A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-related hepatitis

Khaled Sayed, Christine E. Dolin, Daniel W. Wilkey, Jiang Li, Toshifumi Sato, Juliane I Beier, Josepmaria Argemi, Ramon Bataller, Abdus S Wahed, Michael L Merchant, Panayiotis V Benos, Gavin E Arteel
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Abstract

Alcohol-related hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury that can be detected in biological fluids and potentially used for mortality prediction. EDTA plasma samples were collected from AH patients (n= 62); Model for End-Stage Liver Disease (MELD) score defined AH severity as moderate (12-20; n=28) and severe (>20; n=34). The peptidome data was collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition and protease involvement. Machine learning methods were used on patient-specific peptidome and clinical data to develop mortality predictors. Analysis of plasma peptides from AH patients and healthy controls identified over 1,600 significant peptide features corresponding to 130 proteins. These were enriched for ECM fragments in AH samples, likely related to turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes showed a shift in abundance of peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Increase in hepatic expression of these proteases was orthogonally-validated in RNA-seq data of livers from AH patients. Causal graphical modeling identified four peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over MELD score and were used to create a clinically applicable mortality prediction assay. A signature based on plasma peptidome is a novel, non-invasive method for prognosis stratification in AH patients. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms.
血浆肽组特征揭示细胞外基质重塑并预测酒精相关肝炎的预后
酒精相关肝炎(AH)的死亡率很高,而且难以识别高危患者。细胞外基质在肝脏炎症损伤过程中会发生显著重塑,这种重塑可在生物液体中检测到,并有可能用于预测死亡率。从AH患者(62人)中采集了EDTA血浆样本;终末期肝病模型(MELD)评分将AH严重程度定义为中度(12-20分;28人)和重度(20分;34人)。肽组数据由高分辨率、高质量精度的UPLC-MS收集。单变量和多变量分析确定了差异丰富的肽段,这些肽段用于基因本体、母体蛋白矩阵组成和蛋白酶参与。在患者特异性肽组和临床数据上使用了机器学习方法来开发死亡率预测指标。对AH患者和健康对照者的血浆肽进行分析,发现了与130种蛋白质相对应的1600多个重要肽特征。在 AH 样本中,这些肽段富含 ECM 片段,这可能与肝源性蛋白质的周转有关。对中度和重度 AH 肽组的分析表明,来自胶原 1A1 和纤维蛋白原 A 蛋白的肽的丰度发生了变化。在 AH 肽组谱中占主导地位的蛋白酶似乎是 CAPN1 和 MMP12。AH患者肝脏RNA-seq数据正交验证了这些蛋白酶在肝脏表达的增加。在90%的学习图谱中,因果图谱建模确定了与90天死亡率直接相关的四种肽。与 MELD 评分相比,这些肽提高了死亡率预测的准确性,并被用于创建临床适用的死亡率预测分析。基于血浆肽组的特征是对AH患者进行预后分层的一种新颖、无创的方法。我们的研究结果还可能带来新的机制和/或替代生物标志物,以确定新的AH机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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