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Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients
  1. Lydia R Coulthard1,
  2. John C Taylor1,2,
  3. Steve Eyre3,
  4. Biologics in Rheumatoid Arthritis Genetics and Genomics4,
  5. James I Robinson1,
  6. Anthony G Wilson5,
  7. John D Isaacs6,
  8. Kimme Hyrich4,
  9. Paul Emery1,
  10. Anne Barton3,
  11. Jennifer H Barrett1,2,
  12. Ann W Morgan1,
  13. Michael F McDermott1
  1. 1NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), University of Leeds, Leeds, UK
  2. 2Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
  3. 3Arthritis Research UK-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK.
  4. 4Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, ARC-EU, Stopford Building, Manchester, UK
  5. 5School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, UK
  6. 6Institute of Cellular Medicine, Musculoskeletal Research Group, The Medical School, Newcastle University, UK
  1. Correspondence to Professor Michael McDermott, NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK; m.mcdermott{at}leeds.ac.uk

Abstract

Background Rheumatoid arthritis (RA) does not always respond to available treatments, including tumour necrosis factor (TNF) antagonists. A study was undertaken to investigate whether genetic variation within genes, encoding proteins in the p38 signalling network, contribute to the variable response to TNF antagonists.

Methods 968 UK Caucasian patients with RA receiving anti-TNF therapy (infliximab, adalimumab and etanercept) were genotyped for 38 pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 12 candidate genes from the p38 network. Regression analyses were performed to test association between genotype and treatment response at 6 months using both absolute change in DAS28 (Disease Activity Score across 28 joints) and European League Against Rheumatism (EULAR) improvement criteria. Stratified analyses were performed to investigate association with individual therapies.

Results Twelve SNPs in seven genes were associated with improvement in DAS28 at 6 months at a nominal 0.1 significance level, jointly explaining 3% of variance in outcome in a model adjusting for other predictors. These encoded proteins both upstream (RIPK1, MKK6) and downstream (MAPKAPK2, MSK1, MSK2 and MNK1) of p38, and MIF, involved in p38 MAPK deactivation. Three SNPs (rs1258012 in MKNK1, rs4240847 in MAPKAPK2 and rs475032 in RPS6KA4 encoding MSK2) were associated with the EULAR response at the 0.1 level. SNPs in four genes showed correlation with the response to infliximab and adalimumab but not to etanercept. No SNPs had a greater impact on the response to etanercept.

Conclusions More SNPs than would be expected by chance, mapping to the p38 signalling network, showed association with the anti-TNF response as a whole, and particularly with the response to infliximab and adalimumab. Validation of these findings in independent cohorts is warranted.

  • Accepted 10 July 2010

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  • Accepted 10 July 2010
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Footnotes

  • AWM and MFMcD contributed equally to the design and writing of the paper.

  • Funding Arthritis Research UK and the NIHR-Leeds Musculoskeletal Biomedical Research Unit.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the UK Central Office of Research Ethics Committees (04/Q1403/37).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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