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Página principal > Artículos > Artículos publicados > A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
Fecha: | 2019 |
Resumen: | 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. |
Ayudas: | 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 |
Derechos: | 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. |
Lengua: | Anglès |
Documento: | Article ; recerca ; Versió publicada |
Materia: | Rheumatoid arthritis ; Genomics ; Transcriptomics ; Multi-omics association analysis ; Anti-TNF therapy |
Publicado en: | Frontiers in immunology, Vol. 10 Núm. JUL (2019) , p. 1459, ISSN 1664-3224 |
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