The STAT4 rs7574865 polymorphism is associated with differences in disease activity and disability in patients wirh early arthritis

Abstract

Background/Purpose: The presence of shared epitope and the minor allele of single nucleotide polymorphisms (SNPs) of STAT4 (rs7574865) and PTPN22 (rs2476601) have been associated with an increased risk of developing rheumatoid arthritis (RA). However, it is not well established whether these genetic markers could also determine a more severe clinical course of RA. The objective was to determine whether the genetic variants of STAT4 rs7574865 and PTPN22 rs2476601 and the number of copies of the shared epitope in HLA-DRB1 affect disease activity or disability in patients with early arthritis (EA). Methods: We studied 596 patients (75% female, median age at onset 51 years) of the EA registers of Hospital U La Paz and La Princesa in Madrid, who were followed up 2 years with visits every 6 months. Demographic and disease variables (rheumatoid factor, anti-CCP antibody [a-CCP, Euro-Diagnostica ELISA. Arnhem, Holland]), HAQ and variables needed to the estimation of DAS28 were collected. The HLA-DRB1 alleles were determined by medium-resolution technique (PCR-SSO) and sequencing was only done for the determination of certain subtypes of DR4. Genotyping of rs7574865 and rs2476601 was performed using real-time PCR and specific Taqman probes (Applied Biosystems). Multivariate analysis was performed using generalized estimating equations for repeated measures using the function xtgee of Stata 10.1 for Windows (StataCorp LP, College Station, TX, USA). We used the method nullbackward stepwise selectionnull to achieve the best fitting model, removing from the initial model, which included all independent variables, all those with p > 0.15. Results: Female gender (b coefficient = 0.50 (plus or minus) 0.13; p < 0.001), older age ([by 10 year] 0.22 (plus or minus) 0.03; p < 0.001), a-CCP positivity (0.22 (plus or minus) 0.21; p = 0.056) and TT genotype of rs7574865 in STAT4 (0.71 (plus or minus) 0.32; p = 0.024) were associated with greater disease activity as measured by DAS28. A trend towards greater disease activity was detected in active smokers (0.25 (plus or minus) 0.23; p = 0.074), whereas no association was found between the value of DAS28 and the presence of shared epitope and a tendency to lower activity in the homozygous minor allele of SNP in PTPN22 (-0.74 (plus or minus) 0.92; p = 0.132) was also observed. There was no additive or synergistic effect between the presence of a-CCP and STAT4. On the other hand, female gender (0.1 (plus or minus) 0.08; p < 0.015), older age ([by 10 year] 0.03 (plus or minus) 0.02; p = 0.003) and heterozygosity (0.08 (plus or minus) 0.07; p = 0.035) or homozygosity (0.17 (plus or minus) 0.15; p = 0.022) for the T allele of rs7574865 in STAT4 were associated with functional capacity. Conclusion: Our data suggest that EA patients with the minor allele of SNP rs7574865 in STAT4, in addition to a higher risk of developing RA, would have a more severe disease with increased activity and disability. These data have not been observed for the presence of shared epitope or PTPN22 variant that confers increased risk of RA.