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Evidence of a pharmacogenomic response to interleukin-l receptor antagonist in rheumatoid arthritis

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Abstract

Biological activity of the IL-1 system depends on the balance between two proinflammatory proteins (IL-1α and IL-1β) and the related anti-inflammatory protein, the IL-1 receptor antagonist (IL-1Ra). The genes for these proteins lie within 430 kb on human chromosome 2. Based on a clinical trial of human recombinant IL-1ra in rheumatoid arthritis, we tested whether IL-1 genotype might be related to the likelihood of response to anti-IL-1 therapy. A positive response was defined as a reduction of at least 50% in the number of swollen joints by week 24, following treatment with either 150 mg/day IL-1ra or placebo. The response rate to treatment, independent of genotype, was 48% (44/91). A highly significant association was found between carriage of the rarer allele at IL1A(+4845) and response to treatment (P=0.0009; OR=4.85 (1.85,12.70)). The response rate in patients carrying this allele was 63.4% compared with 26.3% in noncarriers. A weaker association was found for IL1B(+3954) (P=0.02). There was a highly significant interaction between treatment (150 mg/day or placebo) and the composite genotype across IL1A(+4845) and IL1B(+3954) (P=7.6 × 10−5). No associations with IL-1 genotypes were found in patients receiving placebo. Thus, a significant pharmacogenomic effect was found in the treatment of RA patients with recombinant IL-1ra.

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Acknowledgements

DM and WR are employed by Amgen Inc. and the research was funded by Amgen Inc. NJC and AC were supported by a grant from the Arthritis and Rheumatism Campaign.

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  1. N J Camp

    Present address: Department of Medical Informatics, University of Utah, Salt Lake City, UT, USA

Authors and Affiliations

  1. Division of Genomic Medicine, University of Sheffield, UK

    N J Camp, A Cox, F S di Giovine & G W Duff

  2. Amgen Inc., CA, USA

    D McCabe & W Rich

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  1. N J Camp
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  2. A Cox
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  3. F S di Giovine
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  4. D McCabe
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  6. G W Duff
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Correspondence to A Cox.

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Camp, N., Cox, A., di Giovine, F. et al. Evidence of a pharmacogenomic response to interleukin-l receptor antagonist in rheumatoid arthritis. Genes Immun 6, 467–471 (2005). https://doi.org/10.1038/sj.gene.6364228

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  • DOI: https://doi.org/10.1038/sj.gene.6364228

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