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Differential DNA Methylation of Networked Signaling, Transcriptional, Innate and Adaptive Immunity, and Osteoclastogenesis Genes and Pathways in Gout
Author(s) -
Wang Zengmiao,
Zhao Ying,
PhippsGreen Amanda,
LiuBryan Ru,
Ceponis Arnoldas,
Boyle David L.,
Wang Jun,
Merriman Tony R.,
Wang Wei,
Terkeltaub Robert
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41173
Subject(s) - biology , dna methylation , epigenome , gout , immunology , cancer research , genetics , gene , gene expression , biochemistry
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 ( PBMC s) 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 Ch AMP 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. IL 23R , 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 TF s with hypomethylated sequence enrichment and for 30 (78.9%) of the 38 enriched KEGG pathways identified via TF s. Evidence of shared differentially methylated gout TF ‐gene networks, including the NF ‐κB activation–limiting TF s MEF 2C and NFATC 2 , 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.