Abstract
IntroductionIn this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations.MethodsThe four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients.ResultsNone of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis.ConclusionOur data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.
Highlights
In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi)
Replication study First, we analyzed the association between the four tested polymorphisms and the efficacy of the TNFi therapy in the 438 RA patients of Spanish Caucasian origin in collection 1
In the subsequent analysis in collection 2, none of the tested polymorphisms showed an association with ΔDAS28 at 6 months (Table 2) (P = 0.995, P = 0.830, P = 0.458 and P = 0.661 for rs12081765, rs1532269, rs17301249 and rs7305646, respectively) or in the stratified analysis according to the European League Against Rheumatism (EULAR)-defined response
Summary
Our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial joints resulting in joint destruction, polyarthritis and functional disability. This inflammatory condition affects approximately 1% of the Caucasian population, making it a significant cause of comorbidity and mortality [1]. Researchers in pharmacogenetic studies have reported several genetic variants associated with clinical response to treatment with TNFi [7,8,9,10,11]. To date, only the PTPRC and PDE3A-SLCO1C1 loci have been associated in more than a single study [12,13,14]
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