**2.** *PTPN22* **gene**

PTPN22 gene is located on chromosomes 1p13.3–p13.1 and encodes a lymphoidspecific tyrosine phosphatase (Lyp). Lyp is an intracellular protein tyrosine phosphatase, bound to the SH3 domain of the C-terminal Src kinase (Csk) through a proline-rich motif. It is believed to suppress kinases mediating T-cell activation [4]. Lyp plays an important role in B-cell signaling, besides functioning as a negative regulator of T cells. It works in signaling cascade at various levels and targets several signaling intermediates involved in T-cell receptor signaling [5, 6]. After HLA, PTPN22 gene is the second-most important predisposing gene for human autoimmune diseases.

The minor allele 1858T in the *PTPN22* locus has a strong and consistent genetic association with autoimmune diseases. In PTPN22 C1858T (rs2476601), cytosine changes to thymidine at nucleotide 1858, resulting in an amino acid change from arginine to tryptophan at codon 620 (R620W), located in the polyproline-binding motif P1 [7, 8]. Yet there is no consensus whether C1858T polymorphism is a gainor loss-of-function variant. The C1858T has been reported as a susceptibility locus associated with several autoimmune diseases. It was first reported in type 1 diabetes mellitus (T1DM) [7].

PTPN22 C1858T polymorphism has been suggested to increase Lyp protein activity which in turn inhibits T-cell signaling and results in a failure to delete autoreactive T cells during thymic selection. The association of this polymorphism is restricted to disorders that have a strong autoantibody component as it results in immune responses against autoantigens [8].

With the advent of new genotyping and molecular biology techniques, a huge amount of data are available for analysis. A large number of genes associated with diseases have been identified by the GWAS, candidate gene, and epidemiological

*The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism… DOI: http://dx.doi.org/10.5772/intechopen.90836*

studies. Therefore, the focus should be on the way genetic associations are reported. Even in the overlapping meta-analyses on the same topic, the limitations such as inclusion and exclusion criteria and number of included studies result in consistency of association results of genes, although the meta-analysis has been considered as a powerful approach to identify true-positive association of genes with disease.

The PTPN22 C1858T variant has been studied in several autoimmune or autoimmunity-related diseases in different ethnic populations worldwide.
