The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma

被引:45
作者
Sato, H
Lagan, AL
Alexopoulou, C
Vassilakis, DA
Ahmad, T
Pantelidis, P
Veeraraghavan, S
Renzoni, E
Denton, C
Black, C
Wells, AU
du Bois, RM
Welsh, KI
机构
[1] Royal Brompton Hosp, Clin Genome Grp, London SW3 6LR, England
[2] Univ London Imperial Coll Sci Technol & Med, NHLI, London SW3 6LR, England
[3] Univ Oxford, Radcliffe Infirm, Oxford OX2 6HE, England
[4] Royal Free Hosp, London NW3 2QG, England
来源
ARTHRITIS AND RHEUMATISM | 2004年 / 50卷 / 02期
关键词
D O I
10.1002/art.20065
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. Scleroderma is characterized by the presence of 3 predominant, yet almost mutually exclusive, antibodies: anticentromere antibody (ACA), anti-topoisomerase antibody, and anti-RNA polymerase antibody. The purpose of this study was to investigate tumor necrosis factor (TNF) polymorphisms in scleroderma, with the specific aim of determining whether TNF polymorphisms would prove to be stronger markers for ACA than class II major histocompatibility complex (MHC). Methods. We studied 214 UK white scleroderma patients and 354 healthy controls. All subjects were investigated for 5 TNF promoter region polymorphisms by sequence-specific polymerase chain reaction. Results. We showed that an NF-kappaB binding site polymorphism (known to be functionally relevant) in the TNF promoter region was present in 51.8% of patients with ACA and 16.3% of patients without ACA (chi(2) = 25.1, P = 0.000004 [corrected P = 0.00002]). Using haplotype mapping, we showed that this was a primary TNF association that could explain the previous weak links between ACA production and class II MHC alleles. In marked contrast to our ACA results, HLA class II (especially DRB1*11) appeared to be primary in that it could explain the weaker TNF association with antitopoisomerase production. Further, we observed a separate TNF haplotype to be associated with scleroderma per se, although the level of significance was much lower (chi(2) = 8.7, P = 0.003 [corrected P = 0.02]). Conclusion. We believe these findings may have importance both for the directional pathogenesis of scleroderma progression and for the treatment of scleroderma with anti-TNF agents.
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页码:558 / 564
页数:7
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