Skip Navigation


Rheumatology Advance Access originally published online on December 21, 2007
Rheumatology 2008 47(2):138-141; doi:10.1093/rheumatology/kem343
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/2/138    most recent
kem343v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Orozco, G.
Right arrow Articles by Martín, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Orozco, G.
Right arrow Articles by Martín, J.
Related Collections
Right arrow Immunogenetics
Right arrow Rheumatoid Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Auto-antibodies, HLA and PTPN22: susceptibility markers for rheumatoid arthritis

G. Orozco1, D. Pascual-Salcedo2, M. A. López-Nevot3, T. Cobo4, A. Cabezón2, E. Martín-Mola4, A. Balsa4 and J. Martín1

1Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, 2Servicio de Inmunología, Hospital La Paz, Madridm, 3Servicio de Inmunología, Hospital Virgen de las Nieves, Granada and 4Servicio de Reumatología, Hospital La Paz, Madrid, Spain.

Correspondence to: J. Martín, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n, 18100 Armilla, Granada, Spain. E-mail: martin{at}ipb.csic.es


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To analyse the relationship between the presence of auto-antibodies [rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP)], HLA-DRB1 alleles and PTPN22 1858 C/T polymorphism and test the value of their combination as susceptibility markers for rheumatoid arthritis (RA).

Methods. Patients with early arthritis were included. At entry in the cohort or during follow-up, 191 patients fulfilled the criteria for RA and 184 individuals suffered from other arthropathies. RF was measured by nephelometry and anti-CCP antibody by enzyme-linked immunosorbent assay. HLA class II alleles were determined by polymerase chain reaction. Samples were genotyped for PTPN22 1858C/T variants using a TaqMan 5'-allele discrimination assay.

Results. The presence of shared epitope (SE) alleles was strongly associated with anti-CCP and RF-positive RA [P = 7.05 x 10–10, odds ratio (OR) 4.57, 95% confidence interval (CI) 2.76–7.57 and P = 1.68 x 10–6, OR 2.99, 95% CI 1.89–4.74, respectively). The combination of the PTPN22 1858T variant and anti-CCP antibodies gave a high specificity for the disease, and was significantly associated with RA (P = 8.86 x 10–5, OR 10.05, 95% CI 1.88–53.73).

Conclusion. The combination of the T variant of the 1858 polymorphism of the PTPN22 gene in combination with the presence of anti-CCP antibodies, preferentially in a SE-positive individual, is associated with the development of RA.

KEY WORDS: Rheumatoid arthritis, Auto-antibodies, Rheumatoid factor, Cyclic citrullinated peptides, HLA-DRB1, PTPN22 gene, Polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Rheumatoid arthritis (RA) is a chronic inflammatory disease, affecting up to 1% of the adult population worldwide. Although the precise aetiology of RA is unknown, a strong genetic component is well established [1].

The strongest and best-known genetic association with RA is that found for particular alleles of HLA-DRB1 [2]. To date, the association of the 1858C/T polymorphism of the PTPN22 gene with RA is the most robust and reproducible one outside the HLA region [3, 4]. Recently, it has been discovered that shared epitope (SE) HLA-DRB1 alleles are exclusively associated with a subgroup of RA patients that test positive for auto-antibodies against cyclic citrullinated peptide (CCP) [5]. This has led to the establishment of a ‘citrullinated’ SE hypothesis [6, 7]. Furthermore, auto-antibodies have also been related with PTPN22 1858C/T polymorphism. Subsequent studies have confirmed this suggestion, since both RF and anti-CCP auto-antibodies have been associated with PTPN22 1858T allele [8–11]. And what is more, the combination of the 1858T variant and anti-CCP antibodies gave a 100% specificity for the disease and strongly predicted the future onset of RA [9].

In the light of these evidences, we tested the value of the combination of PTPN22 1858C/T polymorphism, HLA-DRB1 alleles and the presence of RF and anti-CCP as susceptibility markers for the onset of RA using an inception cohort of patients with inflammatory arthritis.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Our cohort was comprised of 375 subjects (70% women, age 52.9 ±16.4 yrs and disease duration before entry 14.9 ± 8.1 weeks). Patients were referred to the early arthritis clinic (EAC) of La Paz University Hospital, and were included when a rheumatologist confirmed arthritis at least in one joint and if the symptoms have been present <1 yr. All patients were taking non-steroidal anti-inflammatory drugs and/or low doses of oral corticosteroids and none received disease-modifying anti-rheumatic drugs. Patients were excluded if they had crystal-induced, septic arthritis or inflammatory flares of osteoarthritis.

