CN112394102B - 一种检测垂体功能减退症的标志物及其应用 - Google Patents
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Abstract
本发明涉及检测垂体功能减退症的标志物及其应用。本发明以肌酸/肌酐及癸酰左旋肉碱/左旋肉碱两组比值作为评价垂体功能减退症的标志物，使得垂体功能减退症的检测方法简便易行，检测准确率高，具有广阔的产业推广价值。
Description
技术领域
垂体功能减退症被定义为垂体前叶或垂体后叶的单一或多个垂体激素缺乏，临床表现多变，通常起病隐匿，且取决于激素缺乏的程度和严重性。其病因可大致分为先天性和后天性。垂体柄阻断综合征是一种常见的先天性垂体机能减退症，多见于围产期损伤后或胚胎发育异常。后天获得性垂体功能减退症最常见的病因是颅脑肿瘤，或放疗、手术创伤和急性感染治疗后。垂体功能减退症的症状与垂体激素的缺失程度及发病时间相关。
对垂体功能减退症患者糖、脂和蛋白质代谢的研究非常有限。Fleseriu M等(JClin Endocrinol Metab.2016；101(11):3888-3921.)报道了采用激素激发试验对垂体功能减退症进行诊断的方法，但该方法具有较高的风险，因此在临床上，对于婴幼儿、老年或伴有严重心脏病或癫痫的垂体功能减退症患者的诊断存在困难。
针对现有技术的不足，本发明提供了采用生物标志物检测垂体功能减退症的方法，该方法简便易行，检测准确率高，具有广阔的产业推广价值。
发明内容
本发明的目的之一在于提供生物标志物在制备用于诊断垂体功能减退症的试剂盒和/或诊断剂中的应用。
本发明的优选技术方案中，所述生物标志物选自肌酸、肌酐、癸酰左旋肉碱、左旋肉碱中的一种或其组合。
本发明的优选技术方案中，所述生物标志物来自体液或组织。
本发明的优选技术方案中，所述体液选自血浆、血清、尿液中的一种或其组合。
本发明的优选技术方案中，所述组织选自肝、脑、肌肉等。
本发明的优选技术方案中，所述生物标志物的提取方法选自甲醇/乙腈提取法、匀浆裂解法、超声裂解法、液氮研磨法中的一种或多种。
本发明的优选技术方案中，所述应用包括通过测定肌酸/肌酐比值来诊断垂体功能减退症。
本发明的优选技术方案中，所述应用包括通过测定癸酰左旋肉碱/左旋肉碱比值来诊断垂体功能减退症。
本发明的优选技术方案中，所述应用包括通过测定肌酸/肌酐比值及癸酰左旋肉碱/左旋肉碱比值来诊断垂体功能减退症。
本发明的优选技术方案中，肌酸/肌酐比值大于0.0277，和/或癸酰左旋肉碱/左旋肉碱比值小于0.01372诊断为垂体功能减退症。
本发明的优选技术方案中，所述标志物的检测方法包括高效液相色谱分析及质谱鉴定。
与现有技术相比，本发明具有下述有益技术效果：首次提出了以肌酸/肌酐及癸酰左旋肉碱/左旋肉碱两组比值作为评价垂体功能减退症的标志物，检测方法简便易行，准确率高，特别是对不能耐受标准激素激发试验的垂体功能减退症患者的诊断具有重要价值。
附图说明
图1阳性(A)和阴性(B)模式下垂体功能减退症组与健康对照组血清样本代谢物的主成分分析(PCA)得分图
图2阳性(A)和阴性(C)模式下垂体功能减退症组与健康对照组血清样本代谢物的正交偏最小二乘判别分析(OPLS-DA)评分图；阳性(B)和阴性(D)模式下，对比组OPLS-DA模型的置换检验图；垂体功能减退症组与健康对照组差异代谢物的KEGG通路富集分析气泡图(E)图3垂体功能减退组与健康对照组差异代谢物的热图(PT代表垂体机能减退患者；HC代表健康对照组；白色块代表含量低的差异代谢物，黑色块代表含量高的差异代谢物)
