Genome‐wide association study of genetic predictors of anti–tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci

Abstract

Objective Anti–tumor necrosis factor (anti‐TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30–40% of patients treated. Knowledge of the genetic factors that influence response may facilitate personalized therapy. The purpose of this study was to identify genetic predictors of response to anti‐TNF therapy in RA and to validate our findings in independent cohorts. Methods Data from genome‐wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti‐TNF–treated RA patients. Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single‐nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10⁻³) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed. Results Of 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient −0.27, P = 5.67⁻⁰⁵). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37⁻⁰⁴). The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12. Conclusion Using a genome‐wide strategy, we have identified and validated the association of 7 genetic loci with response to anti‐TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.