Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways.
OBJECTIVE
To determine whether genetic variation within genes integral to the Toll-like receptor (TLR) and NFkappaB 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 NFkappaB 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.
Potter
Catherine
C
Musculoskeletal Research Group, Institute of Cellular Medicine, University of Newcastle, 4th Floor Catherine Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Cordell
Heather J
HJ
Barton
Anne
A
Daly
Ann K
AK
Hyrich
Kimme L
KL
Mann
Derek A
DA
Morgan
Ann W
AW
Wilson
Anthony G
AG
Isaacs
John D
JD
D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D004812:Epidemiologic Methods; D000068800:Etanercept; D005260:Female; D005838:Genotype; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D015398:Signal Transduction / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept