The TNF‐863A allele strongly associates with anticentromere antibody positivity in scleroderma
Open Access
- 5 February 2004
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatism
- Vol. 50 (2), 558-564
- https://doi.org/10.1002/art.20065
Abstract
Objective Scleroderma is characterized by the presence of 3 predominant, yet almost mutually exclusive, antibodies: anticentromere antibody (ACA), antitopoisomerase 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-κB 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 (χ2 = 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 (χ2 = 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.Keywords
This publication has 29 references indexed in Scilit:
- Thalidomide Induces Granuloma Differentiation in Sarcoid Skin Lesions Associated with Disease ImprovementClinical Immunology, 2002
- Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DPGenes & Immunity, 2001
- Systemic Sclerosis in German Uranium Miners under Special Consideration of Autoantibody Subsets and HLA Class II AllelesRespiration, 1996
- Phototyping: comprehensive DNA typing for HLA‐A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence‐specific primers (PCR‐SSP)Tissue Antigens, 1995
- HLA and ethnic associations among systemic sclerosis patients with anticentromere antibodiesHuman Immunology, 1995
- Clinical and Prognostic Associations Based on Serum Antinuclear Antibodies in Japanese Patients with Systemic SclerosisArthritis & Rheumatism, 1994
- Immunogenetic associations of scleroderma‐related antinuclear antibodiesArthritis & Rheumatism, 1990
- Clinical associations of anticentromere antibodies and antibodies to topoisomerase i. a study of 355 patientsArthritis & Rheumatism, 1988
- Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosisArthritis & Rheumatism, 1988
- Preliminary criteria for the classification of systemic sclerosis (scleroderma)Arthritis & Rheumatism, 1980