PTPN22: a Confirmed Rheumatoid Arthritis Susceptibility Gene?

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PTPN22: a confirmed rheumatoid arthritis susceptibility gene?

for association with RA, or were located in link- ‘It will be important...to verify age regions identified in whole genome screens. whether the function of the A missense SNP within the PTPN22 gene was (PTPN22) gene in autoimmune found to be associated with RA in their initial disease susceptibility is the same discovery data set (p = 0.0007, OR: 1.65, 95% CI: 1.23–2.20) and also in a second repli- for all diseases.’ cation data set (p = 2.1 x 10-8, OR: 1.97, 2005 was a landmark year for research into the 95% CI: 1.55–2.5) [7]. The polymorphism is a genetics of rheumatoid arthritis (RA). It was C→T substitution (rs2476601) at nucleotide the year that a new confirmed susceptibility gene position 1858 that results in a tryptophan (W) Anne Hinks was identified, along with a new pathological for arginine (R) transition at codon 620. Inter- University of Manchester, pathway important in susceptibility to RA. The estingly, an earlier independent association study Arthritis Research Campaign protein tyrosine phosphatase, nonreceptor on a different autoimmune disease, Type 1 dia- Epidemiology Unit, Manchester, M13 9PT, UK type 22 (PTPN22) gene is a member of the pro- betes (T1D), demonstrated an association with Tel.: +44 161 275 1669; tein tyrosine phosphatase (PTP) family of pro- the same SNP [8]. Fax: +44 161 275 5043; teins, which are key regulatory proteins of the The original association in RA has subse- Anne.Hinks@manchester. immune system. The PTPs work in conjunction quently been replicated by many groups in all ac.uk with protein tyrosine kinases (PTKs), regulate populations studied, including British [9,10], Span- the reversible phosphorylation of tyrosine resi- ish [11], Norwegian [12], Dutch [13], Canadian [14], dues and are fundamental in controlling many New Zealand [15] and Finnish [16] populations. In physiological processes [1,2]. all studies, the direction of the association is the RA, similar to other autoimmune diseases, is same; there is an increase in T allele frequency in a complex genetic disease and dissecting the cases compared with controls, with the ORs for contributing genetic variants is challenging. RA conferred by carriage of the T allele ranging The association of the shared epitope alleles of from 1.38 to 2.04. Together, these data provide major histocompatability complex, class II, DRβ1 compelling evidence that PTPN22 is a genuine (HLA-DRB1) with RA is well established and, susceptibility gene for RA. until this year, has been the only consistently rep- All of the PTPN22 and RA association studies licated RA susceptibility gene and the only region have examined whether there are any potential to be identified in all four whole genome screens interactions between PTPN22 and HLA-DRB1. for RA [3–6]. The HLA-DRB1 gene is thought to In the first study, Begovich and colleagues per- account for approximately 40% of the genetic formed conditional logistic regression to adjust contribution to RA and, therefore, genes account- for the HLA-DRB1 genotype and found that it ing for a large proportion of the genetic risk had little impact on risk estimates [7]. Many remain to be identified. The search for non-HLA other studies have also stratified the data accord- susceptibility genes has been in progress for a ing to shared epitope (SE) status and in all cases, number of years; however, the task is complicated no significant difference in allele or genotype fre- by the fact that the remaining proportion of risk is quencies between SE-positive and -negative cases predicted to be due to multiple genes, each with a has been observed [9,10]. All of these analyses sug- modest effect on overall RA susceptibility (odds gest that PTPN22 is acting independently ratio [OR] < 2.0). There have been several associ- of HLA-DRB1. ations of RA with various genes, although replica- Many studies have also examined the effect of tion of some of these associations in independent gender, age at disease-onset, rheumatoid factor data sets has generally been elusive. (RF) status, family history of disease and severity of However, in 2005, Begovich and colleagues disease course upon the RA–PTPN22 association. performed a case–control association study of All of the studies found no consistent gender potential functional single nucleotide poly- difference in the association of PTPN22 with RA. morphisms (SNPs) located in candidate genes Some studies have shown that the association is

