CN114216984B - 一种骨质疏松症负离子诊断标志物及其检测方法 - Google Patents
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Abstract
本发明提供了一种骨质疏松症负离子诊断标志物及其检测方法,标志物包括两种血清极性负离子,两种血清极性负离子分别为4‑羟基脯氨酸和3‑[3‑(磺氧基)苯基]丙酸。该标志物可准确反应出患者是否患有骨质疏松症,具有检测方便、对人体无放射性损伤的优点,可有效解决现有的双能X线吸收法存在检测受限的问题。
Description
技术领域
本发明属于生物技术领域,具体涉及一种骨质疏松症负离子诊断标志物及其检测方法。
背景技术
随着全球老龄人口的急剧增加,骨质疏松症的发病率也逐年增加。骨质疏松症是一种以骨量减少和微结构恶化而导致骨脆性增加为特征的骨骼疾病,常常伴发长期慢性疼痛、畸形、残疾及不同程度的活动受限,严重影响老年人的生活质量与心理健康。目前,早诊断、早治疗是骨质疏松主要的治疗策略。然而,骨质疏松是一种高度隐匿性疾病,同时缺乏特异、敏感的生物标志物,许多患者在发生骨折后才被确诊。目前,双能X线吸收法(DXA)的测定值是目前全世界公认的诊断骨质疏松症的金标准。DXA结果的评估受检查者的主观影响较大,限制了在基层大规模的推广。同时,被检者在行DXA检查时必须暴露于放射线环境,限制了部分有禁忌症的患者的应用。目前,血液中骨代谢相关标志物的敏感性与特异性均不理想。因此,寻找新的、与疾病严重程度及进展密切相关的标记物,对骨质疏松的早期诊断和治疗将具有重大意义。
疾病发生、发展的驱动基因与环境因素的综合作用共同调控了机体的代谢重塑。代谢物的变化清晰的反映了生物体病理生理状态。在许多疾病中,循环代谢小分子能够促进疾病的早期筛查、预警,以及理解疾病的发生模式。具有将色谱对复杂样品的高分离能力,与质谱具有高选择性、高灵敏度相结合的优点,液相色谱-质谱联用代谢组学分析技术是目前最为常用的检测组织样本或体液(血液、尿液、组织液)样本中广谱内源性代谢小分子的工具,在越来越多研究中得到应用。采用特定的样品前处理方法,以及色谱和质谱条件,利用标准品为参照,对物质定性、定量。从而大大提高了检测的灵敏度、特异度和可重复性,确保代谢物浓度信息不丢失,具有高通量、临床可操作性和数据可挖掘性。目前,研究证实,不同循环代谢物的组合作为诊断或预后标志物,在许多疾病中具有良好的应用前景,但是,目前在诊断骨质疏松症中,并没有找到特别有效的代谢标志物。
发明内容
针对现有技术中存在的上述问题,本发明提供一种骨质疏松症负离子诊断标志物及其检测方法,该负离子标志物可准确反应出患者是否患有骨质疏松症,具有检测方便、对人体无放射性损伤的优点,可有效解决现有的双能X线吸收法存在检测受限的问题。
为实现上述目的,本发明解决其技术问题所采用的技术方案是:
一种骨质疏松症负离子诊断标志物,该负离子诊断标志物分别为4-羟基脯氨酸和3-[3-(磺氧基)苯基]丙酸。
上述骨质疏松症负离子诊断标志物在制备骨质疏松诊断试剂盒中的应用。
一种骨质疏松诊断试剂盒,包括上述极性标志物。
上述的骨质疏松症负离子诊断标志物的检测方法,包括以下步骤:
(1)取血清样本,向其中加入甲醇和乙腈的混合溶液,然后依次进行涡旋振荡、静置;
(2)将步骤(1)中混合物离心,取上清液,对上清液进行冷冻干燥;
(3)向步骤(2)中冷冻干燥物中加入乙腈和水的混合溶液复溶,然后依次进行涡旋振荡和离心,取上清液进行液相色谱-质谱联合检测即可,其中,液相色谱检测的色谱柱为:Acquity HSS C18色谱柱。
进一步地,步骤(1)中甲醇和乙腈的混合溶液中甲醇和乙腈的体积比为1:1。
进一步地,步骤(1)中涡旋振荡3-7min,然后于3-6℃条件下静置8-12min,然后于于3-6℃条件下4500-5100g的离心力作用下离心15-25min。
