A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis
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...
| Autores: | , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/43304 |
| Acceso en línea: | http://hdl.handle.net/10230/43304 http://dx.doi.org/10.3389/fimmu.2019.01459 |
| Access Level: | acceso abierto |
| Palabra clave: | Anti-TNF therapy Genomics Multi-omics association analysis Rheumatoid arthritis Transcriptomics |
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A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritisAterido Ballonga, Adrià, 1990-Cañete Crespillo, Juan de DiosTornero, JesúsBlanco, FranciscoFernández-Gutiérrez, BenjamínPérez-García, CarolinaAlperiz, MercedesOlivé, AlexCorominas, HéctorMartínez-Taboada, VíctorGonzález-Alvaro, IsidoroFernández-Nebro, AntonioErra, AlbaLópez Lasanta, MaríaLópez Corbeto, MireiaPalau, NúriaMarsal, SaraJulià, AntonioAnti-TNF therapyGenomicsMulti-omics association analysisRheumatoid arthritisTranscriptomicsBackground: 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.Frontiers202020202019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/43304http://dx.doi.org/10.3389/fimmu.2019.01459reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésFrontiers in Immunology. 2019 Jul 2;10:1459Copyright © 2019 Aterido, Cañete, Tornero, Blanco, Fernández-Gutierrez, Pérez, Alperi-López, Olivè, Corominas, Martínez-Taboada, González, Fernández-Nebro, Erra, López-Lasanta, López Corbeto, Palau, Marsal and Julià. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) https://creativecommons.org/licenses/by/4.0/. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/433042026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
| title |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
| spellingShingle |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis Aterido Ballonga, Adrià, 1990- Anti-TNF therapy Genomics Multi-omics association analysis Rheumatoid arthritis Transcriptomics |
| title_short |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
| title_full |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
| title_fullStr |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
| title_full_unstemmed |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
| title_sort |
A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis |
| dc.creator.none.fl_str_mv |
Aterido Ballonga, Adrià, 1990- Cañete Crespillo, Juan de Dios Tornero, Jesús Blanco, Francisco Fernández-Gutiérrez, Benjamín Pérez-García, Carolina Alperiz, Mercedes Olivé, Alex Corominas, Héctor Martínez-Taboada, Víctor González-Alvaro, Isidoro Fernández-Nebro, Antonio Erra, Alba López Lasanta, María López Corbeto, Mireia Palau, Núria Marsal, Sara Julià, Antonio |
| author |
Aterido Ballonga, Adrià, 1990- |
| author_facet |
Aterido Ballonga, Adrià, 1990- Cañete Crespillo, Juan de Dios Tornero, Jesús Blanco, Francisco Fernández-Gutiérrez, Benjamín Pérez-García, Carolina Alperiz, Mercedes Olivé, Alex Corominas, Héctor Martínez-Taboada, Víctor González-Alvaro, Isidoro Fernández-Nebro, Antonio Erra, Alba López Lasanta, María López Corbeto, Mireia Palau, Núria Marsal, Sara Julià, Antonio |
| author_role |
author |
| author2 |
Cañete Crespillo, Juan de Dios Tornero, Jesús Blanco, Francisco Fernández-Gutiérrez, Benjamín Pérez-García, Carolina Alperiz, Mercedes Olivé, Alex Corominas, Héctor Martínez-Taboada, Víctor González-Alvaro, Isidoro Fernández-Nebro, Antonio Erra, Alba López Lasanta, María López Corbeto, Mireia Palau, Núria Marsal, Sara Julià, Antonio |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Anti-TNF therapy Genomics Multi-omics association analysis Rheumatoid arthritis Transcriptomics |
| topic |
Anti-TNF therapy Genomics Multi-omics association analysis Rheumatoid arthritis Transcriptomics |
| description |
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. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 2020 2020 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/43304 http://dx.doi.org/10.3389/fimmu.2019.01459 |
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http://hdl.handle.net/10230/43304 http://dx.doi.org/10.3389/fimmu.2019.01459 |
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Inglés |
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Inglés |
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Frontiers in Immunology. 2019 Jul 2;10:1459 |
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https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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