1. ¹Division of Genomic Medicine, University of Sheffield, UK
2. ²Amgen Inc., CA, USA

Correspondence: Dr A Cox, Institute for Cancer Studies, G Floor, Sheffield University Medical School, Beech Hill Road, Sheffield, S10 2RX, UK. E-mail: a.cox@shef.ac.uk

³Current address: Department of Medical Informatics, University of Utah, Salt Lake City, UT, USA.

Received 31 January 2005; Revised 4 April 2005; Accepted 11 April 2005; Published online 2 June 2005.

Abstract

Biological activity of the IL-1 system depends on the balance between two proinflammatory proteins (IL-1 and IL-1) 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.