Immunogenetic aspects of etiopathogenesis of rheumatoid arthritis: the role of - 308 G/A tumor necrosis factor α promoter polymorphism

Czech version

Authors: P. Němec
Authors‘ workplace: Revmatologická ambulance II. interní kliniky FN u sv. Anny v Brně a LF MU Brno
Published in: Čes. Revmatol., 15, 2007, No. 1, p. 25-33.
Category: Summaries of Doctoral Dissertations

Overview

Introduction.
Rheumatoid arthritis (RA) is a polygenic disorder and genetic determination can contribute to both susceptibility and severity of the disease. Tumor necrosis factor (TNF) α, a potent pro-inflammatory cytokine, plays a key role in the pathogenesis of RA. Several alleles from the HLA-DRB1 locus have been often found to be associated with RA. Thereby, the interest is focused on polymorphisms of the TNF α gene, which is located within the highly polymorphic MHC class III region next to HLA-DR locus on chromosome 6 (6p21.3). TNF α concentration is increased in plasma as well as in synovial fluid from patients with RA. Production of TNF α may be related to the polymorphisms in the TNF α gene. In patients with RA, cardiovascular diseases are responsible for death in 35 – 50 % cases, whereas in general adult population in about 20 - 25 % cases. This increased risk may be associated with RA-specific risk factors such as hyperhomocysteinemia, disease-related dyslipidemia, vascular inflammation, or increased levels of TNF α. It is well known that TNF α can play a role in the process of atherosclerosis. The -308 G/A TNF α promoter polymorphism was demonstrated to associate with obesity, dyslipidemia, insulin resistance, and hypertension - risk factors for coronary heart disease. The aim of the study was to analyze literature data, select a candidate gene for RA, and demonstrate possible association between its polymorphism and risk for onset and severity of RA with respect to several features of the disease.

Methods.
A total of 130 patients with RA according to the American College of Rheumatology revised criteria were recruited into the study. The disease duration was at least 2 years. Patients were classified into four groups according to the grade of radiographic progression of the hand and wrist (Steinbrocker radiographic score: grade 1: non-erosive RA – 15 patients, grade II – IV: erosive RA – 114 patients). Control group consisted of 150 subjects with similar age and sex distribution.

Results.
We observed no differences in genotype distributions and allelic frequencies of – 308 G/A TNF α promoter polymorphism between RA patients and control group. Significant difference was found for GG genotype in contrast to other genotypes (AA + AG) in – 308 G/A TNFα promotor polymorphism between patients with non-erosive and erosive diseases. In patients with erosive disease, GG genotype was more frequent (47.0 % vs. 74.6 %; OR = 3.35; 95% CI 0.99 – 11.45; P = 0.03). Statistically significant difference was also in allelic frequencies (Pa = 0.05). The difference between groups of patients with respect to genotype distribution was on the borderline of significance (Pg = 0.06). Comparing non-erosive patients and patients with the worst grade of radiographic involvement of the hand and wrist (grade IV), the prevalence of GG genotype was more than 6-fold higher in patients with erosive RA (40.0 % vs. 87.0 %; OR = 6.29; 95 % CI 1.19–36.43; P = 0,01). The difference in allelic frequencies of – 308 G/A TNF α polymorphism between groups of patients with different disabilities according to HAQ was found. Higher frequency of allele G was found in patients with more severe disability (HAQ > 1.00) (Pa = 0.035). Moreover, comparing genotype GG with other genotypes (AA + AG) of – 308 G/A TNF α polymorphism, we found increased presence of genotype GG in patients with increased (> 3.00 mmol/l) in contrast to patients with normal (1.00 – 3.00 mmol/l) plasma level of LDL cholesterol (OR = 2.29; 95% CI 0.94 – 5.63; P = 0.035). Statistically significant difference between those groups was also found for alellic frequencies (Pa = 0.047). Conclusion: The results of this work indicate an association of – 308 G/A TNF α polymorphism with more severe course of RA. Moreover, potential association of this polymorphism with plasma level of LDL cholesterol in RA patients was found.

Key words:
gene, polymorphism, rheumatoid arthritis, TNF α

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Article was published in

Czech Rheumatology

2007 Issue 1