Background/Purpose: Protein tyrosine phosphatase non-receptor 22 (PTPN22) binds to C-Src tyrosine kinase (CSK) forming a key regulator complex in autoimmunity¹. In this regard, PTPN22 is the main non-HLA genetic risk factor involved in rheumatoid arthritis (RA) susceptibility² and several PTPN22 single-nucleotide polymorphisms (SNPs) have been significantly related with RA³. Moreover, PTPN22 expression profiles have been proposed as biomarkers of RA⁴. Nevertheless, the potential influence of PTPN22 SNPs on PTPN22 expression in RA has not been elucidated and there is no information of the role of CSK in RA. Accordingly, we determined if the most relevant PTPN22 (rs2488457, rs2476601 and rs33996649) and CSK (rs34933034 and rs1378942) polymorphisms may influence on PTPN22 and CSK expression in peripheral blood of RA patients when compared to healthy controls.

Methods:

PTPN22 and CSK mRNA expression was assessed by quantitative real-time PCR in peripheral blood samples from 89 patients with RA, who met the 1987 ACR and the 2010 ACR/European League Against Rheumatism criteria for RA^5-6, and 43 healthy controls recruited from Hospital Universitario Marqués de Valdecilla (Santander, Spain) and Hospital Universitario La Princesa (Madrid, Spain). PTPN22 (rs2488457, rs2476601 and rs3399649) and CSK (rs34933034 and rs1378942) were genotyped by TaqMan SNP genotyping assays. Differences in PTPN22 and CSK expression between patients and controls stratified according to their genotype for each SNP were analyzed by Student´s t test. All the results were adjusted by sex, age at time of study and cardiovascular risk factors.

Results: A significant down-regulation of PTPN22 expression in patients with RA carrying PTPN22 rs2488457 and rs2476601 mutant alleles compared to controls was observed (p=0.009 and p=0.008, respectively). Furthermore, patients with RA carrying CSK rs1378942 mutant allele showed a significantly lower CSK expression than healthy individuals (p<0.0001).

Conclusion: Our study shows for the first time that the mutant allele of PTPN22 rs2488457, PTPN22 rs2476601 and CSK rs1378942 influences on the down-regulation of PTPN22 and CSK, respectively, in RA. The transcriptional suppression of this PTPN22/CSK complex, may have a noteworthy clinical relevance in patients with RA, playing an important role in disease diagnosis and progression.

References: [1] J Exp Med. 1999;189(1):111-121; [2] J Autoimmun. 2015 Nov;64:74-81; [3] PLoS One. 2012;7(12):e51571; [4] PLoS One. 2012;7(3):e33067; [5] Arthritis Rheum. 1988 Mar;31(3):315-2; [6] Arthritis Rheum. 2010 Sep;62(9):2569-81.

Fundings: This study was supported by European Union FEDER funds and “Fondo de Investigación Sanitaria” (grant PI12/00060 and PI15/00525) from the Instituto de Salud Carlos III (ISCIII, Health Ministry, Spain). This work was also partially supported by RETICS Programs RD12/0009 (RIER) from ISCIII, and in part by grants from the European IMI BTCure Programme. SR-M is supported by funds from the RETICS Program (RIER) from the ISCIII (RD16/0012/0009). FG is a recipient of a Sara Borrell postdoctoral fellowship from the ISCIII (CD15/00095). RL-M is supported by funds of the Miguel Servet type I programme from the ISCIII (CP16/00033).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/protein-tyrosine-phosphatase-non-receptor-22-c-src-tyrosine-kinase-complex-down-regulated-in-patients-with-rheumatoid-arthritis/