CN113933434B - 系统性红斑狼疮的代谢标志物 - Google Patents
系统性红斑狼疮的代谢标志物 Download PDFInfo
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Abstract
本发明公开了系统性红斑狼疮的代谢标志物。本发明的第一方面,提供定量检测样本中以下至少一种代谢物的试剂在制备系统性红斑狼疮的诊断试剂盒中的应用:胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺。上述的代谢物与系统性红斑狼疮患者的细胞代谢异常、组织器官损伤相关,因此,可以通过对上述的标志物进行定量检测来判断受试者是否患有系统性红斑狼疮,能够高效区分SLE患者与健康人。
Description
技术领域
本申请涉及系统性红斑狼疮诊断技术领域,尤其是涉及系统性红斑狼疮的代谢标志物。
背景技术
系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种以产生大量自身抗体,引发全身性炎症反应,引起多组织器官损伤甚至死亡的自身免疫性疾病。SLE病情轻重交替,目前没有可以根治的药物,患者需要终身用药。因此,正确的临床诊断从而及早发现,并进行规范化治疗是缓解病情、控制疾病的重要手段。
然而,SLE常累及全身多个组织器官,导致患者临床表现异质性很高,临床诊断困难。最新的临床SLE分类诊断标准(2019EULAR/ACR SLE分类诊断标准)包括一项准入指标(Entry criteria)、三项免疫学指标(immunological domains)和七项临床表型指标(clinical domains)。患者需要经过多项检查才能进行诊断,包括实验室检查(如血常规、尿常规、肝功能、补体、抗核抗体以及脑脊液检查等)、影像学检查(如超声检查心包积液、肺动脉高压;CT检查肺间质病变等)、查体(包括头部、胸部、腹部、皮肤、神经意识、肌肉骨骼等)以及特殊检查(如肾穿刺活检、腰椎穿刺等)等。然而,该标准存在很多缺陷,在实际应用中对临床经验要求高,操作难度较大,耗时较长,且会给病人带来很大痛苦。
近年来,对SLE的基础研究有了较大的突破,发现了一些新的潜在的诊断标志物。然而这些研究样本量较小、研究不深入全面,导致假阳性率较高、特异性较低,缺乏临床转化意义。因此,发现并验证新的诊断生物标志物具有很大的临床意义。
发明内容
本申请旨在至少解决现有技术中存在的技术问题之一。为此,本申请提出一种具有良好的特异性的系统性红斑狼疮的代谢标志物,定量检测这些标志物的试剂能够用于准确地对系统性红斑狼疮进行诊断。
本申请的第一方面,提供定量检测样本中以下至少一种代谢物的试剂在制备系统性红斑狼疮的诊断试剂盒中的应用:胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺。
根据本申请实施例的应用,至少具有如下有益效果:
上述代谢物与系统性红斑狼疮患者的细胞代谢异常、组织器官损伤相关,因此,可以通过对上述的标志物进行定量检测来判断受试者是否患有系统性红斑狼疮,能够高效区分SLE患者与健康人。
在本申请的一些实施方式中,试剂定量检测其中至少两种、至少三种、至少四种或全部五种代谢物。
在本申请的一些实施方式中,样本为血清样本。
在本申请的一些实施方式中,试剂通过核磁共振法、色谱法、光谱法、质谱法中的至少一种方法定量检测代谢物。
在本申请的一些实施方式中,当胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺中的至少一种代谢物的水平上调时,可以诊断为患有系统性红斑狼疮。
本申请的第二方面,提供系统性红斑狼疮的诊断试剂盒,该诊断试剂盒包括定量检测标志物的试剂,标志物为以下代谢物中的至少一种:胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺。
在本申请的一些实施方式中,试剂定量检测其中至少两种、至少三种、至少四种或全部五种代谢物。
在本申请的一些实施方式中,试剂通过核磁共振法、色谱法、光谱法、质谱法中的至少一种方法检测样本中代谢物的水平。
本申请的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本申请的实践了解到。
附图说明
图1是本申请的实施例1中SLE患者脂代谢的信号通路分析结果。其中,A是代谢信号通路分析结果,B是代谢信号通路活性分析结果。
图2是本申请的实施例1中差异代谢物的分析结果的热图。
图3是本申请的实施例1中随机森林机器学习模型鉴定出的SLE诊断的生物标志物。其中,A是随机森林模型的工作流程;B中左侧是5个代谢物生物标志物在模型中的重要性排序,右侧是基于5个代谢物组合的ROC曲线;C是基于5个代谢物标志物的MDS plot结果。
图4是胆固醇(Cholesterol)、油酰胺(Oleamide)、棕榈油酰乙醇酰胺(Palmitoleoylethanolamide)、十八酰胺(Octadecanamide)和亚油酰胺(Linoleamide)5个代谢物分别绘制出的ROC曲线。
具体实施方式
以下将结合实施例对本申请的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本申请的目的、特征和效果。显然,所描述的实施例只是本申请的一部分实施例,而不是全部实施例,基于本申请的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本申请保护的范围。
下面详细描述本申请的实施例,描述的实施例是示例性的,仅用于解释本申请,而不能理解为对本申请的限制。
在本申请的描述中,若干的含义是一个以上,多个的含义是两个以上,大于、小于、超过等理解为不包括本数,以上、以下、以内等理解为包括本数。如果有描述到第一、第二只是用于区分技术特征为目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量或者隐含指明所指示的技术特征的先后关系。
本申请的描述中,参考术语“一个实施例”、“一些实施例”、“示意性实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本申请的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
实施例1
1.研究对象
收集SLE患者和健康对照志愿者的血清样本,SLE组中排除患有其他自身免疫性疾病的患者(如类风湿关节炎患者)、患有系统性代谢疾病的患者(如高血压、糖尿病患者)以及不符合2019EULAR/ACR SLE诊断标准的患者。其中,SLE组为121例,对照组为106例。
2.实验方法
2.1代谢物提取
移取100μL样品至EP管中,加入300μL甲醇(含内标1μg/mL),涡旋混匀30s,超声10min(冰水浴);-40℃静置1h后,将样品4℃,12000rpm离心15min;取上清于进样瓶中上机检测。所有样品另取等量上清混合成QC样品上机检测。
2.2上机检测
使用Agilent 1290(Agilent Technologies)超高效液相色谱仪,通过WatersACQUITY UPLC HSS T3(2.1mm×100mm,1.8μm)液相色谱柱对目标化合物进行色谱分离。液相色谱A相为水相,正离子模式含0.1%的甲酸,负离子模式含5mmol/L的乙酸铵;B相为乙腈。采用梯度洗脱:0~1.0min,1%B;1.0~8.0min,1%~99%B;8.0~10.0min,99%B;10.0~10.1min,99%~1%B;10.1~12min,1%B。流动相流速:0.5mL/min,柱温:35℃,样品盘温度:4℃,进样体积:2μL。
Thermo Q Exactive Orbitrap质谱仪能够在控制软件(Xcalibur,版本:4.0.27,Thermo)控制下进行一级、二级质谱数据采集。详细参数如下:Sheath gas flow rate:45Arb,Aux gas flow rate:15Arb,Capillary temperature:400℃,Full ms resolution:70000,MS/MS resolution:17500,Collision energy:20/40/60in NCE mode,SprayVoltage:4.0kV(positive)或-3.6kV(negative)。
2.3数据处理
使用ProteoWizard软件将质谱原始数据转成mzXML格式,使用自主编写的R程序包(内核为XCMS)进行峰识别、峰提取、峰对齐和积分等处理,然后与BiotreeDB(V2.1)自建二级质谱数据库匹配进行物质注释,算法打分的Cutoff值设为0.3。
3.实验结果
3.1血清代谢组学研究结果
