Background Several genetic risk factors have been revealed for rheumatoid arthritis (RA) whereof HLA-DRB1 shared epitope alleles and PTPN22 remains the two most undisputed for the disease. Hypotheses for how these associations confer their risk exist but the etiology is still not completely explained. The PTPN22 risk allele is associated with a gain of function of the protein product. However, the PTPN22 gene has alternatively spliced transcripts where at least two of the splice forms have confirmed different PTPN22 (LYP) proteins, which may influence the proteins pathways.
Objectives Our hypothesis was that PTPN22 splice forms may have a different expression pattern in patients compared to controls. Such an effect could enhance other effects from the associated risk alleles.
Material and methods The authors have investigated the expression of PTPN22 splice forms in peripheral blood cells and used genotypic and phenotypic data for analysis of RA patients and controls of Caucasian origin.
Results PTPN22 was found to be different in individuals with RA compared to controls. On average, the shorter splice form was reduced (0.8-fold, p=0.08) and the longer was increased (1.2-fold, p=0.006) for patients. This effect was further enhanced if the ratio of the transcripts for each individual was compared (1.4-fold, p=6 × 10−9). This finding was replicated in two independent cohorts of the total size of 165 individuals.
Conclusions The authors found important differences in expression of PTPN22 splice forms between healthy individuals and RA patients, which may increase a gain of function that influence development of the disease. The balance between splice forms may also be of importance during immune response due to great structural differences in the encoded PTPN22 proteins.