Jiang Ping, Shen Yi, Chang Cen, Shi Yiming, Wei Kai, Zhao Jianan, Shan Yu, Zheng Yixin, Zhao Fuyu, Guo Shicheng, He Dongyi
Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Clin Rheumatol. 2025 Jan;44(1):115-123. doi: 10.1007/s10067-024-07158-1. Epub 2024 Nov 27.
This study aimed to explore the potential of HIPK3 DNA methylation as a biomarker for rheumatoid arthritis (RA) by examining its methylation levels in various rheumatic immune diseases and analyzing its correlation with clinical indicators.
We recruited 368 participants, including patients with RA, ankylosing spondylitis (AS), GOUT, psoriatic arthritis (PSA), sjogren's syndrome (SS), systemic lupus erythematosus (SLE), dermatomyositis (DM), and healthy controls (HC), and MethylTargetTM targeted region methylation sequencing technology was employed to analyze the DNA methylation levels of HIPK3 (cg15692052). We analyzed the HIPK3 methylation levels and correlated them with common clinical indicators. Transcriptome data from the GEO dataset (GSE93272) were also analyzed to assess HIPK3 mRNA expression levels in RA patients. Statistical analyses included Spearman correlation, One-Way ANOVA, Kruskal-Wallis tests, and ROC curve analysis.
HIPK3 methylation levels were significantly lower in the RA, SLE, and DM groups compared to the HC group (P < 0.05). RA subgroups based on RF and CCP statuses also showed lower HIPK3 methylation levels compared to the HC group (P < 0.05). Analysis of the GEO dataset revealed significantly elevated HIPK3 mRNA expression in RA patients (P < 0.05). A negative correlation was found between HIPK3 methylation levels and ESR (r = -0.14, P = 7.1e-3), CRP (r = -0.25, P = 4.1e-7), RF (r = -0.18, P = 5.2e-4), and DAS28-CRP (r = -0.12, P = 0.04) in the RA group. ROC analysis indicated that HIPK3 methylation levels had high diagnostic value for RA (AUC = 0.742), SLE (AUC = 0.701), and DM (AUC = 0.948), especially in distinguishing seronegative RA (AUC = 0.612, 0.747, 0.836) and differentiating RA from AS (AUC = 0.788).
The study suggests that HIPK3 hypomethylation in peripheral blood is associated with RA and correlated with inflammatory markers, such as CRP. HIPK3 methylation levels have potential as a novel biomarker for RA diagnosis and predicting inflammation trends, showing particular promise in differentiating RA from other types of arthritis. Key Points • MethylTargetTM targeted region methylation sequencing technology was employed to analyze the DNA methylation levels of HIPK3 (cg15692052). • HIPK3 methylation levels have potential as a novel biomarker for RA diagnosis and predicting inflammation trends.
本研究旨在通过检测多种风湿免疫性疾病中HIPK3的甲基化水平，并分析其与临床指标的相关性，探讨HIPK3 DNA甲基化作为类风湿关节炎（RA）生物标志物的潜力。
我们招募了368名参与者，包括RA患者、强直性脊柱炎（AS）患者、痛风患者、银屑病关节炎（PSA）患者、干燥综合征（SS）患者、系统性红斑狼疮（SLE）患者、皮肌炎（DM）患者和健康对照（HC），并采用MethylTargetTM靶向区域甲基化测序技术分析HIPK3（cg15692052）的DNA甲基化水平。我们分析了HIPK3甲基化水平，并将其与常见临床指标进行关联。还分析了来自GEO数据集（GSE93272）的转录组数据，以评估RA患者中HIPK3 mRNA表达水平。统计分析包括Spearman相关性分析、单因素方差分析、Kruskal-Wallis检验和ROC曲线分析。
与HC组相比，RA、SLE和DM组的HIPK3甲基化水平显著降低（P < 0.05）。基于RF和CCP状态的RA亚组与HC组相比，HIPK3甲基化水平也较低（P < 0.05）。对GEO数据集的分析显示，RA患者中HIPK3 mRNA表达显著升高（P < 0.05）。在RA组中，发现HIPK3甲基化水平与ESR（r = -0.14，P = 7.1e-3）、CRP（r = -0.25，P = 4.1e-7）、RF（r = -0.18，P = 5.2e-4）和DAS28-CRP（r = -0.12，P = 0.04）呈负相关。ROC分析表明，HIPK3甲基化水平对RA（AUC = 0.742）、SLE（AUC = 0.701）和DM（AUC = 0.948）具有较高的诊断价值，尤其在区分血清阴性RA（AUC = 0.612、0.747、0.836）以及鉴别RA与AS（AUC = 0.788）方面。
该研究表明，外周血中HIPK3低甲基化与RA相关，并与CRP等炎症标志物相关。HIPK3甲基化水平有潜力作为RA诊断和预测炎症趋势的新型生物标志物，在鉴别RA与其他类型关节炎方面显示出特别的前景。要点：• 采用MethylTargetTM靶向区域甲基化测序技术分析HIPK3（cg15692052）的DNA甲基化水平。• HIPK3甲基化水平有潜力作为RA诊断和预测炎症趋势的新型生物标志物。
