Abstract
BackgroundThe R620W variant in protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with rheumatoid arthritis (RA). The PTPN22 gene has alternatively spliced transcripts and at least two of the splice forms have been confirmed to encode different PTPN22 (LYP) proteins, but detailed information regarding expression of these is lacking, especially with regard to autoimmune diseases.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The R620W variant in protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with rheumatoid arthritis (RA)
We aim to describe the variance in the expression of the splice forms of PTPN22 in peripheral blood mononuclear cells (PBMCs) in individuals with RA and in healthy controls and in relation to genotype data from this locus and to other RA risk factors
For PTPN22_v4 we saw a reduction in expression (0.85-fold decrease, non-significant) in RA cases and for PTPN22-long isoforms an increase in expression for RA cases (1.20-fold increase, P = 0.006) (Table 1)
Summary
The R620W variant in protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with rheumatoid arthritis (RA). The PTPN22 gene has alternatively spliced transcripts and at least two of the splice forms have been confirmed to encode different PTPN22 (LYP) proteins, but detailed information regarding expression of these is lacking, especially with regard to autoimmune diseases. 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 PTPN22 risk allele R620W and the HLA-DRB1 shared epitope (SE) alleles [10,11]. The alternatively spliced LYP2 has a shorter carboxyl terminus, resulting in the absence of the P2, P3, and P4 motifs [12]
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