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The association between the PTPN22 1858C>T variant and type 1 diabetes depends on HLA risk and GAD65 autoantibodies

Genes & Immunity volume 11, pages 406–415 (2010)Cite this article

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Abstract

The single nucleotide polymorphism 1858C>T in the PTPN22 gene is associated with type 1 diabetes (T1D) in several populations. Earlier reports have suggested that the association may be modified by human leukocyte antigen (HLA), as well as by islet autoantibodies. In a large case–control study of Swedish incident T1D patients and controls, 0–34 years of age, we tested whether the odds ratio (OR) measure of association was dependent on HLA or autoantibodies against the islet autoantigens glutamic acid decarboxylase 65 kDa autoantibodies (GADA), insulin, islet antigen-2, or islet cell. The association between the carrier status of 1858C>T allele in PTPN22 (PTPN22(CT+TT)) and T1D was modified by HLA. In addition, in GADA-positive T1D, the OR was 2.83 (2.00, 3.99), whereas in GADA-negative T1D, the OR was 1.41 (0.98, 2.04) (P for comparison=0.007). The OR of association between PTPN22(CT+TT) and GADA-positive T1D declined with increasing HLA-risk category from 6.12 to 1.54 (P=0.003); no such change was detected in GADA-negative T1D (P=0.722) (P for comparison=0.001). However, the absolute difference in risk between PTPN22(CC) and PTPN22(CT+TT) subjects with high-risk HLA was five times higher than that for subjects with low-risk HLA. We hypothesize that the altered T-cell function because of the PTPN22(1858C>T) polymorphism is exclusively associated with GADA-positive T1D at diagnosis.

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References

  1. Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM . Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 1999; 93: 2013–2024.

    CAS  PubMed  Google Scholar 

  2. Jawaheer D, Seldin MF, Amos CI, Chen WV, Shigeta R, Monteiro J et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet 2001; 68: 927–936.

    Article  CAS  Google Scholar 

  3. Bottini NB, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M 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 

  4. Begovich AB, Carlton VEH, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC 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 

  5. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M et al. Analysis of families in the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 2005; 76: 561–571.

    Article  CAS  Google Scholar 

  6. De Jager PL, Sawcer S, Waliszewska A, Farwell L, Wild G, Cohen A et al. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. Eur J Hum Genet 2006; 14: 317–321.

    Article  CAS  Google Scholar 

  7. Vang T, Miletic AV, Bottini N, Mustelin T . Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity 2007; 40: 453–461.

    Article  CAS  Google Scholar 

  8. Steck AK, Liu S-Y, McFann K, Barriga KJ, Babu SR, Eisenbarth GS et al. Association of the PTPN22/LYP gene with type 1 diabetes. Pediatr Diabetes 2006; 7: 274–278.

    Article  Google Scholar 

  9. Ladner MB, Bottini N, Valdes AM, Noble JA . Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. Hum Immunol 2005; 66: 60–64.

    Article  CAS  Google Scholar 

  10. Kahles H, Ramos-Lopez E, Lange B, Zwermann O, Reincke M, Badenhoop K . Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto's thyroiditis or Addison's disease in the German population. Eur J Endocrinol 2005; 153: 895–899.

    Article  CAS  Google Scholar 

  11. Zhernakova A, Eerligh P, Wijmenga C, Barrera P, Roep BO, Koeleman BPC . Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population. Genes Immun 2005; 6: 459–461.

    Article  CAS  Google Scholar 

  12. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JMM et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53: 3020–3023.

    Article  CAS  Google Scholar 

  13. Hermann R, Lipponen K, Kiviniemi M, Kakko T, Veijola R, Simell O et al. Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes. Diabetologia 2006; 49: 1198–1208.

    Article  CAS  Google Scholar 

  14. Nielsen C, Hansen D, Husby S, Lillevang ST . Sex-specific association of the human PTPN22 1858T allele with type 1 diabetes. Int J Immunogenet 2007; 34: 469–473.

    Article  CAS  Google Scholar 

  15. Santiago J, Martinez A, de la Calle H, Fernandez-Arquero M, Figueredo MA, de la Concha E et al. Susceptibility to type 1 diabetes conferred by the PTPN22 C1858T polymorphism in the Spanish population. BMC Med Genet 2007; 8: 54.

    Article  Google Scholar 

  16. Saccucci P, del Duca E, Rapini N, Verrotti A, Piccinini S, Maccari A et al. Association between PTPN22 C1858T and type 1 diabetes: a replication in continental Italy. Tissue Antigens 2008; 71: 234–237.