具体实施方式
以下将结合实施例具体说明本发明。本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质。
以下实施例1-2中，生物标志物的提取方法具体为：将血清、血浆、尿液等液体样本在4℃环境下缓慢解冻后，分别取100μL，加入400μL预冷甲醇/乙腈溶液(1:1，v/v)，涡旋混合，-20℃静置30min，14000g 4℃离心20min，取上清，真空干燥，即得。质谱分析时加入100μL乙腈水溶液(乙腈：水＝1:1，v/v)复溶，涡旋，14000g4℃离心15min，取上清液进样分析。
实施例1标志物的鉴定
对224份血清样本进行非靶向代谢组学分析，共鉴定出6380个阳性模式特征和6577个阴性模式特征用于MetaboAnalyst分析。经过对数变换和尺度变换，质控样本在阳性和阴性模式的帕累托尺度主成分分析(PCA)得分图上紧密聚类(图1)，具有良好的重现性。正交偏最小二乘判别分析(OPLS-DA)评分图确定了在阳性和阴性模式下，垂体功能减退症组和健康对照组之间的不同代谢物剖面(图2)。图3为垂体功能减退症和健康对照之间差异代谢物的热图。
接着以VIP值>1和P<0.05比较了垂体功能减退症组和健康对照组的代谢表型，共鉴定出59个差异代谢物(表1)。使用KEGG通路富集分析(www.genome.jp/kegg)和人类代谢组数据库(https://hmdb.ca/)进行基于确切概率法的生物学功能分析。KEGG通路富集分析发现，在精氨酸和脯氨酸代谢中，最显著的差异代谢物包括肌酸(VIP＝5.94,FOLD＝9.28)和肌酐(VIP＝9.68,FOLD＝0.74)。在脂肪酸代谢中，最显著的差异代谢物包括左旋肉碱(VIP＝5.56,FOLD＝1.12)和癸酰左旋肉碱(VIP＝4.90,FOLD＝0.15)。
表1垂体机能减退症组与健康对照组的差异代谢物
实施例2标志物的诊断性能
为了识别潜在的具有诊断价值的生物标志物，进行了受试者工作特征曲线(ROC)分析来量化各个代谢标志物的诊断性能。通过Graphpad 8.0计算ROC曲线下面积(AUC)。11种AUC大于0.8的代谢物见表2。其中肌酸/肌酐比值、癸酰左旋肉碱、癸酰左旋肉碱/左旋肉碱比值由于其AUC大于0.9，被认为具有很高的诊断效能。肌酸/肌酐比值的诊断效果优于单独的肌酸或肌酐(AUC 0.976vs 0.894or 0.857)。癸酰左旋肉碱/左旋肉碱比值诊断效果同样优于单独的癸酰左旋肉碱或左旋肉碱(AUC 0.988vs 0.981or 0.822)。
表2.诊断垂体机能减退症的生物标志物
以上所述仅是本发明的实施方式的举例，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。
Claims (5)
1.生物标志物在制备用于诊断垂体功能减退症的试剂盒和/或诊断剂中的应用，所述生物标志物选自肌酐和肌酸、癸酰左旋肉碱和左旋肉碱中的一组或两组。
2.如权利要求1所述的应用，其特征在于，所述生物标志物来自体液或组织。
3.如权利要求2所述的应用，其特征在于，所述体液选自血浆、血清、尿液中的一种或其组合。
4.如权利要求2所述的应用，其特征在于，所述组织选自肝、脑、肌肉。
5.如权利要求1-4任一项所述的应用，其特征在于，所述生物标志物的提取方法选自甲醇/乙腈提取法、匀浆裂解法、超声裂解法、液氮研磨法中的一种或多种。
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