Abstract
ObjectiveAnti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25–30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response.MethodsA total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy.ResultsWe found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042).ConclusionsIn the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.
Highlights
The introduction of Tumor Necrosis Factor (TNF) inhibitors has revolutionized the treatment of rheumatoid arthritis (RA)
We found a significant association between FCGR2A and the response to adalimumab (P=0.022)
Analyzing the subset of anti-CCP positive RA patients (78%), we found a significant association between FCGR2A and the response to infliximab (P=0.035)
Summary
The introduction of Tumor Necrosis Factor (TNF) inhibitors has revolutionized the treatment of rheumatoid arthritis (RA). Anti-TNF alpha agents have made it possible to achieve a minimal inflammatory activity or even disease remission [1,2] Despite their clear efficacy in RA management, there is a substantial group of patients who will fail to respond to this therapeutic approach [3]. Candidate-gene studies, limited to the knowledge of the biological pathways associated to a particular disease or trait, have been successful in identifying new candidate loci for the response to anti-TNF therapy [9]. One such candidate gene is FCGR2A, encoding an Fc receptor mainly expressed in macrophages and dendritic cells [10], and for which there is increasing evidence supporting its association to anti-TNF therapy in RA [11]
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