中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (17): 4498-4507.doi: 10.12307/2026.136

• 组织构建相关数据分析 Date analysis of organization construction • 上一篇    下一篇

基因组学视角揭示类风湿关节炎的血浆蛋白调控靶点

程悦斌1，王宝剑2，戴文康2，殷岳杉2，孙志强1，彭志云1，尚宇航1，马玉峰2   

  1. 1北京中医药大学中医骨伤科学，北京市   100000；2北京中医药大学第三附属医院筋伤(疼痛)科，北京市   100000

  • 收稿日期:2025-04-08 接受日期:2025-07-30 出版日期:2026-06-18 发布日期:2025-12-03
  • 通讯作者: Ma Yufeng, MD, Associate chief physician, Department of Muscle Injury (Pain), The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing 100000, China
  • 作者简介:Cheng Yuebin, MS candidate, Orthopedics of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100000, China
  • 基金资助:
    首都卫生发展科研专项项目(首发2020-2-7036)，项目负责人：马玉峰；北京中医药大学重点攻关项目(2020-JYB-ZDGG-142-3)，项目负责人：马玉峰；北京中医药大学第三附属医院“新药研发培育项目”(BZYSY-2022-XYYF-02)，项目负责人：马玉峰

Revealing the regulatory targets of plasma proteins in rheumatoid arthritis from the perspective of genomics

Cheng Yuebin1, Wang Baojian2, Dai Wenkang2, Yin Yueshan2, Sun Zhiqiang1, Peng Zhiyun1, Shang Yuhang1, Ma Yufeng2   

  1. 1Orthopedics of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100000, China; 2Department of Muscle Injury (Pain), The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing 100000, China
  • Received:2025-04-08 Accepted:2025-07-30 Online:2026-06-18 Published:2025-12-03
  • Contact: 马玉峰，博士，副主任医师，北京中医药大学第三附属医院筋伤(疼痛)科，北京市 100000
  • About author:程悦斌，男，1998年生，北京中医药大学在读硕士，主要从事中医骨伤科方向研究。
  • Supported by:
    Capital Health Development Research Special Project, No. 2020-2-7036 (to MYF); Beijing University of Traditional Chinese Medicine Key Research Project, No. 2020-JYB-ZDGG-142-3 (to MYF); “New Drug R&D Cultivation Project” of The Third Affiliated Hospital of Beijing University of Traditional Chinese Medicine, No. BZYSY-2022-XYYF-02 (to MYF) 

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摘要：



文题释义：
血浆蛋白：是血浆中的蛋白质成分，具有多种重要生理功能，包括运输物质、维持血浆胶体渗透压、参与免疫反应和凝血过程等。在医学研究中，血浆蛋白可作为生物标志物用于疾病的诊断、预后评估，也可作为药物靶点用于疾病治疗。某些血浆蛋白水平的异常变化可能与特定疾病的发生发展相关，通过检测这些蛋白可辅助疾病的早期发现和治疗监测。 
孟德尔随机化：是一种利用遗传变异作为工具变量来评估暴露因素与疾病之间因果关系的统计方法。它基于等位基因在受精卵时期的随机分配，类似于随机对照试验，可减少混杂因素和反向因果关系的偏倚。

背景：类风湿关节炎是一种复杂的自身免疫性疾病，涉及遗传、环境和免疫的多因素交互作用。传统研究多聚焦于个别蛋白质与类风湿关节炎的关联，但缺乏对大规模血浆蛋白与类风湿关节炎因果关系的系统性评估。孟德尔随机化作为一种创新的因果推断方法，利用遗传变异作为工具变量，避免了传统流行病学研究中混杂因素的干扰，为揭示血浆蛋白与类风湿关节炎的因果关系提供了新途径。
目的：研究人体内血浆蛋白与类风湿关节炎之间的潜在关联，探讨血浆蛋白在类风湿关节炎发病过程中可能涉及的生物学途径。
方法：收集血浆蛋白(暴露因素)与类风湿关节炎(结局因素)的公共数据，其中4 907种血浆蛋白的数据源自2022年发表在《Nature Genetics》杂志上对血浆蛋白的全基因组关联研究，现收录于冰岛deCODE Genetics数据库中，该研究涵盖35 559名冰岛人，发现18 084个蛋白质数量性状位点；类风湿关节炎的全基因组关联研究数据来自芬兰数据库(R11版本)，其中类风湿关节炎患者14 818例，对照组为287 796例，所有参与者均为欧洲人群。采用两样本双向孟德尔随机化分析评估血浆蛋白与类风湿关节炎之间的潜在因果关系，孟德尔随机化分析包括逆方差加权法、MR-Egger回归法、加权中位数法、加权模型法和简单模型法5种分析方法。异质性检验、基因水平多效性检验及留一法分析用于检验孟德尔随机化分析结果是否可靠。反向孟德尔随机化以正向孟德尔随机化分析中符合筛选条件的血浆蛋白作为结局进行效应分析和敏感性分析。
结果与结论：①逆方差加权法结果显示，血浆蛋白CRAT、LYG1与类风湿关节炎呈直接的正向因果关联；血浆蛋白FAM177A1、JPH4、SPAG11B与类风湿关节炎呈直接的负向因果关联；②反向孟德尔随机化结果显示，类风湿关节炎与LYG1呈直接的正向因果关联；③双向敏感性分析均未发现存在异质性或水平多效性；④以血浆蛋白作为暴露，类风湿关节炎作为结局，血浆蛋白CRAT、LYG1与类风湿关节炎呈正相关因果关系，血浆蛋白FAM177A1、JPH4、SPAG11B与类风湿关节炎呈负相关因果关系；以类风湿关节炎作为暴露，血浆蛋白CRAT、LYG1、FAM177A1、JPH4、SPAG11B作为结局，类风湿关节炎与血浆蛋白LYG1有正相关因果关系。上述结果提示5种血浆蛋白与类风湿关节炎可能存在因果关系，助力未来类风湿关节炎潜在治疗与监测靶点的研发。尽管在欧洲数据库中发现的蛋白靶点需在中国人群中验证其普适性，但此类因果关联的初步证据可指导国内研究优先聚焦于相关蛋白通路，加速靶向药物研发，同时应加强本土多中心生物样本库与蛋白质组学-全基因组关联研究整合平台建设，以克服欧洲数据库为中心的局限性，推动基于亚洲人群的精准医学研究。

