Integration of Known DNA, RNA and Protein Biomarkers Provides Prediction of Anti-TNF Response in Rheumatoid Arthritis: Results from the COMBINE Study
Integration of Known DNA, RNA and Protein Biomarkers Provides Prediction of Anti-TNF Response in Rheumatoid Arthritis: Results from the COMBINE Study
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DOI：
10.2119/molmed.2016.00078
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发表时间：
2016-01-01
影响因子：
5.7
通讯作者：
Berg, Louise
中科院分区：
文献类型：
--
作者：
Folkersen, Lasse;Brynedal, Boel;Berg, Louise
目的：在类风湿性关节炎（RA）中，最近的几项努力试图发现预测哪些患者将从治疗中获益的方法。然而，结果不一致，很少有成功的复制。我们的目标是建立一个具有DNA，RNA和蛋白质测量的生物库，以测试当前最先进的精准医学将使RA患者受益的说法。方法：我们从61名健康个体和185名开始治疗的RA患者中收集了451份血液样本，在治疗开始前和3个月的随访时间。所有样本都进行了高通量RNA测序，DNA基因分型，广泛的蛋白质组学和流式细胞术测量，以及全面的临床表型。文献综述确定了2种蛋白质、52种单核苷酸多态性（SNP）和72种基因表达生物标志物，这些蛋白质、单核苷酸多态性（SNP）和72种基因表达生物标志物此前曾被提议作为肿瘤坏死因子（TNF）抑制剂反应（.DAS28-CRP）的预测因子。研究结果：从这些公开的TNFi生物标志物中，我们发现2种蛋白质、2种SNP和8种mRNA生物标志物可以在59名TNF起始患者中复制。将这些重复的生物标志物组合成单个特征，我们发现我们可以解释DAS 28-CRP中51%的变异。这对应于预测3个月的敏感性为0.73，特异性为0.78。DAS 28-CRP优于-1.2。结论：联合收割机生物库是目前最大的RA患者多组学数据集合，具有很高的发现和复制潜力。利用这一点，我们调查了目前最先进的药物反应分层的RA，并确定了一个小的集以前发表的生物标志物可在外周血中预测临床反应TNF封锁在这个独立的队列。
OBJECTIVE: In rheumatoid arthritis (RA) several recent efforts have sought to discover means of predicting which patients would benefit from treatment. However, results have been discrepant with few successful replications. Our objective was to build a biobank with DNA, RNA and protein measurements to test the claim that the current state-of-the-art precision medicine will benefit RA patients. METHODS: We collected 451 blood samples from 61 healthy individuals and 185 RA patients initiating treatment, before treatment initiation and at a 3 month follow-up time. All samples were subjected to high-throughput RNA sequencing, DNA genotyping, extensive proteomics and flow cytometry measurements, as well as comprehensive clinical phenotyping. Literature review identified 2 proteins, 52 single-nucleotide polymorphisms (SNPs) and 72 gene-expression biomarkers that had previously been proposed as predictors of Tumor Necrosis Factor (TNF) inhibitor response (.DAS28-CRP). RESULTS: From these published TNFi biomarkers we found that 2 protein, 2 SNP and 8 mRNA biomarkers could be replicated in the 59 TNF initiating patients. Combining these replicated biomarkers into a single signature we found that we could explain 51% of the variation in.DAS28-CRP. This corresponds to a sensitivity of 0.73 and specificity of 0.78 for the prediction of three month.DAS28-CRP better than -1.2. CONCLUSIONS: The COMBINE biobank is currently the largest collection of multi-omics data from RA patients with high potential for discovery and replication. Taking advantage of this we surveyed the current state-of-the-art of drug-response stratification in RA, and identified a small set of previously published biomarkers available in peripheral blood which predicts clinical response to TNF blockade in this independent cohort.