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Rheumatology Advance Access originally published online on June 7, 2006
Rheumatology 2007 46(1):49-56; doi:10.1093/rheumatology/kel170
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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The PTPN22 C1858T functional polymorphism and autoimmune diseases—a meta-analysis

Y. H. Lee1, Y. H. Rho1, S. J. Choi1, J. D. Ji1, G. G. Song1, S. K. Nath2–4 and J. B. Harley2–5

1Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, College of Medicine, Korea University, Seoul, Korea, 2Arthritis and Immunology Research Program, 3Genetic Epidemiology Unit, Oklahoma Medical Research Foundation, 4University of Oklahoma Health Sciences Center and 5US Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA.

Correspondence to: Young Ho Lee, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul 136-705, Korea. E-mail: lyhcgh{at}korea.ac.kr


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To assess whether combined evidence shows the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) C1858T polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases.

Methods. We surveyed studies on the PTPN22 C1858T polymorphism and autoimmune diseases using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes T/T (recessive effect), T/T + C/T (dominant effect) and T-allele in random effects models.

Results. Twenty-nine studies with 43 comparisons including 13 rheumatoid arthritis (RA), six systemic lupus erythematosus (SLE), six type-1 DM (T1D), three Grave's disease (GD), four inflammatory bowel diseases (IBD), three juvenile idiopathic arthritis (JIA), two psoriasis, two multiple sclerosis, two Addison's disease and two Celiac disease were available for the meta-analysis. The overall odds ratios (ORS) for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (OR for T-allele = 1.58, 1.49, 1.85, 1.61, respectively, P < 0.00001). This meta-analysis showed the association between the T-allele and the T/T genotype and JIA (OR = 1.34, P = 0.03; OR = 1.97, P = 0.02) but did not reveal the association between the PTPN22 C1858T polymorphism and IBD, psoriasis, multiple sclerosis, Addison's disease and Celiac disease.

Conclusion. This meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA, supporting evidence of association of the PTPN22 gene with subgroup of autoimmune diseases.

KEY WORDS: PTPN22, Autoimmune diseases, Meta-analysis


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Autoimmune diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction and affect up to 5% of the population [1, 2]. Autoimmune diseases are multifactorial and caused by an interaction of genetic and environmental factors, and share a number of characteristics that suggest common aetiological pathways or mechanisms. Their shared pathophysiology and their co-occurrence in families have led to the hypothesis that autoimmune diseases share some genetic background [3–5]. This has been strengthened by observations through meta-analyses of whole-genome scans that there is non-random clustering of disease susceptibility loci for autoimmune diseases [4]. Genetic susceptibility to autoimmune diseases has been established in the human leucocyte antigen (HLA) region of chromosome 6. Although the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene has shown unequivocal evidence for a role in some autoimmune diseases [6], with the exclusion of the HLA region, attempts to identify genetic variants that confer risk of multiple autoimmune diseases have proven difficult.

One of the best examples of a non-HLA common susceptibility allele for autoimmunity is the 1858C->T single-nucleotide polymorphism (SNP) of protein tyrosine phosphatase non-receptor 22 (PTPN22) (rs2476601) [7, 8]. PTPN22 gene maps to chromosome 1p13.3–p13.1 and encodes a lymphoid-specific phosphatase (Lyp). Lyp is an intracellular PTP and physically bound through proline-rich motif to the SH3 domain of the Csk kinase, which is an important suppressor of kinases that mediate T-cell activation [9]. The ability of Csk and Lyp to inhibit T-cell-receptor signaling requires their physical association [10]. The PTPN22 1858C->T SNP changes the amino acid at position 620 from an arginine (R) to a tryptophan (W) and disrupts the interaction between Lyp and Csk, avoiding the formation of the complex and, therefore, the suppression of T-cell activation. In vitro experiments have shown that the T-allele of PTPN22 binds less efficiently to Csk than the C-allele does, suggesting that T-cells expressing the T-allele may be hyperresponsive, and consequently, individuals carrying this allele may be prone to autoimmunity [11, 12]. A specific role of PTPN22 in T-cell regulation has been confirmed by the results of knocking out the murine homologue of PTPN22, resulting in lowered thresholds for T-cell-receptor signalling in these animals [13]. Recent findings have revealed that the PTPN22 risk-associated variant, Trp620, results in a gain of PTPN22 phosphatase activity in T-cells, opening up new avenues for exploring disease mechanisms. The PTPN22 1858T allele is associated with a number of autoimmune diseases including rheumatoid arthritis (RA) [12, 14–22], systemic lupus erythematosus (SLE) [23–26], type 1 diabetes mellitus (T1D) [27–29] and Grave's diseases (GD) [29–31]. Despite the association of PTPN22 C1858T SNP with the multiple different autoimmune disorders, there are some autoimmune diseases in which PTPN22 C1858T SNP does not appear to play a role in susceptibility [32–37].

