RT Journal Article
T1 A Combined Transcriptomic and Genomic Analysis Identifies a Gene Signature Associated With the Response to Anti-TNF Therapy in Rheumatoid Arthritis.
A1 Aterido, Adria
A1 Cañete, Juan D
A1 Tornero, Jesus
A1 Blanco, Francisco
A1 Fernandez-Gutierrez, Benjamin
A1 Perez, Carolina
A1 Alperi-Lopez, Mercedes
A1 Olive, Alex
A1 Corominas, Hector
A1 Martinez-Taboada, Victor
A1 Gonzalez, Isidoro
A1 Fernandez-Nebro, Antonio
A1 Erra, Alba
A1 Lopez-Lasanta, Maria
A1 Lopez-Corbeto, Mireia
A1 Palau, Núria
A1 Marsal, Sara
A1 Julia, Antonio
K1 Anti-TNF therapy
K1 Genomics
K1 Multi-omics association analysis
K1 Rheumatoid arthritis
K1 Transcriptomics
AB 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.
PB Frontiers Research Foundation
YR 2019
FD 2019-07-02
LK http://hdl.handle.net/10668/14246
UL http://hdl.handle.net/10668/14246
LA en
NO Aterido A, Cañete JD, Tornero J, Blanco F, Fernández-Gutierrez B, Pérez C, et al.  A Combined Transcriptomic and Genomic Analysis Identifies a Gene Signature Associated With the Response to Anti-TNF Therapy in Rheumatoid Arthritis. Front Immunol. 2019 Jul 2;10:1459
NO 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.
DS RISalud
RD Apr 11, 2025