急性加重与非频繁急性加重表型两组患者人群的生物标志物,能提高检测的特异性和准确性,ROC分析结果显示AUC为0.985(95%CI:0.966~1.000),灵敏度为90.9%,特异性为100%,能够用于临床诊断/鉴别诊断频繁急性加重与非频繁急性加重表型患者人群的检测标志物,预警和干预慢阻肺频繁急性加重的发生,以及做好对慢阻肺频繁急性加重的预防和有效治疗。
附图说明
图1为慢阻肺频繁急性加重组与非频繁急性加重组的诺曼图(列线图),通过给每个蛋白基因的表达水平一个评分,对每个患者,就可计算得到一个总分,再通过得分与结局发生概率之间的转换函数来计算每个患者的频繁急性发生的概率;
图2为慢阻肺频繁急性加重组与非频繁急性加重组差异蛋白质火山图,FC>1.2或<0.83和p值<0.05;
图3为慢阻肺频繁急性加重组与非频繁急性加重组差异蛋白质GO分析结果图;
图4为慢阻肺频繁急性加重组与非频繁急性加重组差异蛋白质KEEG分析结果图;
图5为预测慢阻肺频繁急性加重表型的差异蛋白质ROC曲线图;
图6为预测慢阻肺频繁急性加重表型的11个差异蛋白质联合ROC曲线图。
具体实施方式
为进一步阐述本发明所采取的技术手段及其效果,以下结合实施例和附图对本发明作进一步地说明。可以理解的是,此处所描述的具体实施方式仅仅用于解释本发明,而非对本发明的限定。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买获得的常规产品。
实施例1
分别采集慢阻肺34例频繁急性加重患者和42例非频繁急性加重患者的血浆,然后通过高通量蛋白组学方法对慢阻肺频繁急性加重患者血浆和慢阻肺非频繁急性加重患者血浆进行比较分析。
具体过程如下:
本研究纳入2017.3~2018.9于复旦大学附属中山医院门诊就诊的慢阻肺稳定期患者(入组前4周内无急性加重病史),根据既往急性加重史把患者分为频繁急性加重组和非频繁急性加重组。急性加重定义为呼吸道症状急性恶化,导致需要急诊或住院使用抗生素、全身激素治疗。频繁急性加重定义为每年至少发生2次急性加重或因为1次加重而导致住院治疗。研究者记录患者的人口统计学资料,吸烟史及生物燃料、职业暴露史,实验室检查,肺功能,并且采集患者的外周静脉血。所纳入的患者年龄≥40岁,并且有吸烟史(吸烟年数×每日吸烟包数)≥l0、生物燃料或职业暴露史。排除标准:1)3月内急性肺部疾病病史;2)其他慢性肺部疾病病史(如支气管扩张、肺间质纤维化);3)恶性肿瘤病史;4)妊娠及哺乳期患妇女。患者入组后进行静脉采血,采集约5mL血液至抗凝采血管中并尽快离心(4℃、3000rpm、10min),将上层血浆存放于-80℃冰箱。为了检测较低浓度的血浆蛋白,按照制造商的说明,使用去除人类14种高丰度蛋白质和结构蛋白质。胰蛋白酶消化蛋白质后,用高PH反相高效液相色谱法分离肽段。使用Q-Exactive质谱仪(Thermo)和Easy-nanoLC 1200系统进行数据依赖采集和数据独立采集分析。血浆样品的光谱库由Human UniProt蛋白数据库中的原始MS文件构建,并使用Proteome Discoverer(V2.1.0.81)进行分析。通过蛋白质相对定量分析,将光谱库和DIA的原始数据加载到Spectranaut Pulsar X软件中。使用t-检验后p值<0.05并且表达水平倍数变化>1.2或<0.83作为处理DIA数据的标准筛选出频繁急性加重组和非频繁急性加重组之间的差异蛋白质。
结果得到:两组患者的血浆蛋白质经过质谱分析共筛选出47个差异表达蛋白质。其中20个蛋白质呈表达上调,27个蛋白质呈表达下调(图2)。
实施例2
对实施例1筛选出47个差异表达蛋白质进行GO富集分析、KEGG信号通路富集分析和ROC曲线分析。
具体过程如下:使用Metascape(http://metascape.org)进行GO富集分析和KEGG信号通路分析。使用SPSS软件进行ROC曲线分析。
GO富集分析结果如图3所示,其中生物学过程主要富集在以下方面:中性粒细胞脱粒、细胞或亚细胞组分的运动和免疫反应。此外,细胞成分的变化与胞外囊泡、细胞外空间和细胞外区域有关。此外,分子功能的变化与蛋白质同型二聚化活性、核糖核酸酶活性和核酸内切酶活性有关。
KEGG信号通路富集分析结果如图4所示,其中差异蛋白主要参与补体和凝血级联反应、细菌侵袭上皮细胞以及精氨酸和脯氨酸代谢。
ROC曲线分析结果如图5所示,11个差异蛋白质的AUC>0.7,包括:间α-胰蛋白酶抑制因子重链H3、淋巴管内皮透明质酸受体1、对氧磷酶1、丙氨酸乙醛酸转氨酶、免疫球蛋白κ可变区3D-11、胞裂蛋白2、载脂蛋白F、多巴胺β-羟化酶、肌肉肌酸激酶、FAM20C高尔基体相关分泌途径激酶和脂肪储存诱导跨膜蛋白1。
