A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis
Aterido, Adrià (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Cañete, Juan D (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Tornero, Jesús (Hospital Universitario de Guadalajara)
Blanco-García, F.J (Complejo Hospitalario Universitario de A Coruña)
Fernández-Gutiérrez, Benjamín (Hospital Clínico San Carlos (Madrid))
Pérez-García, Carolina (Parc de Salut MAR de Barcelona)
Alperi-López, Mercedes (Hospital Universitario Central de Asturias)
Olivé Marqués, Alejandro (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Corominas, Hèctor (Hospital de Sant Joan Despí Moisès Broggi)
Martínez-Taboada, Víctor (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
González, Isidoro (Hospital Universitario de la Princesa (Madrid))
Fernández-Nebro, Antonio (Hospital Regional Universitario de Málaga)
Erra Duran, Alba (Rheumatology Department. Hospital Sant Rafael)
López Lasanta, María (Hospital Universitari Vall d'Hebron. Institut de Recerca)
López-Corbeto, Mireia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Palau, Núria (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Marsal, Sara (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Julià Cano, Antonio (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. Results: A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0. 05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0. 0015) and infliximab (P = 0. 021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0. 0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2. 41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0. 041). Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA.
Ajuts:	Ministerio de Economía y Competitividad PSE-010000-2006-6 Ministerio de Economía y Competitividad IPT-010000-2010-36 Agència de Gestió d'Ajuts Universitaris i de Recerca FI-DGR2016-00587
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Rheumatoid arthritis ; Genomics ; Transcriptomics ; Multi-omics association analysis ; Anti-TNF therapy
Publicat a:	Frontiers in immunology, Vol. 10 Núm. JUL (2019) , p. 1459, ISSN 1664-3224

DOI: 10.3389/fimmu.2019.01459
PMID: 31312201

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