OBJECTIVE: Anti-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.
METHODS: A 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.
RESULTS: 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 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).
CONCLUSIONS: In 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.