Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Association Between Anti-TNF Treatment Response and Genetic Variants within the TLR and NFB Signalling Pathways

Potter1,  Catherine, Cordell1,  Heather J., Barton2,  Anne, Daly1,  Ann K., Hyrich2,  Kimme, Mann1,  Derek A., Morgan3,  Ann W.

University of Newcastle, Newcastle, United Kingdom
University of Manchester, Manchester, United Kingdom
University of Leeds, Leeds, United Kingdom
Sheffield University, Sheffield, United Kingdom

Purpose:

To investigate association between response to anti-TNF therapy and genetic variation within genes integral to the toll-like receptor (TLR) and NFkB signalling systems, two cardinal regulators of inflammatory and immune responses, in a large UK-wide cohort of patients with rheumatoid arthritis (RA).

Method:

DNA samples from 923 patients receiving anti-TNF therapy (etanercept, infliximab or adalimumab) for the treatment of RA were available from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS). Pairwise-tagging SNPs spanning 24 candidate genes were selected from the HapMap dataset (www.hapmap.org) and genotyped using Sequenom iPLEX™ technology. Multivariate regression analyses were performed to test association between individual SNPs, under an additive model, and treatment response at 6-months follow-up. Treatment response was assessed using both the absolute change in DAS28 and the EULAR response criteria. Separate analyses were also performed to investigate association with individual anti-TNF drugs. P values <= 0.05 were considered statistically significant.

Results:

A total of 189 SNPs were successfully genotyped and analysed in 909 individuals. These patients had long-standing (mean duration = 14 years), active disease (mean DAS28 = 6.7) with a high degree of disability (mean HAQ score = 2.1). At 6 months follow-up, 20% of patients were non-responders, 53% moderate and 27% good responders according to the EULAR criteria. The mean change in DAS28 was an improvement of 2.5 points. Twelve SNPs spanning 9 genes (CHUK, IKBKB, IRAK-3, MyD88, NFkB-2, NFKBIB, PTGS2, TLR-2, TLR-10/1/6) demonstrated association with the absolute change in DAS28 and/or the EULAR response criteria (p<=0.05). In particular, associations to the MyD88 (rs7744) and CHUK (rs11591741) loci were demonstrated under each model applied. These variants map to the 3'UTR and intron 9 of the MyD88 and CHUK genes, respectively. In addition, both SNPs act as tagging markers for additional variants spanning the two genes, signifying a number of potential functional effects. Finally, a greater number of SNPs, including those mapping to MyD88 and CHUK, demonstrated associations specifically in the etanercept subgroup (n=386) compared to the infliximab (n=400) or infliximab/adalimumab combined treatment subgroups (n=523) when analysed separately.

Conclusion:

Several SNPs mapping to the TLR and NFkB signalling systems demonstrated association to anti-TNF response as a whole and, in particular with response to etanercept. Validation of these findings in independent datasets is now warranted before additional genetic and functional analyses are performed to identify the true causal variants.

To cite this abstract, please use the following information:
Potter, Catherine, Cordell, Heather J., Barton, Anne, Daly, Ann K., Hyrich, Kimme, Mann, Derek A., et al; Association Between Anti-TNF Treatment Response and Genetic Variants within the TLR and NFB Signalling Pathways [abstract]. Arthritis Rheum 2009;60 Suppl 10 :749
DOI: 10.1002/art.25829

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