进一步地,步骤(3)中乙腈和水的混合溶液中乙腈和水的体积比为1:3。
进一步地,步骤(3)中涡旋振荡2-4min,然后于3-6℃条件下于4500-5100g的离心力作用下离心15-25min。
进一步地,步骤(3)中液相色谱检测时,流动相A为水,流动相B为乙腈/甲醇溶液,流动相A和流动相B中均含有0.3-0.5%的碳酸氢铵缓冲盐和0.05-0.15%氨水,流动相梯度为:10min内流动相B从2%线性上升至100%,然后进行洗柱和平衡;色谱检测时,流动相流速、进样量和柱温分别为0.3-0.5ml/min、4-6μl和45-55℃。
进一步地,步骤(3)中质谱检测时,使用加热的电喷雾电离源,各项参数为:鞘气40-50arb;辅助气体8-12arb;加热器温度350-370℃;毛细管温度310-330℃;S-Lens RFlevel 50-60%。
上述方案所产生的有益效果为:
本发明中的血清极性负离子可反映出患者骨质疏松的情况,其灵敏度高达93.8%,特异性高达93.8%,AUC=0.974;采用本申请中的血清标志物可实现骨质疏松的无创诊断,且不受限制,具有使用范围广的优点。
附图说明
图1为血清中两种标志物在不同人群中的丰度变化图;
图2为不同人群的ROC分析曲线。
具体实施方式
下面结合附图对本发明的具体实施方式做详细的说明。
试剂:色谱级甲醇、乙腈、甲酸、氨水购自Fisher Science(Fair Lawn,USA)。色谱级碳酸氢铵购自Sigma-Aldrich(St.Louis,USA)。超纯水采用MILI-Q纯净水系统制备(Merck KGaA,Darmstadt,Germany)。
实施例1
一种骨质疏松症负离子诊断标志物,包括两种血清极性负离子,两种血清极性负离子分别为4-羟基脯氨酸和3-[3-(磺氧基)苯基]丙酸,该标志物的检测方法如下:
(1)取50μL血清样本置于96孔板内,加入200μL甲醇/乙腈(1:1,v/v);
(2)涡旋震荡5分钟,4℃条件静置10分钟后板式离心机5010g 4℃下离心20分钟;
(3)上清200μL转移至新96孔板后,置于冷冻干燥仪冻干2-3小时;
(4)密封低温保存,用于质谱分析;
(5)将冻干的上清用80μL乙腈-水(1:3,v/v)复溶,涡旋震荡3分钟,4℃条件下5010g离心20分钟,然后取上清液70μL上样检测,具体检测过程为:采用Acquity HSS C18色谱柱(Waters Co.,USA,1.8μm,2.1×100mm),以水为流动相A,乙腈/甲醇(1:1,v/v)为流动相B,二者均含有0.4%碳酸氢铵缓冲盐与0.1%氨水,流动相梯度为:10分钟内流动相B梯度从2%线性上升至100%,再用5分钟进行洗柱和平衡,流速、进样量和柱温分别为为0.4mL/min、5μL和50℃;
使用加热的电喷雾电离源(ESI-),各项参数如下:鞘气45arb;辅助气体10arb;加热器温度355℃;毛细管温度320℃;S-Lens RF level 55%。代谢组提取物在全扫描模式(FS)下进行,分辨率为70000FWHM,最大进样时间为200ms,自动增益控制目标(AGC)为1×106,数据采集使用500m/z的扫描范围。
实施例2
一种骨质疏松症负离子诊断标志物,包括两种血清极性负离子,两种血清极性负离子分别为4-羟基脯氨酸和3-[3-(磺氧基)苯基]丙酸,该标志物的检测方法如下:
(1)取50μL血清样本置于96孔板内,加入200μL甲醇/乙腈(1:1,v/v);
(2)涡旋震荡5分钟,4℃条件静置10分钟后板式离心机4800g 5℃下离心20分钟;
(3)上清200μL转移至新96孔板后,置于冷冻干燥仪冻干2小时;
(4)密封低温保存,用于质谱分析;
(5)将冻干的上清用80μL乙腈-水(1:3,v/v)复溶,涡旋震荡3分钟,4℃条件下5000g离心15分钟,然后取上清液70μL上样检测,具体检测过程为:采用Acquity HSS C18色谱柱(Waters Co.,USA,1.8μm,2.1×100mm),以水为流动相A,乙腈/甲醇(1:1,v/v)为流动相B,二者均含有0.4%碳酸氢铵缓冲盐与0.1%氨水,流动相梯度为:10分钟内流动相B梯度从2%线性上升至100%,再用5分钟进行洗柱和平衡,流速、进样量和柱温分别为为0.5mL/min、6μL和45℃;
使用加热的电喷雾电离源(ESI-),各项参数如下:鞘气40arb;辅助气体11arb;加热器温度365℃;毛细管温度330℃;S-Lens RF level 50%。代谢组提取物在全扫描模式(FS)下进行,分辨率为70000FWHM,最大进样时间为200ms,自动增益控制目标(AGC)为1×106,数据采集使用200m/z的扫描范围。
试验例
将32例骨质疏松患者血清和32例健康对照人群血清采用实施例1中的方法进行Ultal3000型超高效液相色谱仪和QExactive高分辨质谱仪(Thermo Scientific,USA)分析,然后将检测数据进行统计并绘图,具体分析结果见附图1和附图2。
通过附图1图可以看出,健康人群血清中4-羟基脯氨酸表达相对较高,3-[3-(磺氧基)苯基]丙酸表达相对较低;而骨质疏松患者血清中4-羟基脯氨酸表达相对较低,3-[3-(磺氧基)苯基]丙酸表达相对较高,通过4-羟基脯氨酸和3-[3-(磺氧基)苯基]丙酸两种标志物的表达可准确反应出患者是否患者有骨质疏松症。
通过附图2可以看出,本申请中的骨质疏松症诊断标志物的灵敏度可达到93.8%,特异性可达到93.8%,AUC=0.974。
Claims (8)
1.一种骨质疏松症负离子诊断标志物,其特征在于,该负离子诊断标志物分别为4-羟基脯氨酸和3-[3-(磺氧基)苯基]丙酸。
2.权利要求1所述的骨质疏松症负离子诊断标志物在制备骨质疏松诊断试剂盒中的应用。
3.一种骨质疏松诊断试剂盒,其特征在于,包括权利要求1中的标志物。
4.如权利要求1所述的骨质疏松症负离子诊断标志物的检测方法,其特征在于,包括以下步骤:
(1)取血清样本,向其中加入甲醇和乙腈的混合溶液,然后依次进行涡旋振荡、静置;
(2)将步骤(1)中混合物离心,取上清液,对上清液进行冷冻干燥;
(3)向步骤(2)中冷冻干燥物中加入乙腈和水的混合溶液复溶,然后依次进行涡旋振荡和离心,取上清液进行液相色谱-质谱联合检测即可,其中,液相色谱检测的色谱柱为:Acquity HSS C18 色谱柱,流动相A为水,流动相B为乙腈/甲醇混合溶液,流动相A和流动相B中均含有0.3-0.5%的碳酸氢铵缓冲盐和0.05-0.15%氨水,流动相梯度为:10min内流动相B从2%线性上升至100%,然后进行洗柱和平衡;色谱检测时,流动相流速、进样量和柱温分别为0.3-0.5ml/min、4-6μl和45-55℃;质谱检测时,使用加热的电喷雾电离源ESI-,各项参数为:鞘气40-50arb;辅助气体8-12arb;加热器温度350-370℃;毛细管温度310-330℃;S-Lens RF level 50-60%。
5.如权利要求4所述的骨质疏松症负离子诊断标志物的检测方法,其特征在于,步骤(1)中甲醇和乙腈的混合溶液中甲醇和乙腈的体积比为1:1。
6.如权利要求4所述的骨质疏松症负离子诊断标志物的检测方法,其特征在于,步骤(1)中涡旋振荡3-7min,然后于3-6℃条件下静置8-12min,然后于3-6℃条件下4500-5100g的离心力作用下离心15-25min。
7.如权利要求4所述的骨质疏松症负离子诊断标志物的检测方法,其特征在于,步骤(3)中乙腈和水的混合溶液中乙腈和水的体积比为1:3。
8.如权利要求4所述的骨质疏松症负离子诊断标志物的检测方法,其特征在于,步骤(3)中涡旋振荡2-4min,然后于3-6℃条件下于4500-5100g的离心力作用下离心15-25min。
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