stronger in RA cases with a young age at disease- that have observed an increased statistical risk onset [9,10], whilst others found this had no effect that an individual with an autoimmune disease on the association [11,14]. will have a blood relative with either the same or The issue that appears to be most contra- another autoimmune disease [30–33]. The hypo- dictory across the different studies is from the thesis has been strengthened further in results of the stratification according to RF sta- recent years, following whole genome screens of tus. The initial association study by Begovich different autoimmune diseases. Analysis of the and colleagues suggested that the association results of autoimmune disease whole genome with PTPN22 was only found in the subgroup screens identified 18 distinct clusters, with evi- of patients that were RF positive [7]. This was dence of linkage to two or more autoimmune or also borne out when the researchers further immune-related diseases [34]. This overlap of loci increased their sample size [17] and in another has also been observed in mouse models of RA cohort [10]. Conversely, a number of other autoimmunity [35]. studies have demonstrated an association in both RF-positive and -negative subgroups [9,14,15]. ‘The association of the PTPN22 gene with The issue here is that, as RF is present in RA is the first widely replicated genetic 75–80% of RA cases, the RF-negative subgroup association with this disease since HLA.’ sample sizes in the different studies are modest. However, the RF-negative subgroup sample size However, it is also now becoming clear that was also used by Lee and coworkers and should the PTPN22 missense SNP is not universally have had sufficient power to detect an associa- associated with autoimmune diseases and a bet- tion with PTPN22. It is possible that there has ter picture of which diseases are and are not been a misclassification of RF-positive RA cases associated with PTPN22 will provide a better into the RF-negative RA case subgroup in the understanding of different autoimmune disease studies where there is an association with pathways. Diseases that, to date, do not appear PTPN22, possibly due to different RF detection to be associated with PTPN22 include multiple methodologies, or to the time points, in terms of sclerosis (MS) [9,28,36,37], psoriasis [9,38], psoriatic disease duration, where these tests were per- arthritis [9], Sjögren’s syndrome [39], celiac dis- formed. Alternatively, these differences may ease [40,41], Crohn’s disease [14] and systemic reflect clinical heterogeneity across different sclerosis [S Parameshwar & J Worthington, Unpublished Data]. populations. Additional studies of larger cohorts The function of the protein encoded by of RA cases and controls, as well as combined PTPN22 may provide clues to the role of data or meta-analyses, will be required to give a PTPN22 in autoimmune diseases and the path- better understanding of the association of ways that might be important. PTPN22 encodes PTPN22 with RA and its clinical presentation. the protein lymphoid-specific phosphatase Since the original associations in both T1D (Lyp), which is composed of an N-terminal and RA, there has been a flurry of reports of the phosphatase domain and a noncatalytic C-ter- association of PTPN22 with other autoimmune minal end containing several proline-rich diseases. Diseases that show evidence for associ- motifs. It is expressed in hemopoietic tissues, ation with PTPN22 include RA [7,9–12,14–17], thymus, spleen and bone marrow, as well as in all juvenile idiopathic arthritis (JIA) [9,12,16], subtypes of peripheral blood mononuclear cells, T1D [8,18–23], Graves’ disease [21,24,25], systemic including T and B cells, monocytes, neutrophils lupus erythematosus (SLE) [11,26,27], Hashi- and natural killer cells [7]. Initial studies of the moto’s thyroiditis [28], autoimmune Addison’s function of the protein have largely been deter- disease [24] and generalized vitiligo [29]. mined through experiments on the mouse The fact that PTPN22 is associated with homolog, PEST domain-enriched tyrosine numerous autoimmune diseases lends support to phosphatase (PEP), which is encoded by the the hypothesis that there are common patho- gene PTPN8. Cloutier and Veilette showed that physiological pathways underlying certain there is a synergistic relationship between a PTP autoimmune diseases. The hypothesis of over- (PEP) and a PTK (C-terminal Src tyrosine lapping susceptibility to autoimmune diseases is kinase [Csk]), which together inhibit signaling not a new one, as it was originally proposed fol- of Src family kinases, such as Lyk, Fyn and lowing observations of clustering of different ZAP-20, and thus mediate T-cell inactiva- autoimmune diseases within families. This has tion [42]. They demonstrated that PEP inhibited been confirmed through epidemiological studies T-cell receptor signaling by dephosphorylation

