Rheumatology Advance Access published online on June 22, 2007
Rheumatology, doi:10.1093/rheumatology/kem145
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Tumour necrosis factor-
single nucleotide polymorphisms are not independent of HLA class I in UK Caucasians with adult onset idiopathic inflammatory myopathies
1The University of Manchester, Rheumatic Diseases Centre, Hope Hospital, Salford, 2Centre for Integrated Genomic Medical Research, The University of Manchester, UK, 3Division of Rheumatology & Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA and 4Victorian Transplantation and Immunogenetic Service, Australian Red Cross Blood Transfusion Service, Melbourne, Australia.
Correspondence to:
R. G Cooper, The University of Manchester, Rheumatic Diseases Centre, Hope Hospital, Salford, M6 8HD. E-mail: robert.g.cooper{at}manchester.ac.uk
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Abstract |
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Objective. To investigate haplotype tagging single nucleotide polymorphisms (SNPs) in the tumour necrosis factor 
(TNF-) gene, in UK Caucasian idiopathic inflammatory myopathy (IIM) patients.
Methods. A cross-sectional, case-control study of four TNF- SNPs was undertaken, comparing cases of polymyositis (PM) (n = 121), dermatomyositis (DM) (n = 109) and myositis overlapping with other connective tissue diseases (CTD-overlap) (n = 73) with normal subjects (n = 177). Subgroup analyses were undertaken after stratifying for myositis specific/associated antibodies.
Results. The TNF-308A allele demonstrated a strong association with each myositis disease subgroup vs controls [PM, odds ratio (OR) 2.8, 95% confidence interval 1.9–4.3; DM, OR 2.5, 1.6–3.8; CTD-overlap, OR 3.3, 2.1–5.1]. The TNF-308GA/AA genotype frequency was significantly increased vs controls (PM, OR 3.7, 2.1–6.3; DM, OR 3.2, 1.8–5.5; CTD-overlap, OR 5.0, 2.6–9.6) suggesting a dominant model. The association was strongest in patients possessing anti-aminoacyl transfer RNA synthetase (anti-synthetase) (OR 5.1, 3.3–8.0) or -PM-Scl (OR 5.0, 2.7-8.9) antibodies. The -1031T allele was also a significant risk factor in DM (OR 2.2, 1.4–3.6), anti-synthetase (OR 2.9, 1.6–5.3) and -PM-Scl (OR 5.6, 1.9–6.4) antibody positive patients. The TNF-308A association was lost after adjusting for HLA-B*08, but remained independent of HLA-DQB1*02 (both are alleles forming part of the common ancestral haplotype). The HLA-B*08/TNF-308A/DRB1*03/DQA1*05/DQB1*02 haplotype was a risk factor in all myositis subgroups vs controls (OR 3.0, 1.8–5.3).
Conclusions. TNF-308A and -1031T alleles are significant risk factors in the IIMs. In the IIMs, the TNF-308A allele is part of the common ancestral haplotype, but is not independent of HLA-B*08.
KEY WORDS: Myositis, Polymyositis, Dermatomyositis, Polymorphisms, HLA, TNF-, Antibodies
Submitted 6 February 2007;
revised version accepted 23 April 2007.
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