Protein tyrosine phosphatase non-receptor 22 and C-Src tyrosine kinase genes are down-regulated in patients with rheumatoid arthritis

Sara Remuzgo-Martínez,Gonzalo Ocejo-Vinyals,Santos Castañeda,Trinitario Pina,Miguel A González-Gay,Raquel López-Mejías,Ricardo Blanco,Alfonso Corrales,Javier Llorca,Juan Irure-Ventura,Pablo Moreno-Fresneda,Javier Martín,Virginia Portilla,Fernanda Genre,Jesús González-Vela,Verónica Mijares,Begoña Ubilla

doi:10.1038/s41598-017-10915-9

Abstract

Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility. Nevertheless, its potential influence on PTPN22 expression in RA has not been completely elucidated. Furthermore, PTPN22 binds to C-Src tyrosine kinase (CSK) forming a key complex in autoimmunity. However, the information of CSK gene in RA is scarce. In this study, we analyzed the relative PTPN22 and CSK expression in peripheral blood from 89 RA patients and 43 controls to determine if the most relevant PTPN22 (rs2488457, rs2476601 and rs33996649) and CSK (rs34933034 and rs1378942) polymorphisms may influence on PTPN22 and CSK expression in RA. The association between PTPN22 and CSK expression in RA patients and their clinical characteristics was also evaluated. Our study shows for the first time a marked down-regulation of PTPN22 expression in RA patients carrying the risk alleles of PTPN22 rs2488457 and rs2476601 compared to controls (p = 0.004 and p = 0.007, respectively). Furthermore, CSK expression was significantly lower in RA patients than in controls (p < 0.0001). Interestingly, a reduced PTPN22 expression was disclosed in RA patients with ischemic heart disease (p = 0.009). The transcriptional suppression of this PTPN22/CSK complex may have a noteworthy clinical relevance in RA patients.

Highlights

Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility
After checking that PTPN22 rs2488457, rs2476601 and rs33996649 were in Hardy-Weinberg equilibrium (HWE), we observed a significant down-regulation of PTPN22 in patients with RA carrying PTPN22 rs2488457 risk allele G and rs2476601 risk allele A compared to healthy controls (p = 0.004 and 0.007, respectively) (Fig. 2a,b and Table 1)
Our study disclosed for the first time that two PTPN22 genetic variants, rs2488457, located in the promoter region, and rs2476601, located in exon 14, down-regulate the transcription and function of PTPN22 in patients with RA compared to controls, who have higher PTPN22 expression

Summary

Introduction

Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility. Mutations in the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene are associated with numerous autoimmune diseases[1, 2]. In this regard, several PTPN22 single-nucleotide polymorphisms (SNPs) have been significantly related with susceptibility to rheumatoid arthritis (RA)[3,4,5,6,7]. Since PTPN22 is an intracellular tyrosine phosphatase that mainly inhibits T-cell receptor (TCR) signaling pathway, it is critically involved in the development of autoimmune diseases[1, 2] This function is strengthened by the interaction with C-Src tyrosine kinase (CSK), a negative regulator of TCR signaling[13, 14]. The association between PTPN22 and CSK expression in RA patients and their clinical characteristics was studied

Methods

Results

Conclusion