Taking into account these findings, we sought to assess whether combined evidence shows the association between the PTPN22 C1858T SNP and autoimmune diseases and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Identification of eligible studies and data extraction
We considered all of the studies that examined the association of the PTPN22 C1858T SNP with autoimmune diseases. We performed an exhaustive search on studies that examined the association of the PTPN22 C1858T polymorphism with autoimmune diseases. A search of the literature was made using Medline citation to identify available articles in which the PTPN22 C1858T SNP was determined in patients with autoimmune diseases and control (most recent one was November 2005). References in the studies were reviewed to identify additional studies not indexed by Medline. We used the following Medical Subject Heading (MeSH) terms and/or text words: ‘protein tyrosine phosphatase’, ‘PTPN22’, ‘autoimmune disease’ and ‘autoimmunity’. No restrictions were placed on language, race, ethnicity or geographic area. Autoimmune diseases were diagnosed by their diagnosis criteria. A study was included in this meta-analysis if (i) it was published up to November 2005, (ii) it was original data (independent among studies) and (iii) it provided enough data to calculate OR. We excluded the following: (i) studies that contained overlapping data, (ii) studies in which the number of null and wild genotypes could not be ascertained and (iii) studies such as transmission disequilibrium test, in which family members had been studied, because their analysis was based on linkage considerations. Extraction from each study was conducted independently by two authors and consensus was achieved for all data.

Evaluation of the statistical association
Allele frequencies at the PTPN22 C1858T polymorphism from each respective study were determined by the allele-counting method. A chi-square test was used to determine if observed frequencies of genotypes in controls conformed to Hardy–Weinberg (H–W) expectations.

We examined the contrast of the allelic effect of T (variant allele) vs C (common allele), and also examined the contrast of T/T vs T/C + C/C genotypes as well as the contrast of T/T + T/C vs C/C genotypes. These contrasts correspond to the recessive and dominant effects of the T-allele, respectively. We also analysed genotype-specific risk such as TT vs CC and CT vs CC. The point estimates of the risk, the OR and its 95% confidence interval (CI) were estimated for each study. We assessed the within- and between-study variation or heterogeneity by testing Cochran's Q-statistic [38, 39]. This heterogeneity test assessed the null hypothesis that all studies were evaluating the same effect. A significant Q-statistic (P < 0.10) indicated heterogeneity across studies. The random effects model was used for meta-analysis since the random effect model assumes that different studies may estimate different underlying effects and considers both within and between-study variation.