    Article  CAS  Google Scholar 

  17. Cinek O, Hradsky O, Ahmedov G, Slavcev A, Kolouskova S, Kulich M et al. No independent role of the −1123 G>C and +2740 A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations. Diabetes Res Clin Pract 2007; 76: 297–303.

    Article  CAS  Google Scholar 

  18. Fedetz M, Matesanz F, Caro-Maldonado A, Smirnov II, Chvorostinka VN, Moiseenko TA et al. The 1858 T PTPN22 gene variant contributes to a genetic risk of type 1 diabetes in a Ukrainian population. Tissue Antigens 2006; 67: 430–433.

    Article  CAS  Google Scholar 

  19. Gomez LM, Anaya J-M, Gonzalez CI, Pineda-Tamayo R, Otero W, Arango A et al. PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. Genes Immun 2005; 6: 628–631.

    Article  CAS  Google Scholar 

  20. Ikegami H, Kawabata Y, Noso S, Fujisawa T, Ogihara T . Genetics of type 1 diabetes in Asian and Caucasian populations. Diabetes Res Clin Pract 2007; 77 (3, Supplement 1): S116–S121.

    Article  CAS  Google Scholar 

  21. Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K . Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet 2005; 50: 264–266.

    Article  Google Scholar 

  22. Smyth DJ, Cooper JD, Howson JM, Walker NM, Plagnol V, Stevens H et al. PTPN22 Trp620 explains the association of chromosome 1p13 with type 1 diabetes and shows a statistical interaction with HLA class II genotypes. Diabetes 2008; 57: 1730–1737.

    Article  CAS  Google Scholar 

  23. Rolandsson O, Hagg E, Janer M, Rutledge E, Gaur LK, Nilsson M et al. High GAD65 autoantibody levels in nondiabetic adults are associated with HLA but not with CTLA-4 or INS VNTR. J Intern Med 2003; 253: 447–453.

    Article  CAS  Google Scholar 

  24. Graham J, Hagopian WA, Kockum I, Li LS, Sanjeevi CB, Lowe RM et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 2002; 51: 1346–1355.

    Article  CAS  Google Scholar 

  25. Chelala C, Duchatelet S, Joffret M-L, Bergholdt R, Dubois-Laforgue Dl, Ghandil P et al. PTPN22 R620W functional variant in type 1 diabetes and autoimmunity related traits. Diabetes 2007; 56: 522–526.

    Article  CAS  Google Scholar 

  26. Gupta M, Graham J, McNeeny B, Zarghami M, Landin-Olsson M, Hagopian WA et al. MHC class I chain-related gene-A is associated with IA2 and IAA but not GAD in Swedish type 1 diabetes mellitus. Ann N Y Acad Sci 2006; 1079: 229–239.

    Article  CAS  Google Scholar 

  27. Shin JH, Janer M, McNeney B, Blay S, Deutsch K, Sanjeevi CB et al. IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5. Genes Immun 2007; 8: 503–512.

    Article  CAS  Google Scholar 

  28. Orozco G, Pascual-Salcedo D, Lopez-Nevot MA, Cobo T, Cabezon A, Martin-Mola E et al. Auto-antibodies, HLA and PTPN22: susceptibility markers for rheumatoid arthritis. Rheumatology 2008; 47: 138–141.

    Article  CAS  Google Scholar 

  29. Smith A, Bates M . Confidence limit analyses should replace power calculations in the interpretation of epidemiologic studies. Epidemiology (Cambridge, Mass) 1992; 3: 449–452.

    Article  CAS  Google Scholar 

  30. Mansson L, Torn C, Landin-Olsson M . Islet cell antibodies represent autoimmune response against several antigens. Int J Exp Diabetes Res 2001; 2: 85–90.

    Article  CAS  Google Scholar 

  31. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, Nath SK et al. The PTPN22 C1858T functional polymorphism and autoimmune diseases, a meta-analysis. Rheumatology 2007; 46: 49–56.

    Article  CAS  Google Scholar 

  32. Petrone A, Suraci C, Capizzi M, Giaccari A, Bosi E, Tiberti C et al. The protein tyrosine phosphatase nonreceptor 22 (PTPN22) is associated with high GAD antibody titer in latent autoimmune diabetes in adults. Diabetes Care 2008; 31: 534–538.

    Article  Google Scholar 

  33. Pihoker C, Gilliam LK, Hampe CS, Lernmark Å . Autoantibodies in diabetes. Diabetes 2005; 54: 52–61.

    Article  Google Scholar 

  34. Wasserfall CH, Atkinson MA . Autoantibody markers for the diagnosis and prediction of type 1 diabetes. Autoimmun Rev 2006; 5: 424–428.

