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Ann Rheum Dis 70:98-103 doi:10.1136/ard.2010.133249
  • Clinical and epidemiological research
  • Extended report

Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients

  1. 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
  1. Contributors LC, JR, AM, MD were involved in the design of the study; AW, JI, KH, PE, AB and AM contributed to the recruitment of patients, with collection of patient samples and clinical data; SE did the genotyping; JT and JB performed data analysis; LC, JT, SE, JR, AW, JI, KH, PE, AB, JB, AM and MD contributed to the interpretation of the data and also preparation of the manuscript. Writing of the final manuscript was by LC, JT, JR, JB, AM and MD.

  • Accepted 10 July 2010
  • Published Online First 30 August 2010

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, contributes to the variable response to TNF antagonists.

Methods 1102 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 Seven SNPs, in five 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 (MKK6) and downstream (MAPKAPK2, MSK1, MSK2) of p38, and MAPK14, the p38-α isoform of p38 MAPK. One SNP (rs2716191 in MAP2K6) was associated with EULAR response at the 0.1 level. SNPs generally showed greater correlation with response to infliximab and adalimumab, but not 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.

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.