Tumor Necrosis Factor α-308 and -238 Polymorphisms in Rheumatoid Arthritis. Association with Messenger RNA Expression and sTNF-α

BACKGROUND: Rheumatoid arthritis (RA) is characterized by a progressive joint damage mediated mainly by tumor necrosis factor alpha (TNFalpha). We investigated the relationship of TNFalpha-308 and -238 polymorphisms with messenger RNA (mRNA) expression and soluble TNFalpha (sTNFalpha) in 50 RA and 100 healthy subjects (HS). METHODS: Clinical and laboratory assessments were performed. Spanish Health Assessment Questionnaire Disability Index, Spanish version of Arthritis Impact Measurement Scales and Disease Activity Score using 28 joint count indices were applied to RA patients. The TNFalpha-308 and -238 polymorphisms were performed by polymerase chain reaction and restriction fragment length polymorphism techniques. The mRNA expression of TNFalpha was quantified by real-time polymerase chain reaction. The sTNFalpha levels were measured by enzyme-linked immunosorbent assay. RESULTS: The TNFalpha-308 polymorphism showed an increased frequency of guanine (G)/adenine (A) genotype in RA versus HS (P = 0.03; 95% confidence interval, 1.05-8.08; odds ratio, 2.9) and also the A allele was more frequent in RA patients versus HS (P = 0.04; 95% confidence interval, 1.01-7.29; odds ratio, 2.7). The G/G genotype and also the G allele were more frequent in HS. No significant difference was observed in TNFalpha-238 polymorphism. Rheumatoid arthritis patients showed high TNFalpha mRNA expression (1.33-fold). The G/G genotype was associated with high mRNA and sTNFalpha levels in both TNFalpha polymorphisms. The correlation of sTNFalpha levels with C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, Spanish Health Assessment Questionnaire Disability Index, and Spanish version of Arthritis Impact Measurement Scales, was observed. CONCLUSION: The TNFalpha-308 polymorphism is a susceptibility marker to RA. The G/G genotype is associated with a high mRNA and soluble TNFalpha expression.