We also quantified the effect of heterogeneity by using I2 = 100% x (Q – df)/Q [40]. I2 measures the degree of inconsistency in the studies by calculating the percentage of total variation across studies due to heterogeneity rather than chance [40]. I2 ranges between 0 and 100% and represents the proportion of between-study variability that can be attributed to heterogeneity rather than chance. We assigned adjectives low, moderate and high to I2 values of 25, 50 and 75% [40]. Finally, the overall or pooled estimate of risk (OR) was obtained by DerSimonian and Laird method in the random effect model [41]. Pooled OR in the meta-analysis was performed weighting individual OR with the inverse of their variance. Statistical manipulations were undertaken using program RevMan 4.28 (Oxford, UK). The power of each study was computed as the probability of detecting an association between the PTPN22 C1858T SNP and SLE at the 0.05 level of significance, assuming an OR of 1.5 (small effect size). The power analysis was performed using the statistical program G*Power (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Studies included in the meta-analysis
Thirty-nine relevant studies with the PTPN22 C1858T SNP and autoimmune diseases were identified through Medline search and a review of references (most recent search, November, 2005) [11, 12, 14, 15, 17–22, 23–26, 28–30, 31–37, 42–55]. All studies were published in English. Ten studies were excluded due to data of linkage disequilibrium (LD) from family [16, 45–51, 53] or duplicated data [16, 52]. For consistency, we included studies of only case-control design. The studies in which family members had been studied using LD test were excluded because their analysis was based on linkage considerations and was not case-control design. The data from two studies [16, 52] were overlapped in Begovich et al.'s [12] study. We included Begovich et al.'s [12] study not to use duplicated data in this meta-analysis. Twenty-nine studies met the inclusion criteria for this meta-analysis. Selected characteristics of the studies for the PTPN22 C1858T SNP and autoimmune diseases are summarized in Table 1. Table 1 shows the expected power of each individual study to demonstrate an association between this PTPN22 C1858T SNP and autoimmune diseases. They consisted of 22 Caucasians, one Hispanic and six unknown or mixed ethnicity. Two of the eligible studies contained data on five different autoimmune diseases [14, 25], one study had data on four different diseases [19], two studies for three different diseases [22, 55] and eight studies included subjects of two different groups or diseases [11, 12, 15, 17, 23, 24, 29, 30]. We used data set of Control 1 and cohort and Control 2 and cohorts B + C + D to avoid data overlap with Kyogoku et al.'s study [24]. We treated them independently. A total of 50 separate comparisons were available. We performed a meta-analysis for the diseases if there were at least two comparisons. A total of 43 comparisons were considered in this meta-analysis. These studies encompass 13 RA, six SLE, six T1D, four IBD, three GD, three JIA, two Celiac disease, two psoriasis, two multiple sclerosis (MS) and two Addison's disease (Table 1).


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  		TABLE 1. Characteristics of individual studies included in meta-analysis

 
Association of the functional PTPN22 C1858T SNP and susceptibility of autoimmune diseases
The overall ORs for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (Table 2, Figs 1 and 2). The meta-analysis of the PTPN22 C1858T SNP showed T/T genotype (recessive effect), C/T + T/T genotype (dominant effect) and the risk T-allele associated with susceptibility of RA, SLE, T1D and GD (Table 2). The overall ORs for T-allele were 1.58, 1.49, 1.85 and 1.61 in RA, SLE, T1D, GD, respectively (P < 0.00001). The meta-analysis showed association of T/T genotype (OR = 1.97, 95% CI = 1.14–3.42, P = 0.02) and T-allele with JIA (OR = 1.34, 95% CI = 1.03–1.75, P = 0.03) but not C/T + T/T genotype. There was no association of the PTPN22 1858T allele and susceptibility of psoriasis, IBD, MS, Addison's disease and Celiac disease (Table 2). Data were available for genotype-based analysis in RA, SLE, T1D, GD, JIA and IBD. The genotype-specific analysis showed that a dose–response relation between the T-allele and the risk of the autoimmune diseases was observed (Table 3).


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  		TABLE 2. Meta-analysis of the PTPN22 C1858T polymorphism in autoimmune diseases

 

Figure 1
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  		FIG. 1. ORs and 95% CI from individual studies testing association of the PTPN C1858T polymorphism and RA (A) and SLE (B). The aggregate OR and 95% CI of the risk allele are also given. The weighting factors (weight%) used to calculate the aggregate OR, calculated from the inverse of the variance, is given for each study. The overall ORs for T-allele were significantly increased in RA and SLE.

 

Figure 2
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  		FIG. 2. ORs and 95% CI of individual studies and pooled data for the association of the PTPN 1858T allele and T1D (A), GD (B) and JIA (C). The PTPN 1858T allele was significantly associated with development of the diseases.

