Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis
Antonio Julià,
Antonio Gómez,
María López-Lasanta,
Francisco Blanco,
Alba Erra,
Antonio Fernández-Nebro,
Antonio Juan Mas,
Carolina Pérez-García,
Ma Luz García Vivar,
Simón Sánchez-Fernández,
Mercedes Alperi-López,
Raimon Sanmartí,
Ana María Ortiz,
Carlos Marras Fernandez-Cid,
César Díaz-Torné,
Estefania Moreno,
Tianlu Li,
Sergio H. Martínez-Mateu,
Devin M. Absher,
Richard M. Myers,
Jesús Tornero Molina,
Sara Marsal
Affiliations
Antonio Julià
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain; Corresponding authors.
Antonio Gómez
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain
María López-Lasanta
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain
Francisco Blanco
Rheumatology Department, INIBIC-Hospital Universitario A Coruña, A Coruña, Spain
Alba Erra
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain; Rheumatology Department, Hospital de San Rafael, Barcelona, Spain
Antonio Fernández-Nebro
Rheumatology Department, Hospital Regional Universitario de Málaga, Málaga, Spain
Antonio Juan Mas
Rheumatology Department, Hospital Universitario Son Llàtzer, Mallorca, Spain
Carolina Pérez-García
Reumatology Department, Hospital del Mar, Barcelona, Spain
Rheumatology Department, Hospital Universitario La Princesa, Madrid, Spain
Carlos Marras Fernandez-Cid
Department of Rheumatology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
César Díaz-Torné
Rheumatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Estefania Moreno
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain; Rheumatology Unit, Consorci Sanitari de l'Alt Penedès, Spain
Tianlu Li
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain
Sergio H. Martínez-Mateu
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain
Devin M. Absher
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
Richard M. Myers
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
Jesús Tornero Molina
Department of Rheumatology, Hospital Universitario de Guadalajara, Spain
Sara Marsal
Rheumatology Research Group, Vall d'Hebron University Hospital Research Institute, Barcelona 08035, Spain; Corresponding authors.
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.
