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The PTPN22 R263Q polymorphism confers protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves’ disease in a Mexican population

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Abstract

Objective

The functional PTPN22 R620W polymorphism (rs2476601) is clearly associated with susceptibility to several autoimmune diseases (ADs). However, the PTPN22 R263Q polymorphism (rs33996649) has been scarcely explored in different ADs. Here we aimed to examine the associations of the PTPN22 R620W and R263Q polymorphisms with susceptibility to or protection against rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves’ disease (GD) among Mexican patients.

Methods

We conducted a case–control study including 876 patients (405 with SLE, 388 with RA, and 83 with GD) and 336 healthy control individuals. PTPN22 genotypes were determined using the TaqMan 5′ allele discrimination assay.

Results

PTPN22 R620W was associated with GD susceptibility (OR 4.3, p = 0.004), but was not associated with SLE (OR 1.8, p = 0.19). We previously demonstrated that this polymorphism is associated with RA susceptibility (OR 4.17, p = 0.00036). Moreover, PTPN22 R263Q was associated with protection against SLE (OR 0.09, p = 004) and RA (OR 0.28, p = 0.045), but was not associated with GD.

Conclusions

Our data provide the first demonstration that PTPN22 R620W confers GD susceptibility among Latin-American patients. Moreover, this is the second report documenting the association of PTPN22 R263Q with protection against SLE and RA.

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References

  1. Rincón JF, Cano DL, Morales SJ, Jiménez ML, Cobos RE, Bello JR. The functional PTPN22 C1858T polymorphism confers risk for rheumatoid arthritis in patients from Central Mexico. Clin Rheumatol. 2016;35:1457–62.

    Article  PubMed  Google Scholar 

  2. Stanford SM, Bottini N. PTPN22: the archetypal non-HLA autoimmunity gene. Nat Rev Rheumatol. 2014;10:602–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fousteri G, Liossis SN, Battaglia M. Roles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunity. Clin Immunol. 2013;149:556–65.

    Article  CAS  PubMed  Google Scholar 

  4. Burn GL, Svensson L, Sánchez-Blanco C, Saini M, Cope AP. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett. 2011;585:3689–98.

    Article  CAS  PubMed  Google Scholar 

  5. Nabi G, Akhter N, Wahid M, Bhatia K, Mandal RK, Dar SA, et al. Meta-analysis reveals PTPN22 1858C/T polymorphism confers susceptibility to rheumatoid arthritis in Caucasian but not in Asian population. Autoimmunity. 2016;49:197–210.

    Article  CAS  PubMed  Google Scholar 

  6. Ramirez M, Quintana G, Diaz-Gallo L, Caminos J, Garces M, Cepeda L, et al. The PTPN22 C1858T variant as a risk factor for rheumatoid arthritis and systemic lupus erythematosus but not for systemic sclerosis in the Colombian population. Clin Exp Rheumatol. 2012;30:520–4.

    PubMed  Google Scholar 

  7. Namjou B, Kim-Howard X, Sun C, Adler A, Chung SA, Kaufman KM, et al. PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes. PLoS ONE. 2013;8:e69404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lea WE, Lee YH. The association between the PTPN22 C1858T polymorphism and systemic lupus erythematosus: a meta-analysis update. Lupus. 2011;20:51–7.

    Article  CAS  PubMed  Google Scholar 

  9. Shi L, Wei Y, Xun W, Han D. Meta-analysis of the correlation between PTPN22 gene polymorphisms and susceptibility to systemic lupus erythematosus. Asia Pac J Public Health. 2013;25:22S–9S.

    Article  PubMed  Google Scholar 

  10. Tang L, Wang Y, Zheng S, Bao M, Zhang Q, Li J. PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus erythematosus and rheumatoid arthritis in a Chinese Han population. Hum Immunol. 2016;77:692–8.

    Article  CAS  PubMed  Google Scholar 

  11. Machado-Contreras JR, Muñóz-Valle JF, Salazar-Camarena DC, Marín-Rosales M, Palafox-Sánchez CA. Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity. Clin Exp Med. 2016;16:399–406.

    Article  CAS  PubMed  Google Scholar 

  12. Luo L, Cai B, Liu F, Hu X, Wang L. Association of protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T gene polymorphism with susceptibility to autoimmune thyroid diseases: a meta-analysis. Endocr J. 2012;59:439–45.

    Article  CAS  PubMed  Google Scholar 

  13. Zheng J, Ibrahim S, Petersen F, Yu X. Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue. Genes Immun. 2012;13:641–52.

