Exploration of potential novel drug targets for rheumatoid arthritis by plasma proteome screening.

IF 3.6 2区生物学 Q1 BIOCHEMICAL RESEARCH METHODS

PLoS Computational Biology Pub Date : 2025-09-25 eCollection Date: 2025-09-01 DOI:10.1371/journal.pcbi.1013333

Zhiqiang Ma, Ran Chen, Zibo Feng

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引用次数: 0

Abstract

Background: Circulating proteins play a critical role in rheumatoid arthritis (RA), yet few have been targeted therapeutically. This study aimed to identify novel protein targets for RA therapy.

Methods: We conducted a comprehensive proteome-wide Mendelian Randomization (MR), colocalization analysis, and summary-data-based MR (SMR) to explore potential causal relationships between plasma proteins and RA, with an overall sample size of 1,148,608. The GWAS data on plasma proteins were obtained from the FinnGen study, the UK Biobank Pharma Proteomics Project and Iceland GWAS data. Then, validation of key molecules' differential expression pattern was done using external transcriptomic data from RA patients, while the Drug Signatures Database (DsigDB) was used to identify potential therapeutic drugs. Drugs and target proteins interactions was evaluated with molecular docking and molecular dynamics simulations approaches. Potential side effects of plasma proteins associated with RA were elucidated by phenome-wide association study (Phe-WAS) approach.

Results: Genetically predicted levels of 68 plasma proteins were associated with RA. After colocalization and SMR analysis, 6 plasma proteins (FCRL3, SUGP1, TNFAIP3, EHBP1, HAPLN4, and CILP2) have been passed all tests and identified as having potential as therapeutic targets for RA. Further Receiver operating characteristic curve (ROC) analysis indicated that three protiens (CILP2, TNFAIP3 and EHBP) have a good potential as biomarkers for RA. Differential gene analysis showed the downregulation of HAPLN4, FCRL3, EHBP1 and TNFAIP3 in RA, as well as the upregulation of CILP2 in RA. Further Phe-WAS suggested that targeting these proteins may have potential side effects.

Conclusion: Our study investigated the causal relationships between plasma proteins and RA, deepening our understanding of the molecular mechanisms and facilitating the development of new therapeutic drugs.

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通过血浆蛋白质组筛选探索类风湿关节炎的潜在新药物靶点。

背景：循环蛋白在类风湿关节炎（RA）中起关键作用，但很少有靶向治疗。本研究旨在为RA治疗寻找新的蛋白靶点。方法：我们进行了全面的蛋白质组孟德尔随机化（MR）、共定位分析和基于汇总数据的MR (SMR)，以探索血浆蛋白与RA之间的潜在因果关系，总样本量为1,148,608。血浆蛋白的GWAS数据来自FinnGen研究、UK Biobank Pharma Proteomics Project和冰岛GWAS数据。然后，使用来自RA患者的外部转录组数据验证关键分子的差异表达模式，同时使用药物特征数据库（DsigDB）识别潜在的治疗药物。通过分子对接和分子动力学模拟方法评估药物与靶蛋白的相互作用。通过全现象关联研究（Phe-WAS）方法阐明了与RA相关的血浆蛋白的潜在副作用。结果：68种血浆蛋白的遗传预测水平与RA相关。经过共定位和SMR分析，6种血浆蛋白（FCRL3, SUGP1, TNFAIP3, EHBP1， HAPLN4和CILP2）通过了所有测试，并被确定为有潜力作为RA的治疗靶点。进一步的受试者工作特征曲线（ROC）分析表明，三种蛋白（CILP2、TNFAIP3和EHBP）有很好的潜力作为RA的生物标志物。差异基因分析显示，RA中HAPLN4、FCRL3、EHBP1和TNFAIP3下调，CILP2上调。进一步的Phe-WAS表明靶向这些蛋白可能有潜在的副作用。结论：我们的研究揭示了血浆蛋白与RA之间的因果关系，加深了我们对RA分子机制的认识，促进了新的治疗药物的开发。

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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来源期刊

PLoS Computational Biology BIOCHEMICAL RESEARCH METHODS-MATHEMATICAL & COMPUTATIONAL BIOLOGY

CiteScore

7.10

自引率

4.70%

发文量

820

审稿时长

2.5 months

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