Abstract
The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-α) promoter genotype/haplotype markers. Each patient's disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-α gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-α promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.
Highlights
Tumor necrosis factor-alpha (TNF-α) has been shown to be relevant for the physiopathology of rheumatoid arthritis (RA), and its inhibition by anti-TNF-α antibodies or recombinant soluble receptors results in a major improvement of this disease [1]
Present knowledge suggests that the highest genetic variability is concentrated in the promoter area of the TNF-α gene, where at least eight different single-nucleotide polymorphisms (SNPs) are concentrated, with the potential to affect the binding of transcriptor factors and to control the activity of the promoter and resulting mRNA and protein levels [4]
For every patient included in this study, detailed data were collected in a separate clinical record [9]: disease duration (DD), age of onset, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR) and C-reactive protein at the time of evaluation, the number of previous disease-modifying anti-rheumatic drugs (DMARDs), the use of anti-TNF-α treatments, the dose of prednisolone, previous joint surgeries due to inflammatory destructive arthropathy directly related to RA, the number of years of education, and work disability
Summary
Tumor necrosis factor-alpha (TNF-α) has been shown to be relevant for the physiopathology of rheumatoid arthritis (RA), and its inhibition by anti-TNF-α antibodies or recombinant soluble receptors results in a major improvement of this disease [1]. TNF-α production shows a wide variation, with high- and low-producer phenotypes present in humans [2] but with a strong concordance in monozygotic twins [3], pointing to the influence of genetic variation on the regulation of TNF-α circulating levels. These arguments have favored the view that genetic factors controlling TNF-α could have a major impact on RA outcome. Present knowledge suggests that the highest genetic variability is concentrated in the promoter area of the TNF-α gene, where at least eight different single-nucleotide polymorphisms (SNPs) are concentrated, with the potential to affect the binding of transcriptor factors and to control the activity of the promoter and resulting mRNA and protein levels [4]
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