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Rheumatology 2002; 41: 830-831
© 2002 British Society for Rheumatology
Letters to the Editor |
Association of accelerated erosive rheumatoid arthritis with a polymorphism that alters NF-
B binding to the TNF promoter region
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) 1.04–3.41, P=0.02, 
2 test]. As expected, HLA-DR4 was also a major risk factor (OR 3.62, 95% CI 2.0–6.5, 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 0.93–3.1, P=0.05) with no effect in the HLA-DR4- group (OR 0.98, 95% CI 0.3–2.9).
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These findings raise the possibility that the TNF-863A allele is predictive of severe erosive joint disease in HLA-DR4+ individuals. It is worth noting that rheumatoid disease in general does not appear to be associated with the TNF-863A allele [5]. It would be premature to conclude that this is a causal relationship, as it might reflect linked genetic factors within the major histocompatibility complex (MHC), and our primary conclusion is that future genetic studies of the MHC region in rheumatoid arthritis should examine this specific TNF polymorphism as part of the haplotypic analysis. If the association is verified in other studies, this would suggest NF-
B as a potential therapeutic target for the prevention of severe erosive disease in individuals with rheumatoid arthritis.
Notes
Correspondence to: I. A. Udalova. 
References
- Maini R, St Clair EW, Breedveld F et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet1999;354:1932–9.[ISI][Medline]
- Foxwell B, Browne K, Bondeson J et al. Efficient adenoviral infection with IkappaBalpha reveals that macrophage tumor necrosis factor alpha production in rheumatoid arthritis is NF-kappaB dependent. Proc Natl Acad Sci USA1998;95:8211–5.
[Abstract/Free Full Text] - Higuchi T, Seki N, Kamizono S et al. Polymorphism of the 5'-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens1998;51:605–12.[ISI][Medline]
- Udalova IA, Richardson A, Denis A et al. Functional consequences of genetic variation in NK-kappaB p50/p50 binding to the TNF promoter region. Mol Cell Biol2000;20:9113–9.
[Abstract/Free Full Text] - Seki N, Kamizono S, Yamada A et al. Polymorphisms in the 5'-flanking region of tumor necrosis factor-alpha gene in patients with rheumatoid arthritis. Tissue Antigens1999;54:194–7.[Medline]
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