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

Lookup NU author(s): Professor John Isaacs

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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-alpha 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.


Publication metadata

Author(s): Coulthard LR, Taylor JC, Eyre S, Robinson JI, Wilson AG, Isaacs JD, Hyrich K, Emery P, Barton A, Barrett JH, Morgan AW, McDermott MF

Publication type: Article

Publication status: Published

Journal: Annals of the Rheumatic Diseases

Year: 2011

Volume: 70

Issue: 1

Pages: 98-103

Print publication date: 30/08/2010

ISSN (print): 0003-4967

ISSN (electronic): 1468-2060

Publisher: BMJ Group

URL: http://dx.doi.org/10.1136/ard.2010.133249

DOI: 10.1136/ard.2010.133249


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