The association of PTPN22 with rheumatoid arthritis and juvenile idiopathic arthritis.

Despite the wealth of evidence to support the involvement of multiple genetic factors in rheumatoid arthritis (RA), since the identification of the link between RA and HLA class II genes over 30 yr ago no single convincing non-HLA gene has emerged. Finally last year came a breakthrough with the association of a singlenucleotide polymorphism (SNP) in a candidate gene with RA, a finding replicated in every one of the eight RA cohorts subsequently examined [1–9]. The gene is PTPN22, a negative regulator of T-cell activation and the polymorphism is a C!T substitution (rs2476601) at nucleotide position 1858 that leads to a tryptophan (W) for arginine (R) transition at codon 620. This has a demonstrable functional effect, reducing the interaction between the protein and C-terminal Src tyrosine kinase (Csk) and resulting in an increased risk of inappropriate T-cell activation [1, 10]. What makes the finding particularly interesting is that it is not unique to RA but common to a number of autoimmune diseases, including type 1 diabetes (T1D) [8, 10–15], in which the association was first observed, Graves’ disease [14, 16, 17] and Hashimoto’s thyroiditis [18]. From a rheumatological point of view the association is also found in systemic lupus erythematosus (SLE) [4, 19, 20] and juvenile idiopathic arthritis (JIA) [2, 5], suggesting some commonality of pathobiology for these very distinct conditions. Like so many important findings in biology, the PTPN22 story emerged almost simultaneously from two groups using completely different approaches. A candidate gene strategy was adopted by Bottini et al. [10], and led them to identify the protein tyrosine phosphatases (PTPs) as potential candidate genes for T1D and resulted in their investigation of the missense SNP in PTPN22 for association with this disease. This initial study found that the T allele was increased in T1D cases compared with healthy controls in two populations. In contrast, Begovich et al. [1] used a screening strategy examining 16 000 potential functional SNPs in genes that were candidates for RA or were located in linkage regions identified in RA whole-genome screens. Remarkably, the same missense SNP within the PTPN22 gene was the most significantly associated marker with RA in their initial ‘discovery’ data set of 475 cases (P1⁄4 0.0005; odds ratio for carriage of the T allele1⁄4 1.73, 95% confidence interval1⁄4 1.27–2.38). This association with RA has subsequently been replicated by many groups studying different populations, including UK [2, 3], Spanish [4], Norwegian [5], Canadian [6], New Zealand [7], Dutch [8] and Finnish [9] populations. In all studies, the direction of the association is the same: there is an increase in T allele frequency in cases compared with controls, the odds ratios for RA conferred by carriage of the T allele ranging from 1.38 to 2.04 (Fig. 1). Together, these data provide compelling evidence that PTPN22 is a true susceptibility gene for RA. However, many questions remain to be answered before we will fully understand how carriage of the PTPN22 risk allele influences the disease process in RA and other autoimmune diseases. It is generally accepted that the aetiology of complex disease will only be fully explained once we understand the way in which multiple genetic and non-genetic factors interact. It is therefore not surprising that all the RA studies to date have examined the relationship between PTPN22 and HLA-DRB1.