Associations with tumour necrosis factor (TNF) alpha single nucleotide polymorphisms (SNPs) and the idiopathic inflammatory myopathies (IIMs).

Aim: To investigate the associations of the TNF gene with the IIMs, and explore the relationship with TNF and HLA class II. Methods: DNA samples were obtained from a group of 270 UK Caucasian IIM patients, comprising 103 polymyositis (PM), 95 dermatomyositis (DM), and 72 polymyositis associated with connective tissue disease (PM/CTD). The PM and DM patients had probable or definite myositis (Bohan and Peter, 1975). Patients with PM/CTD fulfilled criteria for their primary CTD, and had 2/5 Bohan and Peter features. Four polymorphic TNF positions (-1031, -863, -308, +489) were typed using a fluorescence-based primer method (SNaPshotTM). These cohorts had previously been typed for HLA-B and -DRB1. The results were compared with those of 173 ethnically matched controls. Each TNF SNP was tested for Hardy-Weinberg, allelic, genotypic, dominant, recessive associations and a trend test. A haplotype trend regression analysis was also performed. Results: Of the SNPs tested, only TNF-863 was not in Hardy-Weinberg. TNF-308A was a significant risk factor when all patients were combined (30.7% of patients vs 14.7% controls, odds ratio [OR] 2.6, 95% confidence interval [CI] 1.8-3.7). The association was still significant when stratified by IIM subgroup, the strongest association being in the PM/CTD group (OR 3.1, 95% CI 2.0-5.0), but no between subgroup differences were present. In most cases, a single copy of the TNF-308A allele was sufficient to increase the frequency, suggesting a dominant mode of inheritance. Furthermore, TNF-1031T was a weak but significant risk factor in DM (85.8% patients vs 74.9% controls, OR 2.0 (95% CI 1.3-3.2), the association being lost after correction for multiple comparisons. Haplotype trend regression analyses revealed significant associations with the 4 SNP haplotypes of TNF for all IIM subtypes (p