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 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.
['Aterido|Adrià|A|', 'Cañete|Juan D|JD|', 'Tornero|Jesús|J|', 'Blanco|Francisco|F|', 'Fernández-Gutierrez|Benjamín|B|', 'Pérez|Carolina|C|', 'Alperi-López|Mercedes|M|', 'Olivè|Alex|A|', 'Corominas|Héctor|H|', 'Martínez-Taboada|Víctor|V|', 'González|Isidoro|I|', 'Fernández-Nebro|Antonio|A|', 'Erra|Alba|A|', 'López-Lasanta|María|M|', 'López Corbeto|Mireia|M|', 'Palau|Núria|N|', 'Marsal|Sara|S|', 'Julià|Antonio|A|']
D000068879:Adalimumab D018501:Antirheumatic Agents D001172:Arthritis, Rheumatoid D001706:Biopsy D015331:Cohort Studies D005260:Female D053263:Gene Regulatory Networks D055106:Genome-Wide Association Study D006801:Humans D000069285:Infliximab D008297:Male D020641:Polymorphism, Single Nucleotide D013583:Synovial Membrane D059467:Transcriptome D016896:Treatment Outcome D014409:Tumor Necrosis Factor-alpha
transcriptomics genomics anti-TNF therapy rheumatoid arthritis multi-omics association analysis