Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which diagnosis and management remain challenging. Defining the circulating proteome in IPF may identify targets for biomarker development. We sought to quantify the circulating proteome in IPF, determine differential protein expression between subjects with IPF and controls, and examine relationships between protein expression and markers of disease severity. This study involved 300 patients with IPF from the IPF-PRO Registry and 100 participants without known lung disease. Plasma collected at enrolment was analysed using aptamer-based proteomics (1305 proteins). Linear regression was used to determine differential protein expression between participants with IPF and controls and associations between protein expression and disease severity measures (percent predicted values for forced vital capacity [FVC] and diffusion capacity of the lung for carbon monoxide [DLco]; composite physiologic index [CPI]). Multivariable models were fit to select proteins that best distinguished IPF from controls. Five hundred fifty one proteins had significantly different levels between IPF and controls, of which 47 showed a |log2(fold-change)| > 0.585 (i.e. > 1.5-fold difference). Among the proteins with the greatest difference in levels in patients with IPF versus controls were the glycoproteins thrombospondin 1 and von Willebrand factor and immune-related proteins C-C motif chemokine ligand 17 and bactericidal permeability-increasing protein. Multivariable classification modelling identified nine proteins that, when considered together, distinguished IPF versus control status with high accuracy (area under receiver operating curve = 0.99). Among participants with IPF, 14 proteins were significantly associated with FVC % predicted, 23 with DLco % predicted, 14 with CPI. Four proteins (roundabout homolog-2, spondin-1, polymeric immunoglobulin receptor, intercellular adhesion molecule 5) demonstrated the expected relationship across all three disease severity measures. When considered in pathways analyses, proteins associated with the presence or severity of IPF were enriched in pathways involved in platelet and haemostatic responses, vascular or platelet derived growth factor signalling, immune activation, and extracellular matrix organisation. Patients with IPF have a distinct circulating proteome and can be distinguished using a nine-protein profile. Several proteins strongly associate with disease severity. The proteins identified may represent biomarker candidates and implicate pathways for further investigation. ClinicalTrials.gov (NCT01915511).

中文翻译：

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多中心IPF-PRO注册中心中特发性肺纤维化生物标志物的外周血蛋白质组学分析

特发性肺纤维化（IPF）是一种进行性肺部疾病，对其诊断和管理仍然充满挑战。在IPF中定义循环蛋白质组可能会确定生物标记物开发的目标。我们试图量化IPF中的循环蛋白质组，确定IPF受试者与对照之间的差异蛋白表达，并检查蛋白表达与疾病严重程度标志物之间的关系。这项研究涉及来自IPF-PRO注册中心的300例IPF患者和100名无已知肺部疾病的参与者。使用基于适体的蛋白质组学（1305种蛋白质）分析入选时收集的血浆。线性回归用于确定IPF参与者与对照之间的差异蛋白表达，以及蛋白表达与疾病严重程度度量之间的关联（强迫肺活量[FVC]和肺对一氧化碳扩散能力[DLco]的预测值的百分比；复合生理学索引[CPI]）。多变量模型适合于选择与对照最能区分IPF的蛋白质。IPF和对照之间的515个蛋白水平有显着差异，其中47个蛋白显示| log2（倍数变化）|。> 0.585（即> 1.5倍差异）。IPF患者与对照组患者中水平差异最大的蛋白是糖蛋白血小板反应蛋白1和von Willebrand因子以及免疫相关蛋白CC基序趋化因子配体17和增加通透性的蛋白。多变量分类模型确定了九种蛋白质，这些蛋白质一起考虑即可以较高的准确度区分IPF与对照状态（接收器工作曲线下的面积= 0.99）。在患有IPF的参与者中，有14种蛋白与FVC％预测值显着相关，有23种与DLco％预测值显着相关，有14种与CPI相关。四种蛋白质（回旋同系物2，spondin-1，聚合免疫球蛋白受体，细胞间粘附分子5）证明了在所有三种疾病严重程度指标之间的预期关系。在路径分析中考虑时，与IPF的存在或严重程度相关的蛋白质富含与血小板和止血反应，血管或血小板衍生的生长因子信号传导，免疫激活和细胞外基质组织有关的途径。IPF患者具有独特的循环蛋白质组，可以使用九种蛋白质来区分。几种蛋白质与疾病的严重程度密切相关。鉴定出的蛋白质可能代表候选生物标志物，并暗示了进一步研究的途径。ClinicalTrials.gov（NCT01915511）。IPF患者具有独特的循环蛋白质组，可以使用九种蛋白质来区分。几种蛋白质与疾病的严重程度密切相关。鉴定出的蛋白质可能代表候选生物标志物，并暗示了进一步研究的途径。ClinicalTrials.gov（NCT01915511）。IPF患者具有独特的循环蛋白质组，可以使用九种蛋白质来区分。几种蛋白质与疾病的严重程度密切相关。鉴定出的蛋白质可能代表候选生物标志物，并暗示了进一步研究的途径。ClinicalTrials.gov（NCT01915511）。