组合这11个差异蛋白质的ROC分析结果显示AUC为0.985(95%CI:0.966~1.000),灵敏度为90.9%,特异性为100%(图6),表明使用特定标志物组合能够进一步提高检测灵敏度和特异性。
实施例3
采用酶联免疫技术对部分血浆差异蛋白质进行逐个检测确定检测到的血浆差异蛋白质的浓度变化。
具体过程包括:
1)按照说明书配制好标准品溶液、检测抗体、辣根过氧化物酶标记的链霉亲和素以及洗液;
2)根据标准品数量和待测样品数量准备需要的板条数,先用300μL/孔洗液浸泡酶标板;
3)依次加入100μL血浆样品和提前配制好的各个浓度的标准品,再加入50μL检测抗体,使用封板膜封板,震荡混匀,25℃孵育90min;
5)弃去孔板内液体,每孔加入300μL洗液,等待1min后弃去洗液,用力在吸水纸上拍干,重复4次;
6)每孔加入100μL辣根过氧化物酶标记的链霉亲和素,使用新的封板膜封板,25℃震荡孵育30min;
7)弃去孔板内液体,每孔加入300μL洗液,等待1min后弃去洗液,用力在吸水纸上拍干,重复4次;
8)每孔加入100μL显色剂,25℃避光孵育20min;
9)每孔加入100μL终止液,充分混匀;
10)在酶标仪上测定OD450nm值;
11)Excel绘制标准曲线,计算血浆差异蛋白质的浓度。
慢阻肺频繁急性加重与非频繁急性加重患者的血浆差异蛋白质列表见表1。
表1慢阻肺频繁急性加重与非频繁急性加重患者血浆差异蛋白质
综上所述,本发明挖掘全新的、可用于慢阻肺稳定期检出与鉴定频繁急性加重与非频繁急性加重表型患者人群的核酸/蛋白质生物标志物,能提高检测的特异性、灵敏性和准确性,与现有的慢阻肺相关诊断与鉴别诊断检测相比,基于本发明标志物的检测所具备的诊疗特异性、监控预警性更高。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一组与慢阻肺频繁急性加重表型相关的标志物,其特征在于,所述标志物包括间α-胰蛋白酶抑制因子重链H3、淋巴管内皮透明质酸受体1、对氧磷酶1、丙氨酸乙醛酸转氨酶、免疫球蛋白κ可变区3D-11、胞裂蛋白2、载脂蛋白F、多巴胺β-羟化酶、肌肉肌酸激酶、FAM20C高尔基体相关分泌途径激酶或脂肪储存诱导跨膜蛋白1中任意一种或至少两种的组合。
2.如权利要求1所述的与慢阻肺频繁急性加重表型相关的标志物和/或检测其的物质在制备预测或辅助预测慢阻肺频繁急性加重表型的产品中的应用。
3.一组预测或辅助预测慢阻肺频繁急性加重表型的产品,其特征在于,所述产品包括检测权利要求1所述的与慢阻肺频繁急性加重表型相关的标志物的表达水平的试剂和/或设备。
4.如权利要求1所述的与慢阻肺频繁急性加重表型相关的标志物在构建慢阻肺频繁急性加重表型预测模型和/或制备慢阻肺频繁急性加重表型预测装置中的应用。
5.一种慢阻肺频繁急性加重表型预测模型,其特征在于,所述预测模型用于执行包括:
输入权利要求1所述的与慢阻肺频繁急性加重病相关的标志物的表达水平,拟合二元logistic回归模型;
利用拟合的二元logistic回归模型,计算Nomogram结果,根据模型中各个蛋白质对结局变量的贡献程度,给每个蛋白质的表达水平进行赋分,然后再将各个评分相加得到总评分,最后通过总评分与结局事件发生概率之间的函数转换关系,计算出受试者是慢阻肺频繁急性加重表型的预测值。
6.一种慢阻肺频繁急性加重表型预测装置,其特征在于,所述装置包括检测单元和评估单元;
所述检测单元用于执行包括:
检测受试者的待测体液样品中权利要求1所述的与慢阻肺频繁急性加重表型相关的标志物的表达水平;
所述评估单元用于执行包括:
将分析单元检测到的与慢阻肺频繁急性加重表型相关的标志物的表达水平输入权利要求5所述的慢阻肺频繁急性加重表型预测模型中进行计算,并判断是否为慢阻肺频繁急性加重患者。
7.根据权利要求6所述的慢阻肺频繁急性加重表型预测装置,其特征在于,所述待测体液样品包括外周循环血、尿液、唾液、痰液、灌洗液、汗液或体液胞外囊泡中的任意一种。
8.根据权利要求6或7所述的慢阻肺频繁急性加重表型预测装置,其特征在于,所述检测的方法包括蛋白质谱法、酶联免疫法或蛋白芯片法。
9.权利要求1所述的与慢阻肺频繁急性加重表型相关的标志物作为靶点可在筛选预防或治疗慢阻肺频繁急性加重表型药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述筛选包括基于候选药物使用前和使用后对所述与慢阻肺频繁急性加重表型相关标志物的影响,从而确定候选药物是否可以用于预防或治疗慢阻肺频繁急性加重表型。
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