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

Arthritis Rheum. 2011 Mar;63(3):645-53. doi: 10.1002/art.30130.

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adult
  • Aged
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / genetics*
  • Cohort Studies
  • Female
  • Genetic Markers
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Precision Medicine / methods*
  • Predictive Value of Tests
  • Trans-Activators / genetics
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

  • Adaptor Proteins, Signal Transducing
  • EYA4 protein, human
  • Genetic Markers
  • Neoplasm Proteins
  • PDZD2 protein, human
  • Trans-Activators
  • Tumor Necrosis Factor-alpha