Chan Gloria G, Koch Clarissa M, Connors Lawreen H
Amyloidosis Center and ‡Department of Pathology and Laboratory Medicine, Boston University School of Medicine , Boston, Massachusetts 02118, United States.
J Proteome Res. 2017 Apr 7;16(4):1659-1668. doi: 10.1021/acs.jproteome.6b00998. Epub 2017 Feb 23.
Transthyretin-associated forms of cardiac amyloidosis are fatal protein misfolding diseases that can be inherited (ATTRm) or acquired (ATTRwt). An accurate diagnosis of ATTR amyloidosis can be challenging as biopsy evidence, usually from the affected organ, is required. Precise biomarkers for ATTR disease identification and monitoring are undiscovered, disease-specific therapeutic options are needed, and the current understanding of ATTR molecular pathogenesis is limited. The aim of this study was to investigate and compare the serum proteomes in ATTRm and ATTRwt cardiac amyloidosis to identify differentially expressed blood proteins that were disease-specific. Using multiple-reaction monitoring mass spectrometry (MRM-MS), the concentrations of 160 proteins were analyzed in serum samples from ATTRm and ATTRwt patients, and a healthy control group. Patient and control sera were matched to age (≥60 years), gender (male), and race (Caucasian). The circulating concentrations of 123/160 proteins were significantly different in patient vs control sera; TTR and retinol-binding protein (RBP4) levels were significantly decreased (p < 0.03) in ATTRm compared to controls. In ATTRm, 14/123 proteins were identified as unique to that group and found generally to be lower than controls; moreover, the concentrations of RBP4 and 6 other proteins in this group were significantly different (p < 0.04) compared to ATTRwt. Predicted interactions among the 14 proteins unique to ATTRm were categorized as reaction and binding associations. Alternatively, 27 proteins were found to be unique to ATTRwt with associated interactions defined as activation, catalysis, and inhibition, in addition to reaction and binding. This study demonstrates significant proteomic differences between ATTR patient and control sera, and disease-associated variations in circulating levels of several proteins including TTR and RBP4. The identification of serum proteins unique to ATTRm and ATTRwt cardiac amyloidosis may have diagnostic and prognostic utility, and may provide important clues about disease mechanisms.
与转甲状腺素蛋白相关的心脏淀粉样变性是致命的蛋白质错误折叠疾病，可分为遗传性（ATTRm）或获得性（ATTRwt）。ATTR淀粉样变性的准确诊断具有挑战性，因为通常需要从受影响器官获取活检证据。尚未发现用于ATTR疾病识别和监测的精确生物标志物，需要针对该疾病的特异性治疗选择，并且目前对ATTR分子发病机制的了解有限。本研究的目的是调查和比较ATTRm和ATTRwt心脏淀粉样变性患者的血清蛋白质组，以鉴定疾病特异性的差异表达血液蛋白质。使用多反应监测质谱（MRM-MS）分析了ATTRm和ATTRwt患者以及健康对照组血清样本中160种蛋白质的浓度。患者和对照血清在年龄（≥60岁）、性别（男性）和种族（白种人）方面进行了匹配。患者血清与对照血清相比，123/160种蛋白质的循环浓度存在显著差异；与对照组相比，ATTRm患者中甲状腺素运载蛋白（TTR）和视黄醇结合蛋白（RBP4）水平显著降低（p < 0.03）。在ATTRm患者中，14/123种蛋白质被鉴定为该组特有的，且通常低于对照组；此外，与ATTRwt患者相比，该组中RBP4和其他6种蛋白质的浓度存在显著差异（p < 0.04）。ATTRm特有的14种蛋白质之间的预测相互作用被归类为反应和结合关联。另外，发现27种蛋白质是ATTRwt特有的，其相关相互作用除反应和结合外，还定义为激活、催化和抑制。本研究证明了ATTR患者血清与对照血清之间存在显著的蛋白质组差异，以及包括TTR和RBP4在内的几种蛋白质循环水平的疾病相关变化。鉴定出ATTRm和ATTRwt心脏淀粉样变性特有的血清蛋白质可能具有诊断和预后价值，并可能为疾病机制提供重要线索。