    Article  PubMed  Google Scholar 

  14. Alkhateeb A, Marzouka NA, Tashtoush R. Variants in PTPN22 and SMOC2 genes and the risk of thyroid disease in the Jordanian Arab population. Endocrine. 2013;44:702–9.

    Article  CAS  PubMed  Google Scholar 

  15. Xue L, Pan C, Gu Z, Zhao S, Han B, Liu W, et al. Genetic heterogeneity of susceptibility gene in different ethnic populations: refining association study of PTPN22 for Graves’ disease in Chinese Han population. PLoS ONE. 2013;8:e84514.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ban Y, Tozaki T, Nakano Y. Association studies of the GPR103 and BCL2L15 genes in autoimmune thyroid disease in the Japanese population. Front Endocrinol (Lausanne). 2016;7:92.

    PubMed  PubMed Central  Google Scholar 

  17. Arechiga AF, Habib T, He Y, Zhang X, Zhang ZY, Funk A, et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J Immunol. 2009;182:3343–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rawlings DJ, Dai X, Buckner JH. The role of PTPN22 risk variant in the development of autoimmunity: finding common ground between mouse and human. J Immunol. 2015;194:2977–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Douroudis K, Shcherbakova A, Everaus H, Aints A. PTPN22 gene regulates natural killer cell proliferation during in vitro expansion. Tissue Antigens. 2010;76:315–8.

    Article  CAS  PubMed  Google Scholar 

  20. Bayley R, Kite KA, McGettrick HM, Smith JP, Kitas GD, Buckley CD, et al. The autoimmune-associated genetic variant PTPN22 R620W enhances neutrophil activation and function in patients with rheumatoid arthritis and healthy individuals. Ann Rheum Dis. 2015;74:1588–95.

    Article  CAS  PubMed  Google Scholar 

  21. Orrú V, Tsai SJ, Rueda B, Fiorillo E, Stanford SM, Dasgupta J, et al. A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum Mol Genet. 2009;18:569–79.

    Article  PubMed  Google Scholar 

  22. Liu J, Chen M, Li R, Yang F, Shi X, Zhu L, et al. Biochemical and functional studies of lymphoid-specific tyrosine phosphatase (Lyp) variants S201F and R266W. PLoS ONE. 2012;7:e43631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rodríguez-Rodríguez L, Taib WRW, Topless R, Steer S, González-Escribano MF, Balsa A, et al. The PTPN22 R263Q polymorphism is a risk factor for rheumatoid arthritis in Caucasian case-control samples. Arthritis Rheum. 2011;63:365–72.

    Article  PubMed  Google Scholar 

  24. Diaz-Gallo LM, Gourh P, Broen J, Simeon C, Fonollosa V, Ortego-Centeno N, et al. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis. Ann Rheum Dis. 2011;70:454–62.

    Article  CAS  PubMed  Google Scholar 

  25. Diaz-Gallo LM, Espino-Paisán L, Fransen K, Gómez-García M, van Sommeren S, Cardeña C, et al. Differential association of two PTPN22 coding variants with Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2011;17:2287–94.

    Article  PubMed  Google Scholar 

  26. Cénit MC, Márquez A, Cordero-Coma M, Fonollosa A, Llorenç V, Artaraz J, et al. Lack of association between the protein tyrosine phosphatase non-receptor type 22 R263Q and R620W function genetic variants and endogenous non-anterior uveitis. Mol Vis. 2013;19:638–43.

    PubMed  PubMed Central  Google Scholar 

  27. López-Mejías R, Genre F, Remuzgo-Martínez S, Sevilla-Pérez B, Castañeda S, Llorca J, et al. Role of PTPN22 and CSK gene polymorphisms as predictors of susceptibility and clinical heterogeneity in patients with Henoch-Schönlein purpura (IgA vasculitis). Arthritis Res Ther. 2015;17:286.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Carlton VE, Hu X, Chokkalingam AP, Schrodi JS, Brandon R, Alexander HC, et al. PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. Am J Hum Genet. 2005;77:567–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Salmond RJ, Brownlie RJ, Morrison VL, Zamoyska R. The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Nat Immunol. 2014;15:875–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu DJ, Zhou W, Enouz S, Orrú V, Stanford SM, Maine CJ, et al. Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. PLoS ONE. 2014;9:e86677.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Maine CJ, Marquardt K, Cheung J, Sherman LA. PTPN22 controls the germinal center by influencing the numbers and activity of T follicular helper cells. J Immunol. 2014;192:1415–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schickel JN, Kuhny M, Baldo A, Bannock JM, Massad C, Wang H, et al. PTPN22 inhibition resets defective human central B cell tolerance. Sci Immunol. 2016;1:pii:aaf7153.

