Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis

Pharmacogenomics J. 2018 Sep;18(5):657-664. doi: 10.1038/s41397-018-0040-6. Epub 2018 Aug 31.


Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 × 10-9). Capture Hi-C data show chromatin interactions in GM12878 cells between rs2540767, in high linkage disequilibrium with rs7195994 (R2 = 0.9) and IRX3, a neighbouring gene of FTO. IRX3 encodes a transcription factor involved in adipocyte remodelling and is regarded as the obesity gene at the FTO locus. Importantly, the rs7195994 association remained significantly associated following adjustment for BMI. In addition, using capture Hi-C data we showed interactions between TNFi-response associated variants and 16 RA susceptibility variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / genetics*
  • Female
  • Genome-Wide Association Study
  • Humans
  • Infliximab / therapeutic use
  • Linkage Disequilibrium / genetics
  • Male
  • Middle Aged
  • Severity of Illness Index
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Young Adult


  • Antirheumatic Agents
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO