Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids

• Published in: Annals of the rheumatic diseases Vol. 81; no. 9; pp. 1290 - 1300
• Main Authors: Estupiñán-Moreno, Elkyn, Ortiz-Fernández, Lourdes, Li, Tianlu, Hernández-Rodríguez, Jose, Ciudad, Laura, Andrés-León, Eduardo, Terron-Camero, Laura Carmen, Prieto-González, Sergio, Espígol-Frigolé, Georgina, Cid, Maria Cinta, Márquez, Ana, Ballestar, Esteban, Martín, Javier
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 15.06.2022; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Arteritis; Biomarkers; CD14 antigen; CD63 antigen; DNA methylation; Epigenetics; Ets-2 protein; Gene expression; Giant Cell Arteritis; Glucocorticoids; Immune Complex Diseases; Inflammation; Interleukin 1; Interleukin 11; Interleukin 6; Monocytes; Ontology; Pathogenesis; Patients; Phenotypes; Remission; Remission (Medicine); Systemic vasculitis; Transcriptomes; Transcriptomics; Vasculitis; Vein & artery diseases; Immune Complex Diseases; Inflammation; Giant Cell Arteritis; Glucocorticoids
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2022-222156

ObjectivesGiant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis.MethodsWe performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls.ResultsWe identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2.ConclusionOur results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment.