OBJECTIVE In gout, autoinflammatory responses to urate crystals promote acute arthritis flares, but the pathogeneses of tophi, chronic synovitis, and erosion are less well understood. Defining the pathways of epigenomic immunity training can reveal novel pathogenetic factors and biomarkers. The present study was undertaken to seminally probe differential DNA methylation patterns utilizing epigenome-wide analyses in patients with gout. METHODS Peripheral blood mononuclear cells (PBMCs) were obtained from a San Diego cohort of patients with gout (n = 16) and individually matched healthy controls (n = 14). PBMC methylome data were processed with ChAMP package in R. ENCODE data and Taiji data analysis software were used to analyze transcription factor (TF)-gene networks. As an independent validation cohort, whole blood DNA samples from New Zealand Māori subjects (n = 13 patients with gout, n = 16 control subjects without gout) were analyzed. RESULTS Differentially methylated loci clearly separated gout patients from controls, as determined by hierarchical clustering and principal components analyses. IL23R, which mediates granuloma formation and cell invasion, was identified as one of the multiple differentially methylated gout risk genes. Epigenome-wide analyses revealed differential methylome pathway enrichment for B and T cell receptor signaling, Th17 cell differentiation and interleukin-17 signaling, convergent longevity regulation, circadian entrainment, and AMP-activated protein kinase signaling, which are pathways that impact inflammation via insulin-like growth factor 1 receptor, phosphatidylinositol 3-kinase/Akt, NF-κB, mechanistic target of rapamycin signaling, and autophagy. The gout cohorts overlapped for 37 (52.9%) of the 70 TFs with hypomethylated sequence enrichment and for 30 (78.9%) of the 38 enriched KEGG pathways identified via TFs. Evidence of shared differentially methylated gout TF-gene networks, including the NF-κB activation-limiting TFs MEF2C and NFATC2, pointed to osteoclast differentiation as the most strongly weighted differentially methylated pathway that overlapped in both gout cohorts. CONCLUSION These findings of differential DNA methylation of networked signaling, transcriptional, innate and adaptive immunity, and osteoclastogenesis genes and pathways suggest that they could serve as novel therapeutic targets in the management of flares, tophi, chronic synovitis, and bone erosion in patients with gout.

中文翻译：

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痛风中网络信号传导、转录、先天性和适应性免疫以及破骨细胞生成基因和通路的差异 DNA 甲基化。


目的 在痛风中，尿酸盐晶体的自身炎症反应会促进急性关节炎发作，但痛风石、慢性滑膜炎和糜烂的发病机制尚不清楚。定义表观基因组免疫训练的途径可以揭示新的致病因素和生物标志物。本研究的目的是利用痛风患者的表观基因组分析来探索差异 DNA 甲基化模式。方法 从圣地亚哥痛风患者队列 (n = 16) 和单独匹配的健康对照 (n = 14) 中获取外周血单核细胞 (PBMC)。使用R中的ChAMP包处理PBMC甲基化组数据。使用ENCODE数据和Taiji数据分析软件分析转录因子（TF）-基因网络。作为一个独立的验证队列，对新西兰毛利受试者（n = 13 名痛风患者，n = 16 名无痛风对照受试者）的全血 DNA 样本进行了分析。结果 通过层次聚类和主成分分析确定，差异甲基化位点将痛风患者与对照组明确区分开。 IL23R 介导肉芽肿形成和细胞侵袭，被确定为多种差异甲基化痛风风险基因之一。全表观基因组分析揭示了 B 细胞和 T 细胞受体信号传导、Th17 细胞分化和白细胞介素 17 信号传导、趋同长寿调节、昼夜节律夹带和 AMP 激活蛋白激酶信号传导的甲基化通路差异富集，这些通路通过胰岛素影响炎症。例如生长因子 1 受体、磷脂酰肌醇 3-激酶/Akt、NF-κB、雷帕霉素信号传导的机制靶点和自噬。痛风队列重叠 37 (52.70 个 TF 中的 9%）具有低甲基化序列富集，以及通过 TF 鉴定的 38 个富集 KEGG 通路中的 30 个（78.9%）。共享差异甲基化痛风 TF 基因网络（包括限制 NF-κB 激活的 TF MEF2C 和 NFATC2）的证据表明，破骨细胞分化是权重最强的差异甲基化途径，在两个痛风队列中都有重叠。结论 这些网络信号传导、转录、先天性和适应性免疫以及破骨细胞生成基因和途径的差异 DNA 甲基化的发现表明，它们可以作为治疗痛风患者痛风发作、痛风石、慢性滑膜炎和骨侵蚀的新治疗靶点。