    Article  CAS  Google Scholar 

  35. Rantapaa-Dahlqvist S . What happens before the onset of rheumatoid arthritis? Curr Opin Rheumatol 2009; 21: 272–278.

    Article  Google Scholar 

  36. Graham J, Kockum I, Sanjeevi CB, Landin-Olsson M, Nystruom L, Sundkvist G et al. Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset. Eur J Immunogenet 1999; 26: 117–127.

    Article  CAS  Google Scholar 

  37. Hansson L, Khamis HJ . Matched samples logistic regression in case-control studies with missing values: when to break the matches. Stat Methods Med Res 2008; 17: 595–607.

    Article  Google Scholar 

  38. Larsson HE, Lynch K, Lernmark B, Nilsson A, Hansson G, Almgren P et al. Diabetes-associated HLA genotypes affect birthweight in the general population. Diabetologia 2005; 48: 1484–1491.

    Article  CAS  Google Scholar 

  39. Kockum I, Sanjeevi CB, Eastman S, Landin-Olsson M, Dahlquist G, Lernmark Å . Complex interaction between HLA DR and DQ in conferring risk for childhood type 1 diabetes. Eur J Immunogenet 1999; 26: 361–372.

    Article  CAS  Google Scholar 

  40. Sanjeevi CB, Lybrand TP, DeWeese C, Landin-Olsson M, Kockum I, Dahlquist G et al. Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study. Diabetes 1995; 44: 125–131.

    Article  CAS  Google Scholar 

  41. Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, Raghu PK et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 1983; 222: 1337–1339.

    Article  CAS  Google Scholar 

  42. Landin-Olsson M, Karlsson FA, Lernmark Å, Sundkvist G . Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the diabetes incidence study in Sweden. Diabetes 1992; 41: 1022–1027.

    Article  CAS  Google Scholar 

  43. Hagopian WA, Karlsen AE, Gottsater A, Landin-Olsson M, Grubin CE, Sundkvist G et al. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J Clin Invest 1993; 91: 368–374.

    Article  CAS  Google Scholar 

  44. Hagopian WA, Sanjeevi CB, Kockum I, Landin-Olsson M, Karlsen AE, Sundkvist G et al. Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children. J Clin Invest 1995; 95: 1505–1511.

    Article  CAS  Google Scholar 

  45. Falorni A, Grubin CE, Takei I, Shimada A, Kasuga A, Maruyama T et al. Radioimmunoassay detects the frequent occurrence of autoantibodies to the Mr 65,000 isoform of glutamic acid decarboxylase in Japanese insulin-dependent diabetes. Autoimmunity 1994; 19: 113–125.

    Article  CAS  Google Scholar 

  46. Grubin CE, Daniels T, Toivola B, Landin-Olsson M, Hagopian WA, Li L et al. A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 1994; 37: 344–350.

    Article  CAS  Google Scholar 

  47. Mire-Sluis AR, Gaines Das R, Lernmark Å, Participants of the study. The World Health Organization International Collaborative Study for islet cell antibodies. Diabetologia 2000; 43: 1282–1292.

    Article  CAS  Google Scholar 

  48. Lan MS, Lu J, Goto Y, Notkins AL . Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol 1994; 13: 505–514.

    Article  CAS  Google Scholar 

  49. Rabin DU, Pleasic SM, Palmer-Crocker R, Shapiro JA . Cloning and expression of IDDM-specific human autoantigens. Diabetes 1992; 41: 183–186.

    Article  CAS  Google Scholar 

  50. Kawasaki E, Eisenbarth GS, Wasmeier C, Hutton JC . Autoantibodies to protein tyrosine phosphatase-like proteins in type I diabetes: overlapping specificities to phogrin and ICA512/IA-2. Diabetes 1996; 45: 1344–1349.

    Article  CAS  Google Scholar 

  51. Olsson ML, Sundkvist G, Lernmark Å . Prolonged incubation in the two-colour immunofluorescence test increases the prevalence and titres of islet cell antibodies in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1987; 30: 327–332.

    Article  CAS  Google Scholar 

  52. Bonifacio E, Lernmark Å, Dawkins RL . Serum exchange and use of dilutions have improved precision of measurement of islet cell antibodies. J Immunol Methods 1988; 106: 83–88.

    Article  CAS  Google Scholar 

  53. van Belle G, Fisher LD, Heagerty PJ, Lumley T . Biostatistics: A Methodology for the Health Sciences, 2nd edn. John Wiley and Sons, Inc.: Hoboken, NJ, 2004.

