Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

Abstract

We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46–2.10, P=1.3 × 10−9). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92–1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35–8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. McInnes IB . Rheumatoid arthritis. From bench to bedside. Rheum Dis Clin N Am 2001; 27: 373–387.

    Article  CAS  Google Scholar 

  2. Gabriel SE . The epidemiology of rheumatoid arthritis. Rheum Dis Clin N Am 2001; 27: 269–281.

    Article  CAS  Google Scholar 

  3. Firestein GS . Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–361.

    Article  CAS  Google Scholar 

  4. Dorner T, Egerer K, Feist E, Burmester GR . Rheumatoid factor revisited. Curr Opin Rheumatol 2004; 16: 246–253.

    Article  CAS  Google Scholar 

  5. Newkirk MM . Rheumatoid factors: what do they tell us? J Rheumatol 2002; 29: 2034–2040.

    CAS  PubMed  Google Scholar 

  6. Davidson A, Bridges Jr SL . Autoimmunity. In: St Clair EW, Pisetsky DS, Haynes BF (eds). Rheumatoid Arthritis. Lippincott Williams and Williams: Philadelphia, 2004, pp 197–212.

    Google Scholar 

  7. Halldorsdottir HD, Jonsson T, Thorsteinsson J, Valdimarsson H . A prospective study on the incidence of rheumatoid arthritis among people with persistent increase of rheumatoid factor. Ann Rheum Dis 2000; 59: 149–151.

    Article  CAS  Google Scholar 

  8. Rantapaa-Dahlqvist S, de Jong BA, Berglin E et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003; 48: 2741–2749.

    Article  Google Scholar 

  9. Nielen MM, van Schaardenburg D, Reesink HW et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50: 380–386.

    Article  Google Scholar 

  10. 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: 330–337.

    Article  CAS  Google Scholar 

  11. Baugh JA, Chitnis S, Donnelly SC et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 2002; 3: 170–176.

    Article  CAS  Google Scholar 

  12. Bombardier C, Deaton R, Gregersen P, Massarotti E, Formica C, Weisman M . Pattern of DMARD use in a North American cohort of patients with early rheumatoid arthritis (SONORA). Arthritis Rheum 2002; 46: S344 (abstract).

    Google Scholar 

  13. Fries JF, Wolfe F, Apple R et al. HLA-DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias. Arthritis Rheum 2002; 46: 2320–2329.

    Article  CAS  Google Scholar 

  14. Hasegawa K, Martin F, Huang G, Tumas D, Diehl L, Chan AC . PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 2004; 303: 685–689.

    Article  CAS  Google Scholar 

  15. Bottini N, Musumeci L, Alonso A et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004; 36: 337–338.

    Article  CAS  Google Scholar 

  16. 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: 504–507.

    Article  CAS  Google Scholar 

  17. Arbuckle MR, McClain MT, Rubertone MV et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 1526–1533.

    Article  CAS  Google Scholar 

  18. Hoppu S, Ronkainen MS, Kulmala P, Akerblom HK, Knip M, Childhood Diabetes in Finland Study Group. GAD65 antibody isotypes and epitope recognition during the prediabetic process in siblings of children with type I diabetes. Clin Exp Immunol 2004; 136: 120–128.

    Article  CAS  Google Scholar 

  19. Strieder TG, Prummel MF, Tijssen JG, Endert E, Wiersinga WM . Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease. Clin Endocrinol (Oxford) 2003; 59: 396–401.

    Article  Google Scholar 

  20. Weyand CM, Kurtin PJ, Goronzy JJ . Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am J Pathol 2001; 159: 787–793.

    Article  CAS  Google Scholar 

  21. Luzina IG, Atamas SP, Storrer CE et al. Spontaneous formation of germinal centers in autoimmune mice. J Leukocyte Biol 2001; 70: 578–584.

    CAS  PubMed  Google Scholar 

  22. Weyand CM, Goronzy JJ . Ectopic germinal center formation in rheumatoid synovitis. Ann NY Acad Sci 2003; 987: 140–149.

    Article  CAS  Google Scholar 

  23. Haberman AM, William J, Euler C, Shlomchik MJ . Rheumatoid factors in health and disease: structure, function, induction and regulation. Curr Dir Autoimmun 2003; 6: 169–195.

    Article  Google Scholar 

  24. Randen I, Thompson KM, Pascual V et al. Rheumatoid factor V genes from patients with rheumatoid arthritis are diverse and show evidence of an antigen-driven response. Immunol Rev 1992; 128: 49–71.

    Article  CAS  Google Scholar 

  25. Kang YM, Zhang X, Wagner UG et al. CD8T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med 2002; 195: 1325–1336.

    Article  CAS  Google Scholar 

  26. Mattey DL, Dawes PT, Clarke S et al. Relationship among the HLA-DRB1 shared epitope, smoking, and rheumatoid factor production in rheumatoid arthritis. Arthritis Rheum 2002; 47: 403–407.

    Article  CAS  Google Scholar 

  27. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F . Methotrexate therapy and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359: 1173–1177.

    Article  CAS  Google Scholar 

  28. Wolfe F, Michaud K, Gefeller O, Choi HK . Predicting mortality in patients with rheumatoid arthritis. Arthritis Rheum 2003; 48: 1530–1542.

    Article  Google Scholar 

  29. Jawaheer D, Li W, Graham RR et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 2002; 71: 585–594.

    Article  CAS  Google Scholar 

  30. Woolf B . On estimating the relationship between blood group and disease. Ann Hum Genet 1955; 19: 251–253.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge all RA patients who participated in each of the RA studies. We thank Lyn Maguire for support of the SONORA Project and Marlena Kern for her commitment to SONORA and all the projects within Robert S Boas Center for Genomics and Human Genetics, TL Bugawan and E Trachtenberg for HLA typing, A Chokkalingham and V Carlton for valuable comments on this manuscript, and Abbott Laboratories for financial support of the SONORA study. PKG is supported in part by NIH grants RO1 AR44422 and NO1-AR-2-2263.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A T Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, A., 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 6, 129–133 (2005). https://doi.org/10.1038/sj.gene.6364159

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364159

Keywords

This article is cited by

Search

Quick links