University of California, San Diego.
University of Otago, Dunedin, New Zealand.
Arthritis Rheumatol. 2020 May;72(5):802-814. doi: 10.1002/art.41173. Epub 2020 Mar 23.
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.
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.
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.
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.
在痛风中，尿酸盐晶体的自身炎症反应促进急性关节炎发作，但痛风石、慢性滑膜炎和侵蚀的发病机制尚不清楚。定义表观基因组免疫训练途径可以揭示新的致病因素和生物标志物。本研究旨在利用痛风患者的全基因组分析初步探讨差异 DNA 甲基化模式。
从圣地亚哥痛风患者队列（n=16）和个体匹配的健康对照者（n=14）中获取外周血单核细胞（PBMC）。使用 R 中的 ChAMP 包处理 PBMC 甲基组数据。使用 ENCODE 数据和太极数据分析软件分析转录因子（TF）-基因网络。作为独立验证队列，分析新西兰毛利人受试者的全血 DNA 样本（n=13 例痛风患者，n=16 例无痛风对照者）。
通过层次聚类和主成分分析，差异甲基化位点清楚地区分了痛风患者和对照者。IL23R 是多个差异甲基化痛风风险基因之一，它介导肉芽肿形成和细胞侵袭。全基因组分析显示 B 和 T 细胞受体信号、Th17 细胞分化和白细胞介素 17 信号、趋同长寿调控、昼夜节律调节和 AMP 激活蛋白激酶信号的差异甲基组途径富集，这些途径通过胰岛素样生长因子 1 受体、磷脂酰肌醇 3-激酶/Akt、NF-κB、雷帕霉素靶蛋白信号和自噬影响炎症。痛风队列重叠了 70 个 TF 中 37 个（52.9%）序列低甲基化富集和 38 个通过 TF 鉴定的 KEGG 途径中 30 个（78.9%）。共享差异甲基化痛风 TF-基因网络的证据，包括 NF-κB 激活限制 TF MEF2C 和 NFATC2，指向破骨细胞分化作为重叠于两个痛风队列中最强的加权差异甲基化途径。
这些关于网络信号、转录、先天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，它们可能成为痛风患者急性发作、痛风石、慢性滑膜炎和骨侵蚀管理的新治疗靶点。
