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A Combined Transcriptomic and Genomic Analysis Identifies a Gene Signature Associated With the Response to Anti-TNF Therapy in Rheumatoid Arthritis

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URI: http://hdl.handle.net/20.500.12105/17885
DOI: 10.3389/fimmu.2019.01459
Full text access: http://hdl.handle.net/10668/14246
Publication date
2019-07-02
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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
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anti-TNF therapy Genomics Multi-omics association analysis Rheumatoid arthritis Transcriptomics
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Adalimumab Antirheumatic Agents Arthritis, Rheumatoid Biopsy Cohort Studies Female Gene Regulatory Networks Genome-Wide Association Study Humans Infliximab Male Polymorphism, Single Nucleotide Synovial Membrane Transcriptome Treatment Outcome Tumor Necrosis Factor-alpha
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IBIMA-Plataforma BIONAND - Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (Andalucía)
IDIBAPS - Instituto de Investigaciones Biomédicas August Pi i Sunyer (Cataluña)
IIS-PRINCESA - Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (Madrid)
INIBIC - Instituto de Investigación Biomédica A Coruña (Galicia)
IR-HUVH - Instituto de Investigación Hospital Universitari Vall d’Hebron (Cataluña)
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research article