Background & Aims

Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn’s disease and ulcerative colitis that can be detected and quantified before diagnosis.

Methods

We obtained serum samples from patients archived before a diagnosis of Crohn’s disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti–Saccharomyces cerevisiae IgA or IgG, anti–Escherichia coli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn’s disease were identified based on changes in protein abundance at different time periods preceding diagnosis.

Results

We identified a panel of 51 protein biomarkers that were predictive of Crohn’s disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72.

Conclusions

We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn’s disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.

中文翻译：

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血清生物标记物可在诊断前长达5年的时间内识别出会发展成炎症性肠病的患者。

背景与目标

需要生物标志物来鉴定有发炎性肠病风险的患者。我们旨在鉴定在诊断前可以检测和定量的克罗恩病和溃疡性结肠炎的血清生物标志物。

方法

我们从1998年至2013年作为美国国防部医疗工作的一部分，从诊断为克罗恩病（n = 200）或溃疡性结肠炎（n = 199）之前存档的患者以及200名健康个体（对照组）获得了血清样本。监控系统。我们测量抗微生物的抗体的水平（抗酿酒酵母的IgA或IgG，抗大肠埃希氏 杆菌每个样品中的外膜孔蛋白C，抗CBir1，抗鞭毛蛋白2，抗鞭毛蛋白X和核周抗中性粒细胞胞质抗体）和1129种蛋白质。然后，我们使用功能主成分分析来得出每个标记的时变轨迹，然后将其用于多变量模型以预测疾病状态。使用接收器工作特性曲线（AUROC）下的面积评估了在不同的预诊断时间点的预测性能。根据诊断前不同时间段蛋白质丰度的变化，确定克罗恩病患者血清中上调的生物途径。

结果

我们确定了一组51种蛋白质生物标记物，它们在5年内可预测克罗恩病，AUROC为0.76，在1年内诊断为AUROC为0.87。基于面板中包含的蛋白质，CD的即将发展与补体级联反应，溶酶体，先天免疫应答和糖胺聚糖代谢的变化有关。血清抗体和蛋白质可识别出在5年内诊断为溃疡性结肠炎的患者，其AUROC仅为0.56，在1年内诊断为溃疡性结肠炎，而AUROC为0.72。

结论

我们鉴定了一组血清抗体和蛋白质，这些蛋白质和蛋白质可预测能够在5年内以高准确度诊断出克罗恩病的患者。相比之下，我们未发现与溃疡性结肠炎的未来诊断有关的生物标志物。