 

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  		TABLE 3. Meta-analysis of genotype-based risk of the PTPN22 C1858T polymorphism in autoimmune diseases

 
Evaluation of study quality and heterogeneity
The distribution of the genotype in the control group of each study was consistent with H–W equilibrium except for Wagenleiter et al.'s study [34]. Deviation from H–W equilibrium among controls could imply some potential biases in the selection of control or genotyping errors, but excluding the study with absence of H-W equilibrium in controls did not materially affect the overall results. The statistical power of each study ranged from 47.0 to 99.9% (Table 1). Eighteen of the 27 studies used in the meta-analysis had more than 80% statistical power to an effect. Heterogeneity was found in meta-analysis for T-allele and RA and for TT genotype and SLE. However, sensitivity analysis excluding two comparisons with the highest and lowest ORs in the meta-analysis with heterogeneity yielded largely similar result without heterogeneity (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
We combined the evidence on the association of the PTPN22 1858T allele and susceptibility of autoimmune diseases. The results of this meta-analysis provide strong evidence of an association of the PTPN22 missense SNP with autoimmune diseases including RA, SLE, GD, T1D and JIA. In addition, there was a trend to increase the OR for TT genotype compared with that for CT + TT genotype in autoimmune diseases. It has been proposed that there is a gene dosage effect that individuals homozygous for the PTPN22 1858T allele (W620) would have more severely reduced binding of Lyp with Csk than would individuals who are heterozygous, thereby reducing the ability to down-regulate T-cell activation. In turn, these individuals would have overall increased reactivity of the immune system and increased risk of developing autoimmune disease. Our data may support this hypothesis, since we found that the greatest risk of multiple autoimmune diseases in individuals with homozygous for the T-allele.

There has been accumulating evidence to suggest the presence of common genetic factors that predispose to autoimmunity. Non-random clustering of disease susceptibility loci has been observed both in rodent models of autoimmune disease and in linkage studies of autoimmune diseases in humans [3–5]. The finding that the PTPN22 1858T allele is associated with subgroup of autoimmune diseases provides support for the idea that susceptibility to multiple autoimmune diseases may have some common susceptibility alleles or pathways.

No association was found between the PTPN22 1858T allele and psoriasis, IBD, MS, Addison's disease and Celiac disease. In studies in which one is searching for genetic factors having a small effect on the risk, the sample size is instrumental. We could not rule out the possibility that autoimmune diseases not being associated with PTPN22 1858T allele could be due to lack of power to detect a true association. However, PTPN22 1858T allele is unlikely to be associated in psoriasis, IBD, Addison's disease and MS because both individual studies and the meta-analysis did not show significant association. The different results of association between the PTPN22 polymorphisms and patients with RA, SLE, GD, T1D and JIA and those with psoriasis, IBD, MS, Addison's disease and Celiac disease may support the notion that different pathogenic mechanisms are involved in the development of polygenic diseases. Seven studies were conducted one time in each different disease, such as Wegener's granulomatosis [54], progressive systemic sclerosis (PSS) [19], giant cell arteritis [37], primary scelerosing cholangitis (PSC) [25], vitiligo [43], Hashmoto's thyroiditis [55] and ankylosing spondylitis (AS) [44]. No significant association was found between the PTPN22 C1858T SNP and the diseases except for vitiligo (C/T + T/T vs C/C; OR = 1.84, 95% CI = 1.01–3.17, P = 0.03) and Wegener's granulomatosis. The PTPN22 1858T allele frequency was significantly increased in antineutrophil cytoplasmic antibody (ANCA)-positive Wegener's granulomatosis patients compared with healthy controls (OR = 2.01, 95% CI = 1.37–2.86, P < 0.001) [54].