All patients were followed up every 6 months in the EAC for at least 2 yrs, unless they went into clinical and analytical remission and diagnosis was different from RA. At entry in the cohort or during follow-up, 191 patients fulfilled four or more of the 1987 revised American College of Rheumatology criteria for RA [12], and the remaining 184 individuals suffered from other arthropathies (mainly undifferentiated arthritis, psoriatic arthritis, reactive arthritis or undifferentiated spondyloarthropathy).

At baseline, blood tests were carried out to determine acute phase reactants and rheumatoid factor (RF) and serum samples were stored at –40°C for posterior determinations. In all patients, auto-antibodies were measured every 12 months and no change from negative to positive was seen in the first 2 yrs of the disease.

All the subjects were of Spanish Caucasian origin and were included in this study after informed consent. We obtained approval for the study from local ethical committee of the hospital.

Auto-antibodies measurement
RF was measured by nephelometry (Behring, Nephelometer Analyzer II), with a detection limit of 15 u/ml. Anti-CCP antibody was detected by a second-generation enzyme-linked immunosorbent assay in patient sera (Immunoscan RA Mark2; Eurodiagnostica, Arnhem, The Netherlands). The cut-off level for anti-CCP antibody positivity was set at 25 arbitrary units, according to the manufacturer's instructions.

Genotyping methods
DNA from patients and controls was obtained from peripheral blood, using standard methods. Samples were genotyped for PTPN22 1858C/T variants using a TaqMan 5'-allele discrimination Assay-By-Design method (Applied Biosystems, Foster City, CA, USA), as previously described [4].

HLA genotyping
Genotyping for HLA-DRB1 was carried out using a reverse dot-blot kit with sequence-specific oligonucleotide probes (Dynal RELITM SSO HLA-DRB1 typing kit; Dynal Biotech, Bromborough, UK). When necessary, high-resolution typing of HLA-DRB1*03 samples was performed using Dynal AllSetTM SSP DRB1*03.

Statistical analysis
Statistical analysis to compare allelic and genotypic distributions was performed by {chi}2-test calculated on 2 x 3 or 2 x 2 contingency tables. Statistical significance was P < 0.05. For non-parametric data analysis, Mann–Whitney U-test was used for ordinal variables and Fisher's exact test for dichotomous variables. Multivariate stepwise logistic regression analysis was performed using the Statistical Package for the Social Sciences, version 10.0 (SPSS, Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Seropositivity for anti-CCP and RF was strongly associated with RA [P = 7.68 x 10–28, odds ratio (OR) 18.91, 95% confidence interval (CI) 10.12–35.34 and P = 2.83 x 10–26, OR 11.92, 95% CI 7.26–19.61, respectively). However, the association for the RF was weaker than that found for anti-CCP. In addition, there was a strong association between RF positivity and anti-CCP positivity (P = 3.64 x 10–21, OR 38.82, 95% CI 14.54–103.66; {kappa} = 0.667, S.E. = 0.06, 95% CI 0.56–0.78).

As shown in Table 1, the presence of SE alleles was strongly associated with anti-CCP-positive RA (P = 7.05 x 10–10, OR 4.57, 95% CI 2.76–7.57). Furthermore, the presence of DR3 allele (DRB1*0301) showed a high trend of protection against anti-CCP-positive RA (P = 0.01, OR 0.48, 95% 0.26–0.89). Similarly, DERAA alleles carriage seems to be protective for anti-CCP-positive RA (P = 0.01, OR 0.49, 96% CI 0.28–0.89). Interestingly, no association was observed with the SE in the anti-CCP-negative RA patients, indicating that the SE does not associate with RA as such, but rather with a defined anti-CCP phenotype. In addition, we did not observe any association with DERAA and DR3 alleles in the anti-CCP-negative RA patients group.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Distribution of SE, DERAA and DR3 alleles in RA patients, stratified by the presence of anti-CCP and RF, and non-RA patients

 
With regard to RF autoantibodies, the carriage of SE alleles was also associated with RA in the RF-positive patients group, due to the strong correlation between RF positivity and anti-CCP positivity (P = 1.68 x 10–6, OR 2.99, 95% CI 1.89–4.74). Moreover, no association was observed with the SE in the RF-negative RA patients. Furthermore, we found an association between the presence of the DERAA alleles and RF positivity, in a protective way (P = 0.03, OR 0.57, 95% CI 0.34–0.98). However, we did not observe any association with the carriage of the DR3 allele in the RF-positive RA group.