  33. Vermeren S, Miles K, Chu JY, Salter D, Zamoyska R, Gray M. PTPN22 is a critical regulator of Fcγ receptor-mediated neutrophil activation. J Immunol. 2016;197:4771–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chang HH, Dwivedi N, Nicholas AP, Ho IC. The W620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and NETosis. Arthritis Rheumatol. 2015;67:2323–34.

    Article  CAS  PubMed  Google Scholar 

  35. Rieck M, Arechiga A, Onengut-Gumuscu S, Greenbaum C, Concannon P, Buckner JH. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J Immunol. 2007;179:4704–10.

    Article  CAS  PubMed  Google Scholar 

  36. Demoruelle MK, Deane K. Antibodies to citrullinated protein antigens (ACPAs): clinical and pathophysiologic significance. Curr Rheumatol Rep. 2011;13:421–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Burch HB, Cooper DS. Management of Graves’ disease: a review. JAMA. 2015;314:2544–54.

    Article  CAS  PubMed  Google Scholar 

  38. Pujol-Borrell R, Giménez-Barcons M, Marín-Sánchez A, Clobran R. Genetics of Graves’ disease: special focus on the role of TSHR gene. Horm Metab Res. 2015;47:753–66.

    Article  CAS  PubMed  Google Scholar 

  39. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, et al. The codón 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab. 2004;89:5862–5.

    Article  CAS  PubMed  Google Scholar 

  40. Mendoza-Rincón JF, Rodríguez-Elias AK, Fragoso JM, Vargas-Alarcón G, Maldonado-Murillo K, Rivas-Jiménez ML, et al. MHC2TA and FCRL3 genes are not associated with rheumatoid arthritis in Mexican patients. Rheumatol Int. 2016;36:249–54.

    Article  PubMed  Google Scholar 

  41. Moreno-Estrada A, Gignoux CR, Fernández-López JC, Zakharia F, Sikora M, Contreras AV, et al. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits. Science. 2014;344:1280–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Maine CJ, Teijaro JR, Marquardt K, Sherman LA. PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection. Proc Natl Acad Sci USA. 2016;113:E7231–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

This study was supported by a grant from the Consejo Nacional de Ciencia y Tecnología de México (CONACyT) (FOSISS; project no. 233107). Daniela Josabeth López Cano is grateful to CONACyT for the scholarship.

Author information

Authors and Affiliations

  1. Research Unit on Endocrine and Metabolic Diseases, Hospital Juárez de México (HJM), Av. Instituto Politécnico Nacional No. 5160, Delegación Gustavo A. Madero, 07760, Mexico City, D.F., Mexico

    Daniela Josabeth López-Cano, Daniel Cadena-Sandoval & Julian Ramírez-Bello

  2. Superior School of Medicine Postgraduate Program, Nacional Polytechnic Institute, Mexico City, Mexico

    Daniela Josabeth López-Cano

  3. Research Unit on Immunity and Inflammation, HJM, Mexico City, Mexico

    Olga Beltrán-Ramírez

  4. Department of Rheumatology, HJM, Mexico City, Mexico

    Rosa Elda Barbosa-Cobos

  5. Department of Immunology, National Institute of Cardiology (NIC), Mexico City, Mexico

    Fausto Sánchez-Muñoz, Luis Manuel Amezcua-Guerra & Yaneli Juárez-Vicuña

  6. Department of Endocrinology, HJM, Mexico City, Mexico

    María Concepción Aguilera-Cartas

  7. Direction of Research, HJM, Mexico City, Mexico

    José Moreno

  8. Blood Bank, HJM, Mexico City, Mexico

    Jesús Bautista-Olvera

  9. Laboratory of Hematology, Regional Research Center, Autonomous University of Yucatan, Mérida, Yucatan, Mexico

    Guillermo Valencia-Pacheco

  10. Regional General Hospital (ISSSTE), Health Services Yucatan (HSY), Mérida, Yucatan, Mexico

    Ricardo F. López-Villanueva

Authors
  1. Daniela Josabeth López-Cano
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  2. Daniel Cadena-Sandoval
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Corresponding author

Correspondence to Julian Ramírez-Bello.

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Responsible Editor: John Di Battista.

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López-Cano, D.J., Cadena-Sandoval, D., Beltrán-Ramírez, O. et al. The PTPN22 R263Q polymorphism confers protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves’ disease in a Mexican population. Inflamm. Res. 66, 775–781 (2017). https://doi.org/10.1007/s00011-017-1056-0

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  • DOI: https://doi.org/10.1007/s00011-017-1056-0

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