https://orcid.org/0009-0002-7487-1311 (程悦斌) 


中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 血浆蛋白, 类风湿关节炎, 孟德尔随机化, 全基因组关联研究, 敏感性分析, 单核苷酸多态性, 遗传学, 异质性, 水平多效性

Abstract: BACKGROUND: Rheumatoid arthritis is a complex autoimmune disease, which involves the interaction of many factors including heredity, environment and immunity. Traditional research focuses on the relationship between individual protein and rheumatoid arthritis, but lacks systematic evaluation of the causal relationship between large-scale plasma proteins and rheumatoid arthritis. Mendelian randomization, as an innovative causal inference method, uses genetic variation as a tool variable, which avoids the interference of confounding factors in traditional epidemiological research and provides a new way to reveal the causal relationship between plasma protein and rheumatoid arthritis.
OBJECTIVE: To study the potential relationship between human plasma protein and rheumatoid arthritis, and to explore the possible biological pathways involved in the pathogenesis of rheumatoid arthritis.
METHODS: The public data of plasma protein (exposure factor) and rheumatoid arthritis (outcome factor) were collected. Among them, the data of 4 907 types of plasma proteins came from genome-wide association studies published in the journal Nature Genetics in 2022, which is now included in the Icelandic deCODE Genetics database. The study covered 35 559 Icelanders and found 18 084 protein quantitative trait loci. Genome-wide association study data of rheumatoid arthritis came from FinnGen database (R11 version), including 14 818 cases of rheumatoid arthritis and 287 796 cases in the control group. All participants were from the European population. The potential causal relationship between plasma protein and rheumatoid arthritis was evaluated by two-way Mendelian randomized analysis. Mendelian randomized analysis included five analysis methods: inverse variance weighted method, MR-Egger regression method, weighted median method, weighted model method and simple model method. Heterogeneity test, horizontal pleiotropy test and leave-one-out analysis were used to test whether the results of Mendelian randomized analysis are reliable. Reverse Mendelian randomization analysis took the plasma protein that met the screening conditions in the positive Mendelian randomization analysis as the outcome for effect analysis and sensitivity analysis.
RESULTS AND CONCLUSION: (1) The results of inverse variance weighting method showed that plasma proteins CRAT and LYG1 were directly and positively correlated with rheumatoid arthritis. Plasma proteins FAM177A1, JPH4 and SPAG11B had a direct negative causal relationship with rheumatoid arthritis. (2) Reverse Mendelian randomization results showed that rheumatoid arthritis had a direct positive causal relationship with LYG1. (3) No heterogeneity or horizontal pleiotropy was found in two-way sensitivity analysis. (4) With plasma proteins as the exposure and rheumatoid arthritis as the outcome, two plasma proteins CRAT and LYG1 were positively correlated with rheumatoid arthritis, and three plasma proteins FAM177A1, JPH4 and SPAG11B were negatively correlated with rheumatoid arthritis. With rheumatoid arthritis as the exposure and plasma proteins CRAT, LYG1, FAM177A1, JPH4, SPAG11B as the outcome, rheumatoid arthritis had a positive causal relationship with the plasma protein LYG1. The above results suggest that there may be causal relationship between these five plasma proteins and rheumatoid arthritis, which will help the development of potential therapeutic and monitoring targets for rheumatoid arthritis in the future. Although the protein targets found in European databases need to be verified in the China population, the preliminary evidence of such causal associations can guide domestic research to give priority to related protein pathways and accelerate targeted drug research and development. At the same time, it calls for strengthening the construction of a local multi-center biological sample bank and a proteomics-genome-wide association studies integrated platform to overcome the limitations of European databases and promote precision medical research based on Asian populations.


Key words: plasma protein, rheumatoid arthritis, Mendelian randomization, genome-wide association studies, sensitivity analysis, single nucleotide polymorphism, genetics, heterogeneity, horizontal pleiotropy

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