Background/Purpose:

Rheumatoid arthritis (RA) is the most common inflammatory arthritis affecting up to 1% of the population. Tumor Necrosis Factor (TNF) inhibitors have significantly improved the management of many RA patients. However, ~30% of anti-TNF treated patients do not show a significant clinical improvement. To date, little is known on the biological mechanisms that underlie the differential response to anti-TNF agents. The objective of this study was to identify genetic variation associated with the clinical response to anti-TNF therapy in RA using a sequential multi-omics approach.

Methods:

We performed a genome-wide multi-omics analysis integrating multiple sources of molecular information. First, we aimed to identify the gene expression modules associated with anti-TNF response. For this objective, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy and determined the gene expression profiles using Illumina microarrays. Modules of coexpressed genes were subsequently identified using the WGCNA approach. The association between the synovial gene coexpression modules and anti-TNF response was then performed using the first principal component of variation from each module. Clinical response was determined at week 14 using the EULAR criteria. To analyze the association between the transcriptomic modules and the anti-TNF response at the genetic level, we used a cohort of 348 anti-TNF treated RA patients from Spain recruited by the IMID Consortium. The statistical association analysis was performed using genome-wide data from the Spain cohort (N=1,387,382 SNPs) and the set-based test implemented in PLINK. The gene modules that were significantly associated with the anti-TNF response were subsequently tested for validation in an independent GWAS cohort of 2,706 anti-TNF treated RA patients available from the Synapse public repository. The functional implication of the validated modules was evaluated via pathway and cell type epigenetic enrichment analyses.

Results:

The genome-wide coexpression analysis in RA synovial biopsies identified a total of 148 gene coexpression modules. From these, 15 transcriptomic modules were found to be associated with the clinical response to anti-TNF therapy (P<0.05). At the genetic level, we detected two of the 15 gene modules to be significantly associated with the response to adalimumab (P=0.015) and infliximab (P=0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the gene coexpression module associated with the response to adalimumab (P=0.0019). The validated module was found to be significantly enriched in genes that are involved in the metabolism of nucleotides (P=2.41e-05). The epigenetic analysis revealed a significant enrichment of the adalimumab-associated variants in key epigenetic marks from different immune cell types including Tregs (P=0.04).

Conclusion:

These findings show the existence of a genetic basis for the clinical response to anti-TNF therapy. Our results also suggest that the genetic variation affecting clinical response is treatment-specific and, therefore, biomarker development in RA should take into account this diversity at the molecular level.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multi-omics-analysis-identifies-a-gene-signature-associated-with-the-clinical-response-to-anti-tnf-therapy-in-rheumatoid-arthritis/