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

Lydia R. Coulthard, John C. Taylor, Steve Eyre, James I. Robinson, Anthony G. Wilson, John D. Isaacs, Kimme Hyrich, Paul Emery, Anne Barton, Jennifer H. Barrett, Ann W. Morgan, Michael F. McDermott

    Research output: Contribution to journalArticlepeer-review

    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 (infl iximab, 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. Stratifi ed analyses were performe dto investigate association with individual therapies. Results: Seven SNPs, in fi ve genes, were associated with improvement in DAS28 at 6 months at a nominal 0.1 signifi cance 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-a 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 infl iximab 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 infl iximab and adalimumab. Validation of these fi ndings in independent cohorts is warranted.
    Original languageEnglish
    Pages (from-to)98-103
    Number of pages5
    JournalAnnals of the rheumatic diseases
    Volume70
    Issue number1
    DOIs
    Publication statusPublished - Jan 2011

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