@article{10902/18465,
year = {2019},
url = {http://hdl.handle.net/10902/18465},
abstract = {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.},
organization = {The present study was funded by the Spanish Ministry of Economy and Competitiveness (Grant Nos. PSE-010000-2006-6 and IPT-010000-2010-36) and by the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, FIDGR 2016, Grant No. 00587), which is supported by the Secretaria d’Universitats i Recerca (Economy and Knowledge Department, Generalitat de Catalunya), and cofunded by the European Social Fund. The study sponsor had no role in the collection, analysis, or interpretation of the data.},
publisher = {Frontiers Research Foundation},
publisher = {Frontiers Immunol 2019. Jul 2;10:1459},
title = {A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis},
author = {Aterido, Adrià and Cañete, Juan D. and Tornero, Jesús and Blanco, Francisco and Fernández-Gutierrez, Benjamín and Pérez, Carolina and Alperi-López, Mercedes and Olivè, Alex and Corominas, Héctor and Martínez Taboada, Víctor Manuel and González, Isidoro and Fernández-Nebro, Antonio and Erra, Alba and López-Lasanta, María and López Corbeto, Mireia and Palau, Núria and Marsal, Sara and Julià, Antonio},
}