Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis
Julià Cano, Antonio (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Gómez Moruno, Antonio (Hospital Universitari Vall d'Hebron. Institut de Recerca)
López-Lasanta, María (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Blanco-García, F.J (Complejo Hospitalario Universitario de A Coruña)
Erra, Alba (Hospital de San Rafael (Madrid). Servicio de Reumatología)
Fernández-Nebro, Antonio (Hospital Regional Universitario de Málaga)
Mas, Antonio Juan (Hospital Universitari Son Llàtzer (Palma de Mallorca, Balears))
Pérez-García, Carolina (Hospital del Mar (Barcelona, Catalunya))
García Vivar, Ma Luz (Hospital de Basurto)
Sánchez-Fernández, Simón (Hospital General La Mancha Centro. Servicio de Reumatología)
Alperi-López, Mercedes (Hospital Universitario Central de Asturias)
Sanmartí, Raimon (Fundació Clínic. Servei de Reumatologia)
Ortiz, Ana María (Hospital Universitario de La Princesa. Servicio de Reumatología)
Fernandez-Cid, Carlos Marras (Hospital Universitario Virgen de la Arrixaca (Múrcia))
Díaz Torne, César (Institut d'Investigació Biomèdica Sant Pau)
Moreno Ruzafa, Estefanía (Consorci Sanitari de l'Alt Penedès. Unitat de Reumatologia)
Li, Tianlu (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martínez-Mateu, Sergio H. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Absher, Devin M. (HudsonAlpha Institute for Biotechnology)
Myers, Richard M. (HudsonAlpha Institute for Biotechnology)
Tornero Molina, Jesús (Hospital Universitario de Guadalajara. Servicio de Reumatología)
Marsal, Sara (Hospital Universitari Vall d'Hebron. Institut de Recerca)

Data:	2022
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI15/00424
Nota:	Altres ajuts: European Regional Development Fund/European Social Fund.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Rheumatoid arthritis ; TNF inhibitors ; Treatment response ; Epigenetics ; DNA methylation
Publicat a:	EBioMedicine, Vol. 80 (june 2022) , p. 104053, ISSN 2352-3964

DOI: 10.1016/j.ebiom.2022.104053
PMID: 35576644

16 p, 2.3 MB

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