The rs7574865 polymorphism of the <i>STAT4</i> gene and risk of early rheumatoid arthritis development (the REMARKA study)

Abstract

The aim of the study was investigation of association of the rs7574865 polymorphism of STAT4 gene (Signal Transducer and Activator of Transcription 4, a family of signal transduction and transcription activation molecules 4) with very early rheumatoid arthritis (RA) in Russian patients, and the study of the relationship of "phenotype – genotype", particularly of positivity for antibodies to cyclic citrullinated peptides (ACCP), their concentration, the presence of erosive joint damage at inclusion in patients the study with the STAT4 gene polymorphism. Material and methods. The study was conducted in the framework of the program REMARKA (Russian study of Methotrexate and biological drugs in Early active Arthritis). 85 patients with very early RA with a duration of symptoms no more than 6 months, not receiving disease modifying anti-rheumatic drugs (DMARD) and biologicals were included. Results and discussion. The analysis of the distribution of genotypes and alleles of STAT4 rs7574865 polymorphism showed that the frequencies of g/G, G/T and T/T genotypes differ at the level of the prominent tendency to statistical significance between patients with RA and the control group (p=0.05). The frequency of minor allele T in RA is significantly higher than that in the control group, and this allele is associated with a predisposition to RA [odds ratio (OR) 1.7; 95% confidence interval (CI) 1.1–2.8; p=0.03]. In the study of the "genotype – phenotype" relationship, STAT4 gene polymorphism correlated with erosive joint damage (r2=0.289; p=0.008). In carriers of the homozygous genotype TT, the number of erosions at inclusion in the study was significantly higher compared with carriers of genotypes GG/GT (median 5.50 [0.754; 7.5] and 0.00 [0.00; 2.00], respectively; p=0.003). The risk of erosion is also associated with the polymorphism of the STAT4 gene (OR 8.6; 95% CI 1.0–204.9; p=0.03). A difference of the ACCP level depending on STAT4 gene polymorphism was revealed: carriers of at least one minor allele T (G/T+T/T) had significantly higher concentration of ACCP than that in carriers of homozygous GG genotype: 248.97±151.00 and 179.51±147.01 U/ml, respectively; p=0.048).Conclusion. The study showed that in Russian patients with very early RA, the STAT4 gene rs7574865 polymorphism is associated with both predisposition to the disease and prognostically unfavorable manifestations (phenotypes) of the disease, namely, with the development of erosion in the early stages of the disease and an increase of the ACCP level.

Keywords

• rheumatoid arthritis
• <i>stat4</i> gene
• single nucleotide polymorphism
• destructive joint damage
• antibodies to cyclic citrullinated peptides