Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis
Por:
Julia, A, Gomez, A, Lopez-Lasanta, M, Blanco, F, Erra, A, Fernandez-Nebro, A, Mas, AJ, Perez-Garcia, C, Vivar, MLG, Sanchez-Fernandez, S, Alperi-Lopez, M, Sanmarti, R, Ortiz, AM, Fernandez-Cid, CM, Diaz-Torne, C, Moreno, E, Li, TL, Martinez-Mateu, SH, Absher, DM, Myers, RM, Molina, JT, Marsal, S
Publicada:
1 jun 2022
Ahead of Print:
1 may 2022
Resumen:
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.
Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Filiaciones:
Julia, A:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Gomez, A:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Lopez-Lasanta, M:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Blanco, F:
INIBIC Hosp Univ A Coruna, Dept Rheumatol, La Coruna, Spain
Erra, A:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Hosp San Rafael, Dept Rheumatol, Barcelona, Spain
Fernandez-Nebro, A:
Hosp Reg Univ Malaga, Dept Rheumatol, Malaga, Spain
Mas, AJ:
Hosp Univ Son Llatzer, Dept Rheumatol, Mallorca, Spain
Perez-Garcia, C:
Hosp del Mar, Reumatol Dept, Barcelona, Spain
Vivar, MLG:
Hosp Univ Basurto, Dept Rheumatol, Bilbao, Spain
Sanchez-Fernandez, S:
Hosp Gen Mancha Ctr, Dept Rheumatol, Alcazar De San Juan, Spain
Alperi-Lopez, M:
Hosp Univ Cent Asturias, Dept Rheumatol, Oviedo, Spain
Sanmarti, R:
Dept Rheumatol, Fundacio Clin Recerca Biomed, Barcelona, Spain
Ortiz, AM:
Hosp Univ La Princesa, Dept Rheumatol, Madrid, Spain
Fernandez-Cid, CM:
Hosp Univ Virgen de la Arrixaca, Dept Rheumatol, Murcia, Spain
Diaz-Torne, C:
Hosp Santa Creu & Sant Pau, Dept Rheumatol, Barcelona, Spain
Moreno, E:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Consorci Sanitari Alt Penedes, Rheumatol Unit, Barcelona, Spain
Li, TL:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Martinez-Mateu, SH:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Absher, DM:
HudsonAlpha Inst Biotechnol, Huntsville, AL USA
Myers, RM:
HudsonAlpha Inst Biotechnol, Huntsville, AL USA
Molina, JT:
Hosp Univ Guadalajara, Dept Rheumatol, Guadalajara, Spain
Marsal, S:
Vall dHebron Univ Hosp Res Inst, Rheumatol Res Grp, Barcelona 08035, Spain
Green Published, All Open Access, Gold, Green
|