Background The presence of the T allele on the single-nucleotide polymorphism (SNP) rs7574865 has been associated with a high risk for the development of various autoimmune diseases including rheumatoid arthritis (RA). The SNP rs7574865 is located on the third intron of the STAT4 gene and, although this association has been documented in different populations, the functional impact of the occurrence of this genetic variant it is still not known.
Objectives To study the impact of the rs7574865 SNP on the transcription of STAT4 gene in a population of patients with early arthritis (EA).
Methods Data from 69 patients from our prospective EA register (90% women, age at disease onset 52.5 [42-68] (mean [p25-p75] years, time of disease duration at inclusion in the register 4.5 [2.6-7.9] months) were analyzed. Follow-up was carried out for two years with visits at baseline and at 6, 12 and 24 months. 64% of the patients met the EULAR/ACR 2010 criteria for classification of RA at the first visit. Rheumatoid factor (RF) was positive in 55% of patients and anti-cyclic citrullinated peptide antibodies (ACPA) were positive in 48%. Sociodemographic variables (gender, age, tobacco use, marital status, etc.) were collected at the first visit and disease-related variables (patient and physician disease assessment, tender and swollen joints counts, current and previous treatment, erythrocyte sedimentation rate, C-reactive protein, RF, ACPA, etc.) were collected according to the protocol at each visit. STAT4 and GAPDH, as housekeeping gene, levels were determined using quantitative real-time PCR with specific primers in a total of 182 visits (2.6 visits per patient). The genotype of the SNP rs7574865 on STAT4 was assessed through specific TaqMan probes (Applied Biosystems). In order to evaluate the effect of the independent variables on levels of STAT4 expression, a generalized linear model, nested by patient and visit, was fitted using the xtgee command of Stata 10.1 for Windows (StataCorp LP, College Station, TX, USA).
Results The level of STAT4 mRNA expression was very heterogeneous in the study population, though there was a trend towards a reduction during the follow-up. Multivariate analysis revealed that the presence of at least one T allele on rs7574865 (p=0.009) and high disease activity compared to remission (p=0.006) were associated with higher levels of STAT4 mRNA. As there was a reduction in the disease activity over the course of follow-up, that influenced on statistical model, when we removed the disease activity variable and included the time visit variable, the statistical model showed a significantly lower level of STAT4 at the 6- and 24-month visits (p=0.045 and 0.037, respectively) compared to baseline. No other sociodemographic, clinical or laboratory variables showed a statistically significant association with the expression of STAT4 mRNA.
Conclusions Our data suggest that the presence of the T allele on the SNP on STAT4 gene rs7574865 is associated with increased levels of STAT4 mRNA that might lead to enhanced signalling of these molecules whose receptor is coupled to STAT4.
This work has been partially financed by the RETICS program, RD08/0075 (RIER) and FIS 080754, from the Instituto de la Salud Carlos III (ISCIII).
Disclosure of Interest None Declared
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