PTPN22 R620W (rs2476601)

Rheumatoid arthritis is a chronic inflammatory disease that can lead to bone erosion and joint injuries that lead to permanent disability. One SNP associated AR is located in a gene coding for an enzyme (PTPN22) known to be involved in the control of immune T cells. The PTPN22 gene encodes a hematopoietic cells specific tyrosine phosphatase, that interacts through the proline-rich domain of P1 with the kinase Csk. This physical interaction controls the state of tyrosine phosphorylation of regulatory molecules that are part of the cascade of signal transduction in the TCR complex as ZAP70 and determines an inhibition of the activation of lymphocytes T. Under normal conditions, the enzyme acts as 'negative regulator', that is, deactivating a specific signaling molecule which in turn interrupts the communication lines and prevents the hyperactivity of the immune cells. In the presence of the mutation this setting appears to be ineffective and T cells respond in an exaggerated way, causing inflammation and tissue damage.

The missense mutation falls in the first proline-rich domain of the PTPN22 gene and results in the substitution of a tryptophan with an arginine at codon 620 (R620W). The mutation is present in almost 28 percent of individuals who suffer from the disease but only in 17 percent of the general population. The SNP C1858T in PTPN22 (or R620W) was also associated with other autoimmune diseases such as type I diabetes, systemic lupus erythematosus and autoimmune thyroiditis, suggesting a genetic predisposition to generalized autoimmunity mediated by T cells.

In recent years a growing interest has been devoted to antibodies against citrullinated proteins and a synthetic cyclic citrullinated peptide (cyclic citrullinated peptide, CCP) is now currently used as an antigenic target for a diagnostic test (anti-CCP2) which has proved highly sensitive and specific for arthritis rheumatoid arthritis (RA). The interest for anti-CCP is further increased by the fact that these autoantibodies appear early in the serum of subjects destined to develop the disease (Nielen et al, 2004) and correlate with erosive form and worse prognosis (Kroot et al, 2000; Vencovsky et al, 2003). The combination of the variant 1858T with the anti-CCP antibodies leads to a 100% specificity for the disease.