Bliziotis Nikolaos G, Kluijtmans Leo A J, Tinnevelt Gerjen H, Reel Parminder, Reel Smarti, Langton Katharina, Robledo Mercedes, Pamporaki Christina, Pecori Alessio, Van Kralingen Josie, Tetti Martina, Engelke Udo F H, Erlic Zoran, Engel Jasper, Deutschbein Timo, Nölting Svenja, Prejbisz Aleksander, Richter Susan, Adamski Jerzy, Januszewicz Andrzej, Ceccato Filippo, Scaroni Carla, Dennedy Michael C, Williams Tracy A, Lenzini Livia, Gimenez-Roqueplo Anne-Paule, Davies Eleanor, Fassnacht Martin, Remde Hanna, Eisenhofer Graeme, Beuschlein Felix, Kroiss Matthias, Jefferson Emily, Zennaro Maria-Christina, Wevers Ron A, Jansen Jeroen J, Deinum Jaap, Timmers Henri J L M
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Department of Analytical Chemistry, Institute for Molecules and Materials, Radboud University, 6500 HB Nijmegen, The Netherlands.
Metabolites. 2022 Jul 24;12(8):679. doi: 10.3390/metabo12080679.
Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing's syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.
尽管存在相当高的发病率和死亡率，但包括原发性醛固酮增多症（PA）、嗜铬细胞瘤和功能性副神经节瘤（PPGL）以及库欣综合征（CS）在内的多种内分泌性高血压（EHT）病例仍未被发现。我们旨在建立不同形式EHT的特征，研究潜在的混杂效应，并建立无偏倚的疾病生物标志物。从七个国家的13个生物样本库中获取血浆样本，并使用非靶向核磁共振代谢组学进行分析。我们将106例原发性高血压（PHT）患者的未分层样本与231例EHT患者的样本进行了比较，其中包括104例PA患者、94例PPGL患者和33例CS患者。对光谱进行了PHT与EHT形式的多变量统计比较，并获得了相关特征。应用了三种方法来研究和校正混杂效应。尽管我们发现了可以将PHT与EHT形式区分开的特征，但也存在与样本来源中心和样本年龄特征的关键相似之处。研究设计限制了所采用校正方法的适用性。就现有的样本而言，无法识别出PHT与EHT的生物标志物。混杂效应的复杂性，通过其对校正方法的稳健性得到证明，凸显了在回顾性多中心代谢组学研究中就如何处理可能归因于分析前因素的变异性达成共识的必要性。