    Book  Google Scholar 

  54. Agresti A . Categorical Data Analysis, 2nd edn. A John Wiley & Sons, Inc.: Hoboken, New Jersey, 2002.

    Book  Google Scholar 

  55. Baniasadi V, Das SN . No evidence for association of PTPN22 R620W functional variant C1858T with type 1 diabetes in Asian Indians. J Cell Mol Med 2008; 12: 1061–1062.

    Article  CAS  Google Scholar 

  56. Douroudis K, Prans E, Haller K, Nemvalts V, Rajasalu T, Tillmann V et al. Protein tyrosine phosphatase non-receptor type 22 gene variants at position 1858 are associated with type 1 and type 2 diabetes in Estonian population. Tissue Antigens 2008; 72: 425–430.

    Article  CAS  Google Scholar 

  57. Zoledziewska M, Perra C, Orru V, Moi L, Frongia P, Congia M et al. Further evidence of a primary, causal association of the PTPN22 620W variant with type 1 diabetes. Diabetes 2008; 57: 229–234.

    Article  CAS  Google Scholar 

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Acknowledgements

ÅL was supported in part by the National Institutes of Health (grant DK53004, DK26910), University of Washington Diabetes Endocrinology Research Center (grant # 5 P30 DK17047), the Juvenile Diabetes Research Foundation International (grant 1-2001- 873), Swedish Research Council (K2008-55X-15312-04-3), K & A Wallenberg Foundation, Swedish Childhood Diabetes Fund and UMAS Fund, as well as the Skåne County Council Foundation for Research and Development. NB and MM were supported in part by NIH Grant R01 DK026190. MJ was supported in part by NIH grant DK053004.

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Author notes

  1. M Maziarz, M Janer, J C Roach, W Hagopian, J P Palmer, K Deutsch, C B Sanjeevi, I Kockum, N Breslow and Å Lernmark: See Appendix.

Authors and Affiliations

  1. Department of Biostatistics, University of Washington, Seattle, WA, USA

    M Maziarz & N Breslow

  2. Institute for Systems Biology, Seattle, WA, USA

    M Janer, J C Roach & K Deutsch

  3. Pacific Northwest Diabetes Research Institute, Seattle, WA, USA

    W Hagopian

  4. Department of Medicine, University of Washington, Seattle, WA, USA

    J P Palmer & Å Lernmark

  5. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    C B Sanjeevi

  6. Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden

    I Kockum

  7. Department of Clinical Sciences, Lund University, Malmö, Sweden

    Å Lernmark

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on behalf of the Swedish Childhood Diabetes Register and the Diabetes Incidence in Sweden Study Group

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Appendix

Appendix

The following authors are from the Diabetes Incidence in Sweden Study Group: Jinko Graham, Brad MacNeney, Hans Arnqvist, Department of Internal Medicine, University of Linköping, Linköping; Mona Landin-Olsson, Department of Clinical Sciences, Lund University, Lund; Lennarth Nyström, Department of Epidemiology and Public Health, University of Umeå, Umeå; Lars Olof Ohlson, Sahlgrenska Hospital, University of Göteborg, Göteborg; and Jan Östman, Center for Metabolism and Endocrinology, Huddinge University Hospital, Stockholm. The following authors are from the Swedish Childhood Diabetes Study Group, all from Departments of Pediatrics: M Aili, Halmstad; LE Bååth, Östersund; E Carlsson, Kalmar; H Edenwall, Karlskrona; G Forsander, Falun; BW Granström, Gällivare; I Gustavsson, Skellefteå; R Hanås, Uddevalla; L Hellenberg, Nyköping; H Hellgren, Lidköping; E Holmberg, Umeå; H Hörnell, Hudiksvall; Sten-A Ivarsson, Malmö; C Johansson, Jönköping; G Jonsell, Karlstad; B Lindblad, Mölndal; A Lindh, Borås; J Ludvigsson, Linköping; U Myrdal, Västerås; J Neiderud, Helsingborg; K Segnestam, Eskilstuna; L Skogsberg, Boden; L Strömberg, Norrköping; U Ståhle, Ängelholm; B Thalme, Huddinge; K Tullus, Danderyd; T Tuvemo, Uppsala; M Wallensteen, Stockholm; O Westphal, Göteborg; and J Åman, Örebro.

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Maziarz, M., Janer, M., Roach, J. et al. The association between the PTPN22 1858C>T variant and type 1 diabetes depends on HLA risk and GAD65 autoantibodies. Genes Immun 11, 406–415 (2010). https://doi.org/10.1038/gene.2010.12

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