Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis

EBioMedicine

Antonio Gómez¹  Antonio Juan Mas²  Devin M. Absher³  Estefania Moreno⁴  Sara Marsal⁵  Simón Sánchez-Fernández⁶  Carlos Marras Fernandez-Cid⁷  Raimon Sanmartí⁸  Carolina Pérez-García⁹  Mercedes Alperi-López^1,10  Ana María Ortiz^1,11  César Díaz-Torné^1,12  Ma Luz García Vivar^1,13  Tianlu Li^1,14  Alba Erra^1,15  Richard M. Myers^1,16  Sergio H. Martínez-Mateu^1,16  María López-Lasanta^1,16  Antonio Julià^1,16  Francisco Blanco^1,16  Jesús Tornero Molina^1,16  Antonio Fernández-Nebro^1,16 

[1] Corresponding authors.;Rheumatology Department, Hospital de San Rafael, Barcelona, Spain;Rheumatology Unit, Consorci Sanitari de l'Alt Penedès, Spain;Department of Rheumatology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain;HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA;Reumatology Department, Hospital del Mar, Barcelona, Spain;Rheumatology Department, Fundació Clínic Recerca Biomèdica, Barcelona, Spain;Rheumatology Department, Hospital General La Mancha Centro, Alcázar de San Juan, Spain;Rheumatology Department, Hospital Regional Universitario de Málaga, Málaga, Spain;Rheumatology Department, Hospital Universitario Basurto, Bilbao, Spain;Rheumatology Department, Hospital Universitario Central de Asturias, Oviedo, Spain;Rheumatology Department, Hospital Universitario La Princesa, Madrid, Spain;Rheumatology Department, Hospital Universitario Son Llàtzer, Mallorca, Spain;Rheumatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;Rheumatology Department, INIBIC-Hospital Universitario A Coruña, A Coruña, Spain;Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain;

关键词: Rheumatoid arthritis;    TNF inhibitors;    Treatment response;    Epigenetics;    DNA methylation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary:Background: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. Methods: Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. Findings: Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. Interpretation: Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems. Funding: The Instituto de Salud Carlos III.

【 授权许可】

Unknown