154 Future Rheumatol. (2006) 1(2) PTPN22: a confirmed rheumatoid arthritis susceptibility gene? – EDITORIAL

of the Src family kinases, but this dephosphory- signaling may lead to weaker signaling and a fail- lation was dependent on the interaction of PEP ure to delete autoreactive T cells during thymic with the SH3 domain of Csk. A PEP knockout selection or insufficient activity of T regulatory mouse on a nonautoimmune background has cells [44]. been created and observations of the phenotype Recent data proposing the gain-of-function have confirmed the role of PEP in T-cell func- mutation suggests a role of T regulatory cells in tion. There was evidence of enlargement of the susceptibility. Experiments on collagen-induced spleen and lymph nodes and increased numbers arthritis (CIA) in mice suggests that intrinsic of effector/memory T cells, particularly in older CD25+ regulatory T cells modulate the severity mice. There is also evidence for its role in the of the disease, which is an accepted model of humoral immune response, with the develop- RA, and that adoptive transfer of these cells can ment of germinal centers and increased concen- be used for the treatment of CIA [45]. tration of certain antibody isotypes. There was All of the functional data so far has focused no evidence of increased levels of autoantibodies on T cells; however, it is also evident that and no signs of overt autoimmune disease, there- PTPN22 is expressed in a wide range of hemo- fore it can be concluded that other initiators, poietic cell types, including neutrophils, macro- genetic or environmental, are necessary to phages and natural killer cells, and the role of develop autoimmune disease in these mice [43]. PTPN22 in these cell types has yet to be established, leaving an array of potential disease ‘...these data provide compelling mechanisms still to be explored [7]. evidence that PTPN22 is a genuine Another hypothesis is related to the role of susceptibility gene for RA.’ PTPN22 in the humoral immune response. This hypothesis has originated from the initial The R620W SNP is situated in the proline- nonassociation reports, where it appeared that rich P1 domain of PTPN22, which, from the the diseases that were not associated with work of Cloutier and Villette, is known to bind PTPN22 were diseases that are not classically to the SH3 binding domain of Csk [42]. Func- associated with circulating autoantibodies (MS, tional studies have attempted to establish psoriasis, psoriatic arthritis and celiac disease). whether the substitution affects binding to Csk. This interpretation was also consistent with the Immunoprecipitation analysis suggested that the observations that the association with RA R620 variant binds Csk, whereas the W620 has appeared, in some studies, to be restricted to RA reduced binding to Csk [7,8]. It is proposed that cases that were autoantibody RF positive. Fur- this reduced binding of Lyp to Csk leads to a ther evidence from animal models suggests that reduced ability to downregulate T-cell activa- PTPN22 is also important in B-cell function, in tion. It has been observed in some of the addition to playing a role in T-cell inactivation. PTPN22 association studies that there is a dos- There was evidence of increased antibody levels age effect and that individuals homozygous for and increased numbers of germinal centers in the PTPN22*T allele would have a more severely the PEP knockout mouse. This evidence has led reduced binding with Csk than individuals who to speculation that PTPN22 may be associated are heterozygous. Therefore, it is likely that with the generation of disease-associated auto- PTPN22 is important in setting thresholds for antibodies. The development of autoantibodies T-cell receptor signaling. Defective binding of in diseases such as RA, T1D and autoimmune Lyp to Csk would, in effect, lead to lower thresh- thyroid disease (AITD) often predates the devel- olds for T-cell activation, overall increased activ- opment of overt clinical disease by a number ity of the immune system and thus a greater of years and autoantibodies are also observed in potential of mounting an autoimmune response. normal healthy individuals. It will be interesting However, recent data provided evidence to to examine whether PTPN22 is also associated the contrary, suggesting that carriage of the with autoantibody production in normal indi- R620W variant is associated with more efficient viduals. However, we should be cautious, as inhibition of T-cell activation. This contradicts there are a number of observations that chal- the more simplistic model of autoimmunity, lenge this data. First, a number of studies, which would predict that T cells with defects in including our study, found that association with T-cell activation would be likely to cause dis- PTPN22 is also significant in RF-negative RA ease. It has been speculated that the increased cases and in antinuclear antibody-negative JIA efficiency of PTPN22 Trp620 to inhibit TCR cases. Second, two autoimmune diseases that do www.futuremedicine.com 155 EDITORIAL – Hinks

not appear to be associated with PTPN22 are diseases that showed no association with the systemic sclerosis and Sjögren’s syndrome, two R620W variant. Studies of the wider region diseases that are typically associated with the around PTPN22 found that the PTPN22 asso- presence of autoantibodies. ciated SNP lies within a 293 kb LD block of Despite the convincing functional data sup- 41 haplotype map SNPs. At least six other porting the PTPN22 R620W variant as the known genes map to that LD block and on the causal SNP in these associations with auto- National Center for Biotechnology Informa- immune diseases, only one study so far has tion SNP database there are 625 known SNPs investigated the possibility that the observed that fall within that region [101]. One of these association is due to linkage disequilibrium SNPs was found to be in complete LD (R2 = 1) (LD) with another SNP, or indeed that there with the R620W variant, meaning that it is are additional PTPN22 variants associated with impossible to distinguish the effects of these disease but independent of the R620W variant. SNPs using genetic data alone. The SNP was Carlton and colleagues reported the most thor- situated between two genes and was predicted ough investigation of PTPN22 to date. The to disrupt potential transcription factor bind- coding regions of the PTPN22 gene were ing sites [21]. Therefore, whilst it cannot be screened for previously unidentified SNPs and assumed with complete certainty that the these were then genotyped along with all other PTPN22 R620W variant is the one and only known SNPs from public databases. Strong LD autoimmune-predisposing SNP in the region, across the gene and ten common haplotypes the functional data and the PTPN22 haplotype (frequency >1%) were identified. Only one of analysis provide compelling evidence that it these haplotypes contained the W620 risk allele plays a significant role. and this haplotype is strongly associated with The association of the PTPN22 gene with RA RA. Another haplotype that was identical at all is the first widely replicated genetic association other SNPs, apart from carrying the R620 with this disease since HLA. It has been a suc- allele, showed no association, providing evi- cess story in the field of rheumatological genet- dence that the W620 allele is the disease-predis- ics and in the wider spectrum of autoimmune posing allele on this haplotype. However, there disease. It will be important to understand the was evidence that the R620W SNP does not finer details of its role in immune regulation and explain all the association with RA, as there to verify whether the function of the gene in were three SNPs, rs1310182, rs3811021 and autoimmune disease susceptibility is the same rs3789604, which were associated with RA for all diseases. There are a number of potential independently of R620W. The latter two SNPs mechanisms through which it functions and are in complete LD, suggesting they represent a these will require exploration in more detail. single association, whilst the other cannot be The association with PTPN22 is only one com- excluded as a disease-predisposing locus, its ponent of the complex genetic and environmen- association with RA is not independent of both tal pathogenesis of diseases such as RA; however, R620W and rs3789604 [46]. It will be a priority a greater understanding of the role of PTPN22 to analyze these other variants in other RA pop- and its pathway in these diseases may lead to the ulations, but it would also be interesting to discovery of other interacting susceptibility genotype these variants in the autoimmune genes and potential therapies.

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