The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis

Abstract

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.

Figure 1. Patients with early arthritis who were homozygous for the minor rs7574865 allele of STAT4 exhibited stronger disease activity during the follow-up.

The data are categorized according to the rs7574865 genotype of STAT4 (upper panel), the rs2476601 genotype of PTPN22 (middle panel), and the number of copies of the shared epitope (SE; lower panel). Data represent the interquartile range (p75, upper edge of the box; p25, lower edge; p50, midline), p95 (line above the box) and p5 (line below the box) of the DAS28 adjusted for gender and age (aDAS28). Dots represent outliers.

Figure 2. Effect of the rs7574865 and rs2476601 polymorphisms in STAT4 and PTPN22 on the level of disease activity in patients with early arthritis.

A) STAT4 genotypes: GG, white bars; GT, gray bars; TT, black bars. B) PTPN22 genotypes: CC, white bars; CT, gray bars; TT, black bars. Data represent the proportion of visits in which remission, or low, moderate or high disease activity was recorded in the patients of each genotype. This figure illustrates the findings presented in Table 3, in which the statistical significance of the differences in disease activity associated with the genotype of each polymorphism is shown.

Figure 3. Patients with early arthritis who are homozygous for the minor rs7574865 allele of STAT4 exhibit increased disability during follow-up.

The data are categorized according to the rs7574865 genotype of STAT4 (upper panel), the rs2476601 genotype of PTPN22 (middle panel), and the number of copies of the shared epitope (SE; lower panel). The data are presented as the interquartile range (p75, upper edge of the box; p25, lower edge; p50, midline), the p95 (line above box) and p5 (line below the box) of the HAQ adjusted for gender and age (aHAQ). Dots represent outliers.