共鉴定到366个代谢物,包括脂类、氨基酸类、糖类、维生素等。基于这些代谢物的表达水平,进一步分析代谢信号通路的变化,结果如图1的A所示,从图中可以看出,SLE患者具有与健康人明显不同的代谢活动,多条代谢信号通路在SLE患者中都发生了明显的变化。进一步分析代谢通路活性的变化,发现在SLE患者中脂代谢相关信号通路活性变化最大,包括初级胆汁酸合成以及鞘脂代谢活性增加,花生四烯酸代谢、固醇类激素代谢以及非饱和脂肪酸合成活性的降低,然而,其他代谢通路活性,如氨基酸代谢,则没有明显的变化,如图1的B所示。
对366个代谢物进行统计分析,共鉴定出76个发生显著变化的差异代谢物,如图2所示,其中大部分为脂类物质。同时,我们观察到脂肪酸肉碱在SLE患者中水平降低,如dodecanoylcarnitine、decanoylcarnitine、L-octanolycarnitine和cis-5-tetradecenoylcarnitine,以及游离脂肪酸水平的增加,表明脂肪酸线粒体氧化在SLE患者中受到抑制。此外,多个脂肪酸胺的表达水平显著增加,包括初级脂肪酸胺(primary fattyacid amide)和N-酰基乙醇胺(N-Acylethanolamines)。
3.2随机森林模型鉴定标志物结果
为了鉴定SLE诊断的可能生物标志物,基于76个差异表达的血清代谢物分别构建随机森林(random forest)机器学习模型,构建方法如图3的A所示。参考图3的B,最终训练得出的代谢物诊断模型中,5个差异代谢物被鉴定为潜在的生物标志物,依照其在模型中的重要性从大到小排列依次为胆固醇(Cholesterol)、油酰胺(Oleamide)、棕榈油酰乙醇酰胺(Palmitoleoylethanolamide)、十八酰胺(Octadecanamide)和亚油酰胺(Linoleamide),该诊断模型中,ROC曲线下面积在训练集与测试集中均为1。参考图3的C,MDS plot结果显示上述5种代谢物可以明显区分SLE患者与健康人。该结果表明上述基于5种代谢物的诊断模型具有很高的诊断效率。
按照上述方法对5个代谢物分别建立诊断模型,绘制ROC曲线如图4所示。图4中5个代谢物的检测灵敏度、特异性如表1所示。
表1. 5个代谢物单独作为标志物的诊断价值
结合图4和表1可以看出,本实施例中筛出的胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺这5种代谢物的AUC值均在0.99以上,并且具有良好的特异性和灵敏度,可以作为单独的诊断标志物进行使用。可以理解的是,也可以从中选择两种或两种以上构建标志物的组合用于诊断。
实施例2
另外选取46例SLE患者及47例用于对照的健康人,采集外周血10ml,并分离血清,采用MRM法检测其中对应的代谢物的含量,利用实施例1中最终训练出的5种代谢物的联合诊断模型,对上述93例样本进行诊断模型的验证,结果显示,敏感度为82.6%、特异性为83.0%。上述验证结果表明,本申请所提供的代谢物的组合对于系统性红斑狼疮的诊断具有良好的诊断价值。
上面结合实施例对本申请作了详细说明,但是本申请不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本申请宗旨的前提下作出各种变化。此外,在不冲突的情况下,本申请的实施例及实施例中的特征可以相互组合。
Claims (8)
1.定量检测样本中以下至少两种代谢物的试剂在制备系统性红斑狼疮的诊断试剂盒中的应用:胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺。
2.根据权利要求1所述的应用,其特征在于,所述试剂定量检测全部五种代谢物。
3.根据权利要求1所述的应用,其特征在于,所述样本为血清样本。
4.根据权利要求1至3任一项所述的应用,其特征在于,当胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺中的至少一种代谢物的水平上调时,诊断为患有系统性红斑狼疮。
5.根据权利要求1至3任一项所述的应用,其特征在于,所述试剂通过核磁共振法、色谱法、光谱法、质谱法中的至少一种方法定量检测所述代谢物。
6.系统性红斑狼疮的诊断试剂盒,其特征在于,包括定量检测标志物的试剂,所述标志物为以下代谢物中的至少两种:胆固醇、油酰胺、棕榈油酰乙醇酰胺、十八酰胺和亚油酰胺。
7.根据权利要求6所述的试剂盒,其特征在于,所述试剂定量检测全部五种代谢物。
8.根据权利要求6所述的试剂盒,其特征在于,所述试剂通过核磁共振法、色谱法、光谱法、质谱法中的至少一种方法检测样本中代谢物的水平。
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