Human Molecular Genetics Advance Access originally published online on August 19, 2008
Human Molecular Genetics 2008 17(22):3532-3538; doi:10.1093/hmg/ddn245
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Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis
1 Academic Rheumatology Group, University of Sheffield, D Floor Medical School, Beech Hill Road, Sheffield S10 2RX, UK 2 University of Manchester, Manchester M13 9PT, UK 3 Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, UK 4 University of Newcastle, Newcastle NE2 4HH, UK 5 University of Leeds, Leeds LS9 7TF, UK
* To whom correspondence should be addressed. Tel: +44 114 2713308; Fax: +44 114 2711711; Email: j.maxwell{at}sheffield.ac.uk
Received July 6, 2008; Accepted August 14, 2008
Anti-tumour necrosis factor (TNF) agents have revolutionized the treatment of patients with rheumatoid arthritis (RA). These therapies are, however, expensive and 30% of patients fail to respond. In a large cohort of Caucasian RA patients treated with anti-TNF medications (total n = 1050, etanercept n = 455, infliximab n = 450), we investigated whether genotypes of eight single nucleotide polymorphisms in the region containing the TNF gene were associated with response to anti-TNF therapy. Linear regression analyses adjusted for baseline 28 joint disease activity score (DAS28), baseline health assessment questionnaire score, gender and concurrent disease modifying anti-rheumatic drug treatment were used to assess association of these polymorphisms with treatment response, defined by change in DAS28 after 6 months. Analyses were performed in the entire cohort, and also stratified by anti-TNF agent. Association between DAS28 response and TNF-308 (rs1800629) genotype (P = 0.001) was detected across the whole cohort. After stratification by anti-TNF agent, the rare TNF-308AA genotype was associated with a significantly poorer response compared with TNF-308GG in etanercept (P = 0.001, n = 7) but not infliximab (P = 0.8, n = 17) treated patients. Conversely, the GA genotype at TNF-238 (rs361525) was associated with a poorer response to infliximab (P = 0.028, n = 40), but not etanercept (P = 0.6, n = 33). Owing to the small numbers of patients in some of the genotype groups examined, our data must be regarded as preliminary and will require replication in further large cohorts of anti-TNF-treated patients. If confirmed, our findings suggest the potential for genotype at these markers to aid selection of anti-TNF agent in patients with RA.
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