The balance of expression of PTPN22 splice forms is significantly different in rheumatoid arthritis patients compared with controls

We have investigated the mRNA expression of known PTPN22 splice forms with TaqMan real-time PCR in relation to ZNF592 as an endogenous reference in peripheral blood cells from three independent cohorts with RA patients (n = 139) and controls (n = 111) of Caucasian origin. Polymorphisms in the PTPN22 locus (25 SNPs) and phenotypic data (gender, disease activity, ACPA and RF status) were used for analysis. Additionally, we addressed possible effects of methotrexate treatment on PTPN22 expression.We found consistent differences in the expression of the PTPN22 splice forms in unstimulated peripheral blood mononuclear cells between RA patients and normal controls. This difference was more pronounced when comparing the ratio of splice forms and was not affected by methotrexate treatment.Our data show that RA patients and healthy controls have a shift in balance of expression of splice forms derived from the PTPN22 gene. This balance seems not to be caused by treatment and may be of importance during immune response due to great structural differences in the encoded PTPN22 proteins.It is well established that rheumatoid arthritis (RA) is a heritable disease with a substantial genetic influence on the outcome. PTPN22 is one of the few undisputed genetic risk factors for RA that has been replicated in many Caucasian populations, and evidence for its being a true susceptibility gene is strong [1,2]. Since the discovery of the importance of PTPN22 in the function of lymphocytes [3,4], and especially after its association with different autoimmune diseases [1], several attempts have been made to explain the biological mechanism of how PTPN22 gene variants may influence protein activity and subsequent differences in cell function. The best-associated polymorphism, rs2476601, which affects amino acid 620, is an R to W missense polymorphism that may alter the function of the protein. Many studies have focused on this change of function and have indeed found evidence for immune reg