Elucidating the molecular pathways of control of autoreactive T-lymphocytes is important in understanding the aetiology of autoimmune diseases. Interestingly, the existence of humoral abnormalities in the PTPN22-knockout mice is consistent with the fact that autoantibody production is a prominent feature of all the human diseases that are significantly associated with the PTPN22 C1858T SNP [13]. Overall, these data support the hypothesis that the PTPN22 gene is important in autoantibody-related autoimmune diseases. Autoantibodies are frequently found in all of diseases associated with the PTPN22 C1858T SNP such as RA, SLE, GD, T1D and JIA. In Wegener's granulomatosis, the PTPN22 1858T allele was associated with patients with ANCA-positive disease but not ANCA-negative disease [54]. However, PSS that shows autoantibodies such as anti-Ro, anti-La, rheumatoid factor and antinuclear antibodies was not associated with the PTPN22 1858T allele [19]. Although autoantibodies are not frequently found in vitiligo, the PTPN22 1858T allele was associated with the disease [43]. These findings along with association of PTPN22 1858T allele with PSS may appear to countermand the hypothesis that PTPN22 C1858T SNP is associated with autoimmune diseases caused by autoantibodies. But there was only one study on the association between the PTPN22 SNP and PSS and vitiligo, respectively. It is needed to study that the PTPN22 C1858T SNP may predispose individuals to autoimmunity by facilitating the generation of certain disease-associated autoantibodies.

Studies in population and family-based cohorts with RA, T1D or GD unequivocally have demonstrated that the PTPN22 1858T allele is associated with autoimmunity [24, 45–48, 51, 53]. However, there was no association in SLE family-based studies in contrast to case-control studies [24, 49]. Two transmission disequilibrium tests (TDT) in SLE families did not reveal significant association of the PTPN22 T allele and SLE. Kyogoku et al. [24] showed 70 transmissions and 57 non-transmissions from Caucasian heterozygous founders to SLE-affected offsprings (P = 0.22). Wu et al. [49] revealed 105 transmissions and 112 non-transmissions from Caucasian SLE families (P = 0.6), but interestingly showed increased T-allele frequency in SLE with autoimmune thyroid disease than in SLE alone (16.75 vs 8.5%; P = 0.008, OR = 2.16, 95% CI 1.25–3.72) [49]. A possible reason of this difference between the results of case-control studies and family-based studies may include clinical, genetic heterogeneity or statistical power. Gomez et al.'s [19] study showed the highest OR in five SLE studies with a CI only just overlapping with the point estimate of the pooled OR. Omitting this study did not affect the results from the meta-analysis.

Some limitations were to be discussed in this meta-analysis. First, publication bias and heterogeneity may be present, distorting the meta-analysis. We could not draw funnel plots for each meta-analysis due to the small number of studies. We performed sensitivity test in meta-analysis with heterogeneity, but we could not rule out the possibility that they might influence the results of this meta-analysis. Second, the number of studies and the number of subjects in the studies included in the meta-analysis by specific diseases were small. The subgroup analysis for psoriasis, MS, Addison's disease and Celiac disease included only two studies for the meta-analysis. This may not have enough power to explore the association between the PTPN22 C1858T SNP and the diseases. Third, most of the studies were performed in European-descent populations. Further studies are needed in other ethnic populations because of possible ethnic difference of the PTPN22 C1858T SNP. Fourth, although the available genetic data implicate the PTPN22 1858T variant as a determinant of autoimmune disease susceptibility, the possibility that the PTPN22 focus contains another disease-associated, and possibly causal, variant needs to be examined.

In conclusion, this meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA and suggests that the PTPN22 1858T allele may have no or only a negligible effect on psoriasis, IBD, MS, Addison's disease and Celiac disease. This meta-analysis provides further evidence that the PTPN22 gene plays a significant role in the aetiology of subgroup of autoimmune diseases and common autoimmune susceptibility alleles may not be shared among all autoimmune diseases but rather among subgroups of these conditions. The involvement of PTPN22 in autoimmune diseases provides confirmation of the hypothesis that common genes underlie diverse autoimmune phenotypes.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
Funding to pay the Open Access publication charges for this article was provided by ...

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 29 December 2005; revised version accepted 11 April 2006.
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