Objective To determine whether genetic variation within genes integral to the Toll-like receptor (TLR) and NFκB signalling systems, two cardinal regulators of inflammatory and immune responses, contributes towards the observed variation in response to tumour necrosis factor (TNF) blocking agents in patients with rheumatoid arthritis (RA).
Methods Pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 24 candidate genes were selected and genotyped in a large UK cohort of patients receiving anti-TNF therapy for RA. Multivariate regression analyses were performed to test association between individual genotypes, under an additive model, and treatment response at 6 months' follow-up assessed using both the absolute change in 28-joint count Disease Activity Score (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Analyses were performed across subgroups comprising etanercept-, infliximab- and infliximab/adalimumab-treated patients as well as the combined anti-TNF-treated cohort. p Values <0.05 were considered statistically significant.
Results A total of 187 SNPs were successfully genotyped and analysed in 909 patients. Eight SNPs spanning six genes demonstrated nominal evidence of association with response (DAS28) across the anti-TNF-treated subgroups, six of which were restricted to etanercept-treated patients. Twelve SNPs spanning nine genes demonstrated nominal evidence of association with treatment response (DAS28 and/or EULAR) across the combined anti-TNF cohort. These included SNPs mapping to MyD88 (rs7744) and CHUK (rs11591741), which were associated under each model applied (etanercept-treated and combined anti-TNF cohort analysis (DAS28 and EULAR)).
Conclusions Several SNPs mapping to the TLR and NFκB signalling systems demonstrated association with anti-TNF response as a whole and, in particular, with response to etanercept. Validation of these findings in an independent cohort is now warranted.
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Members of BRAGGSS are given in the online supplementary data.
Funding The authors thank JGW Patterson Foundation for funding this work. Work in Newcastle's Musculoskeletal Research Group is supported by the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust
Competing interests None.
Ethics approval This study was conducted with the approval of the UK Central Office of Research Ethics Committees (COREC) approval (04/Q1403/37).
Provenance and peer review Not commissioned; not externally peer reviewed.