Imunogenetické aspekty v etiopatogenezi arthritidy. Role promotorového polymorfismu-308G/A genu pro tumor nekrotizující faktor alfa.
| Title in English | Imunogenetic aspects in ethiopathogenesis of rheumatoid arthritis: Role of promotor polymorphism - 308 G / A gene in tumor necrosis factor ? |
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| Authors | |
| Year of publication | 2007 |
| Type | Article in Periodical |
| Magazine / Source | Čes. revmatologie |
| MU Faculty or unit | |
| Citation | |
| Field | Other specializations of internal medicine |
| Keywords | gen; polymorphism; rheumatoid arthritis; TNF alfa |
| Description | Rheumatoid arthritis (RA) is a polygenic disorder and genetic determination can contribute to both susceptibility and severity of the disease. Tumor necrosis factor (TNF) alfa, a potent pro-inflammatory cytokine, plays a key role in the pathogenesis of RA. Several alleles from the HLA-DRBl locus have been often found to be associated with RA. Thereby, the interest is focused on polymorphisms of the TNF alfa gene, which is located within the highly polymorphic MHC class III region next to HLA-DR locus on chromosome 6 (6p21.3). TNF alfa concentration is increased in plasma as well as in synovial fluid from patients with RA. Production of TNF alfa may be related to the polymorphisll1s in the TNF alfa 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 alfa. It is well known that TNF alfa can play a role in the process of atherosclerosis. The -308 G/A TNF alfa 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 possibe 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 Rheumatotogy 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 I: 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 alfa 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 TNF alfa promoter 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 radiogtaphic 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 alfa 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 alfa polymorphism, we found increased presence of genotype GG in patients with increased ( above 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). Conc1usion: The results of this work indicate an association of - 308 G/A TNF l alfa polymorphism with more severe course of RA. Moreover, potential association of this polymorphism with plasma level of LDL cholesterol in RA patients was found. |