Wellcome Trust Centre for Human Genetics, 7 Roosevelt Drive, Oxford University, Oxford OX3 7BN, UK
SIR, Clinical trials of monoclonal antibody therapy have highlighted the important role played by tumour necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis [1]. Production of TNF by synovial tissue from patients with rheumatoid arthritis is dependent on the NF-B transcription factor pathway [2]. The TNF promoter region contains several binding sites for NF-
B, one of which contains a single-nucleotide polymorphism situated 863 nucleotides upstream of the transcription start site [3]. The TNF-863A allele specifically reduces binding of NF-
B p50/p50 homodimer to this part of the TNF promoter region, and reporter gene analysis indicates that the variant allele acts to enhance inducible TNF production in primary human monocytes [4]. These functional properties suggest that this polymorphism might affect susceptibility to rheumatoid arthritis.
Eighty-one patients undergoing joint replacement surgery for severe rheumatoid arthritis were recruited at the Nuffield Orthopaedic Centre in Oxford. All were rheumatoid factor-seropositive (rheumatoid arthritis particle agglutination titre >1/80) and had accelerated erosive disease requiring large joint replacement within 15 yr of onset of symptoms. Controls were 176 healthy adult blood donors recruited from the Oxford and Bristol region: all cases and controls were local residents of Caucasoid origin. The study was approved by the Central Oxford Regional Ethics Committee.
Genotyping of the TNF-863A allele was performed on genomic DNA by polymerase chain reaction (PCR) using sequence-specific primers (TNF-863C, CGAGTATGGGGACCCCCC; TNF-863A, GAGTATGGGGACCCCCA) with a common reverse primer (CCGGGAATTCACAGACCCC). HLA-DR was typed by PCR with sequence-specific oligonucleotides.
Results are shown in Table 1. The proportion of individuals carrying the TNF-863A allele was higher in cases than controls [odds ratio (OR) 1.89, 95% confidence interval (CI) 1.043.41, P=0.02,
2 test]. As expected, HLA-DR4 was also a major risk factor (OR 3.62, 95% CI 2.06.5, P<0.0001) and statistical correction for HLA-DR4 type reduced the effect of TNF-863A (Mantel-Haenszel weighted OR=1.62, P=0.16). Inspection of the stratified data suggests that possession of the TNF-863A allele increases the risk of accelerated erosive rheumatoid arthritis in HLA-DR4+ individuals (OR 2.16, 95% CI 0.933.1, P=0.05) with no effect in the HLA-DR4- group (OR 0.98, 95% CI 0.32.9).
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Notes
Correspondence to: I. A. Udalova.
References
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