These data indicate that the SE alleles primarily predispose to the presence of anti-CCP antibodies, and are not an independent risk factor for the development of RA.

Regarding the PTPN22 1858C/T polymorphism, the genotype and allele distribution of the single nucleotide polymorphism (SNP) were in agreement with the Hardy–Weinberg equilibrium among both the RA patients and the non-RA patients. Allele and genotype frequencies did not differ significantly from those described in a Spanish population [4]. However, when allele or genotype frequencies were compared, no statistically significant differences were found. Thus, it seems that PTPN22 itself does not predispose to the onset of RA in our inception cohort of patients with inflammatory arthritis from Spain, which is in contrast with the previously reported association of PTPN22 with RA compared with the general Spanish population [4].

Next, we analysed the relationships between the PTPN22 1858C/T polymorphism and antibodies to CCP and the RF (Table 2). The combination of the 1858T variant and anti-CCP antibodies gave a high specificity for the disease (83.2%, calculated as number of patients with a true negative test divided by the total number of patients without the disease), since only one of the controls presented this combination. This patient suffered from palindromic rheumatism that has been described to be an abortive form of RA and without treatment can progress to RA [13]. Carriage of the PTPN22 1858T variant and presence of anti-CCP antibodies were significantly associated with the development of RA, compared with the rest of combinations (P = 8.86 x 10–5, OR 10.06, 95% CI 1.88–53.73), whereas the combination of the lack of the T variant of the SNP and anti-CCP negativity was strongly protective (P = 8.2 x 10–21, OR 0.12, 95% CI 0.07–0.19). We also observed an association with RA for the combination of the T variant and the presence of RF antibodies (P = 0.002, OR 4.18, 95% CI 1.47–11.91); however, this association was much weaker than that found for the combination of the PTPN22 T allele and anti-CCP auto-antibodies.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Distribution of the PTPN22 1858C/T SNP stratified by the presence of anti-CCP and RF antibodies

 
The distribution in RA patients and non-RA patients in the combination of the presence of SE, anti-CCP and T allele of the PTPN22 polymorphism did not reach statistically significant differences, probably due to the relatively low number of individuals included in the study and the high degree of stratification performed (data not shown).

Using multivariate stepwise logistic regression analysis with all variables included and RA diagnosis as a dependent variable, only anti-CCP and RF auto-antibodies entered in the forward and backward method (OR 22.4, 95% CI 11.2–44.6 and OR 9.8, 95% CI4.3–22.0, respectively).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
The most interesting findings of this work are the following: (i) the presence of the SE allele is strongly associated with anti-CCP positivity, although the SE does not associate with RA as such, but rather with a defined anti-CCP phenotype, and (ii) the combination of the 1858T variant and anti-CCP antibodies gave a high specificity for the disease. Therefore, we have replicated previously described remarkable findings in an ethnically different Spanish cohort [5, 9, 14–16]. Despite the high specificity for RA given by the 1858T variant of the PTPN22 gene and seropositivity for anti-CCP, this test had low sensitivity for RA diagnostic. Therefore, in order to establish a combination of variables as a diagnostic tool, it would be necessary to include other markers of severity/outcome, such as radiological changes or bone erosions. Unfortunately, these data were not available for our cohort. However, our data suggest that PTPN22 polymorphism and anti-CCP might be helpful as RA prognostic markers.

Our data, together with data from other groups [14, 17–20] suggest that the SE alleles predispose for anti-CCP positivity rather than for RA. Thus, it has been proposed the hypothesis that HLA SE containing molecules play a role in the activation of CD4+ T cells through preferential presentation of citrullinated antigens. These citrulline-specific T cells may provide the help required for the IgG antibodies response to citrullinated antigens. On the basis of these and other data, van Gaalen et al. [7] formulated a two-hit model for the pathogenesis of RA, which incorporates a novel ‘citrullinated’ SE hypothesis.

