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

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Jonathan Massey1, Darren Plant2, Kimme Hyrich2,3

  • 1Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.

The Pharmacogenomics Journal
|September 1, 2018
PubMed

Insights

Genetic variants near the FTO gene predict response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients. The rs7195994 variant influences swollen joint count reduction, independent of BMI.

Area of Science:

  • Genetics
  • Immunology
  • Rheumatology

Background:

  • Rheumatoid arthritis (RA) involves chronic joint inflammation.
  • Tumor necrosis factor alpha inhibitors (TNFi) revolutionized RA treatment.
  • Significant non-response rates limit current TNFi efficacy.

Purpose of the Study:

  • Identify genetic predictors of treatment response in RA patients receiving TNFi.
  • Analyze changes in Disease Activity Score 28 (DAS28) and its components.

Main Methods:

  • Genome-wide association study (GWAS) of 1752 UK RA patients treated with TNFi.
  • Analysis of Disease Activity Score 28 (DAS28) changes over 3-6 months.
  • Capture Hi-C data used to investigate chromatin interactions.

Main Results:

  • The FTO gene locus variant rs7195994 associated with infliximab response (p=9.74×10⁻⁹) in swollen joint count (SJC28).
  • rs7195994 is in high linkage disequilibrium with rs2540767, interacting with IRX3.
  • Association remained significant after adjusting for Body Mass Index (BMI).
  • TNFi-response variants interact with 16 RA susceptibility variants.

Conclusions:

  • Genetic variations, specifically rs7195994 at the FTO locus, can predict TNFi treatment response in RA patients.
  • IRX3, a gene near FTO, is implicated in RA treatment response.
  • These findings may inform personalized medicine approaches for RA management.

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