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Background  The number of copies of the  HLA-DRB1  shared epitope, and the minor alleles of the  STAT4  rs7574865 and the  PTPN22  rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis.    Methodology and Results  We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up.  HLA-DRB1  alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5′ allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in  STAT4  was associated with increased disease activity (DAS28) as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01–0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in  PTPN22  was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = −0.27 [−0.56– −0.01], p = 0.042; TT genotype = −0.68 [−1.64– −0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in  STAT4  was associated with greater disability as compared with the GG genotype.    Conclusions  Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in  STAT4  may develop a more severe form of the disease with increased disease activity and disability.

The TT Genotype of the STAT4 rs7574865 Polymorphism Is Associated with High Disease Activity and Disability in Patients with Early Arthritis