In addition, we have found that the absence of HLA-DRB1*0301 is associated with anti-CCP-positive RA, which is slightly different from the finding by Verpoort et al. [21] and Irigoyen et al. [22] who stated that HLA-DR3 is associated with anti-CCP-negative RA. They proposed that this association is not due to the HLA-DR3 gene itself, but to other genes in linkage disequilibrium with it. In this sense, a microsatellite marker (MIB*350) that is part of an ancestral haplotype associated with DRB1*0301 was described as a risk factor for RA in Dutch and Spanish populations independently of DR3 [23, 24]. Nevertheless, it remains unclear as to which locus inside this cluster is responsible for the association. A fine mapping of this locus could help to shed light on the different associations between DR3 and anti-CCP positivity in North American, Dutch and Spanish populations.

We found an association between the absence of the protective DERAA alleles and anti-CCP and RF-positive RA. However, DERAA alleles were not associated with anti-CCP and RF-negative RA. This is in contrast with previous findings that show that the protective effect of DERAA is independent of the patient's anti-CCP status [21, 25].

We have replicated the finding that carriage of the T allele of this polymorphism, in combination with seropositivity for anti-CCP auto-antibodies predisposes for RA and has a high specificity for the disease [9], suggesting that the T variant could influence the outcome of RA once auto-antibodies, such as anti-CCP auto-antibodies, have developed. In fact, the only non-RA patient in this cohort with anti-CCP antibodies and the T variant, has palindromic rheumatism that has been described as an abortive form of RA [13]. Nevertheless, a relatively low number of patients were included in the study. Therefore, further investigation using bigger cohorts is needed in order to confirm the possible clinical application of these markers.

We did not observe any association of the T allele with RA in combination with the presence of the RF in accordance with previous works [4, 26, 27], which strengthens the arising hypothesis that anti-CCP, rather than RF, are the auto-antibodies that characterize RA. This also could explain why PTPN22 1858C/T is not associated with several auto-immune diseases in which auto-antibodies are present, such as coeliac disease [28], since the polymorphism was proposed as a common genetic marker for auto-antibody-mediated auto-immune disease [29]. In the light of these evidences, it seems that the SNP could be involved in the regulation of some auto-antibodies, such as anti-CCP, but not others, such as RF. Thus, the implication of PTPN22 in auto-immunity seems to be conditioned to the auto-antibody milieu of each disease.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Ma Paz Ruiz Blas and Antonia Martín for excellent technical assistance, Rosario Madero for her statistical work and patients for their essential collaboration.

Funding: This work was supported by grant FER/Abbott 2004 and Plan Nacional de I+D (grants SAF03-3460 and SAF06-00398).

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature (2003) 423:356–61.[CrossRef][Medline]
  2. Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis. Genes Immun (2004) 5:151–7.[CrossRef][Web of Science][Medline]
  3. Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (ptpn22) is associated with rheumatoid arthritis. Am J Hum Genet (2004) 75:330–7.[CrossRef][Web of Science][Medline]
  4. Orozco G, Sanchez E, Gonzalez-Gay MA, et al. Association of a functional single-nucleotide polymorphism of ptpn22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum (2005) 52:219–24.[CrossRef][Web of Science][Medline]
  5. Huizinga TW, Amos CI, van der Helm-van Mil AH, et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum (2005) 52:3433–8.[CrossRef][Web of Science][Medline]
  6. de Vries RR, Huizinga TW, Toes RE. HLA and RA revisited: citrullinated food for the SE hypothesis, the DR6 effect, and nima. Hum Immunol (2006) 67:454–9.[CrossRef][Web of Science][Medline]
  7. van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE. The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis. J Immunol (2005) 175:5575–80.[Abstract/Free Full Text]
  8. Lee AT, Li W, Liew A, et al. The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status. Genes Immun (2005) 6:129–33.[CrossRef][Web of Science][Medline]
  9. Johansson M, Arlestig L, Hallmans G, Rantapaa-Dahlqvist S. PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res Ther (2005) 8:R19.
  10. Kokkonen H, Johansson M, Innala L, Jidell E, Rantapaa-Dahlqvist S. The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern sweden. Arthritis Res Ther (2007) 9:R56.[CrossRef][Medline]
  11. Feitsma AL, Toes RE, Begovich AB, et al. Risk of progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele in anti-citrullinated peptide antibody positive patients. Rheumatology (2007) 46:1092–5.[Abstract/Free Full Text]
  12. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum (1988) 31:315–24.[Web of Science][Medline]
  13. Salvador G, Gomez A, Vinas O, et al. Prevalence and clinical significance of anti-cyclic citrullinated peptide and antikeratin antibodies in palindromic rheumatism. An abortive form of rheumatoid arthritis? Rheumatology (2003) 42:972–5.[Abstract/Free Full Text]
  14. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum (2006) 54:1117–21.[CrossRef][Web of Science][Medline]
  15. van Gaalen FA, van Aken J, Huizinga TW, et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPS) influences the severity of rheumatoid arthritis. Arthritis Rheum (2004) 50:2113–21.[CrossRef][Web of Science][Medline]
  16. Berglin E, Padyukov L, Sundin U, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther (2004) 6:R303–8.[CrossRef][Web of Science][Medline]
  17. de Vries RR, Huizinga TW, Toes RE. Redefining the HLA and RA association: to be or not to be anti-CCP positive. J Autoimmun (2005) 25(Suppl 1):21–5.[CrossRef][Web of Science][Medline]
  18. Kaltenhauser S, Pierer M, Arnold S, et al. Antibodies against cyclic citrullinated peptide are associated with the DRB1 shared epitope and predict joint erosion in rheumatoid arthritis. Rheumatology (2007) 46:100–4.[Abstract/Free Full Text]
  19. Cha S, Choi CB, Han TU, Kang CP, Kang C, Bae SC. Association of anti-cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis. Arthritis Rheum (2007) 56:1454–63.[CrossRef][Web of Science][Medline]
  20. Furuya T, Hakoda M, Ichikawa N, et al. Differential association of HLA-DRB1 alleles in japanese patients with early rheumatoid arthritis in relationship to autoantibodies to cyclic citrullinated peptide. Clin Exp Rheumatol (2007) 25:219–24.[Web of Science][Medline]
  21. Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, et al. Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum (2005) 52:3058–62.[CrossRef][Web of Science][Medline]
  22. Irigoyen P, Lee AT, Wener MH, et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum (2005) 52:3813–8.[CrossRef][Web of Science][Medline]
  23. Zanelli E, Jones G, Pascual M, et al. The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci. Hum Immunol (2001) 62:75–84.[CrossRef][Web of Science][Medline]
  24. Pascual M, Mataran L, Jones G, et al. HLA haplotypes and susceptibility to rheumatoid arthritis. More than class II genes. Scand J Rheumatol (2002) 31:275–8.[CrossRef][Web of Science][Medline]
  25. van der Helm-van Mil AH, Huizinga TW, Schreuder GM, Breedveld FC, de Vries RR, Toes RE. An independent role of protective HLA class II alleles in rheumatoid arthritis severity and susceptibility. Arthritis Rheum (2005) 52:2637–44.[CrossRef][Web of Science][Medline]
  26. Hinks A, Barton A, John S, et al. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum (2005) 52:1694–9.[CrossRef][Web of Science][Medline]
  27. van Oene M, Wintle RF, Liu X, et al. Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations. Arthritis Rheum (2005) 52:1993–8.[CrossRef][Web of Science][Medline]
  28. Rueda B, Nunez C, Orozco G, et al. C1858T functional variant of PTPN22 gene is not associated with celiac disease genetic predisposition. Hum Immunol (2005) 66:848–52.[CrossRef][Web of Science][Medline]
  29. Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet (2004) 75:504–7.[CrossRef][Web of Science][Medline]
Submitted 24 July 2007; revised version accepted 19 November 2007.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Rheumatology (Oxford)Home page
V. Goeb, P. Dieude, R. Daveau, M. Thomas-L'Otellier, F. Jouen, F. Hau, P. Boumier, F. Tron, D. Gilbert, P. Fardellone, et al.
Contribution of PTPN22 1858T, TNFRII 196R and HLA-shared epitope alleles with rheumatoid factor and anti-citrullinated protein antibodies to very early rheumatoid arthritis diagnosis
Rheumatology, August 1, 2008; 47(8): 1208 - 1212.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/2/138    most recent
kem343v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Orozco, G.
Right arrow Articles by Martín, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Orozco, G.
Right arrow Articles by Martín, J.
Related Collections
Right arrow Immunogenetics
Right arrow Rheumatoid Arthritis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?