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Diabetologia

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01.06.2006 | Article

Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes

verfasst von: R. Hermann, K. Lipponen, M. Kiviniemi, T. Kakko, R. Veijola, O. Simell, M. Knip, J. Ilonen

Erschienen in: Diabetologia | Ausgabe 6/2006

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Abstract

Aims/hypothesis

We analysed the contribution of the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) to the emergence of beta-cell-specific humoral autoimmunity and progression to type 1 diabetes in man. We also explored the heterogeneity in the disease-predisposing effect of this polymorphism in relation to known disease loci, sex and age at disease onset.

Subjects and methods

A population-derived Finnish birth cohort with increased disease susceptibility conferred by HLA-DQB1 was monitored for the appearance of islet cell autoantibodies, and individuals found to be positive were tested for autoantibodies against insulin (IAA), glutamic acid decarboxylase and islet antigen-2 (n=574; mean follow-up time 4.9 years). Gene interaction effects on disease susceptibility were analysed in case–control and family series (546 patients, 538 controls, 245 nuclear families). All subjects were typed for HLA DR-DQ, insulin gene (INS), CTLA4 and PTPN22 C1858T polymorphisms.

Results

The PTPN22 1858TT genotype was associated with the appearance of IAA (adjusted hazard ratio=4.6, 95% CI 2.4–9.0; p=0.000013). PTPN22, INS and HLA-DRB1 had an additive effect on the emergence of IAA. The 1858TT and CT genotypes conferred an increased risk of developing additional autoantibodies or clinical disease (hazard ratio=4.1, 95% CI 1.5–11.6; and 1.6, 95% CI 1.1–2.4, respectively; p=0.003). The strong effect of PTPN22 on disease susceptibility (p=2.1×10⁻⁸) was more pronounced in males (p=0.021) and in subjects with non-DR4-DQ8/low-risk HLA genotypes (p=0.0004).

Conclusions/interpretation

In the pathogenesis of type 1 diabetes the underlying mechanism of the PTPN22 C1858T polymorphism appears to involve regulation of insulin-specific autoimmunity. Importantly, it strongly affects progression from prediabetes to clinical disease.

Pociot F, McDermott MF (2002) Genetics of type 1 diabetes mellitus. Genes Immun 3:235–249PubMedCrossRef

Hermann R, Turpeinen H, Laine AP et al (2003) HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families. Tissue Antigens 62:162–169PubMedCrossRef

Nejentsev S, Gombos Z, Laine AP et al (2000) Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. Diabetes 49:2217–2221PubMedCrossRef

Noble JA, Valdes AM, Bugawan TL, Apple RJ, Thomson G, Erlich HA (2002) The HLA class I A locus affects susceptibility to type 1 diabetes. Hum Immunol 63:657–664PubMedCrossRef

Zavattari P, Lampis R, Motzo C et al (2001) Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci. Hum Mol Genet 10:881–889PubMedCrossRef

Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176–183PubMedCrossRef

Barratt BJ, Payne F, Lowe CE et al (2004) Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53:1884–1889PubMedCrossRef

Nistico L, Buzzetti R, Pritchard LE et al (1996) The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum Mol Genet 5:1075–1080PubMedCrossRef

Ueda H, Howson JM, Esposito L et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511PubMedCrossRef

10.

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

11.

Smyth D, Cooper JD, Collins JE et al (2004) 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 53:3020–3023PubMedCrossRef

12.

Qu H, Tessier MC, Hudson TJ, Polychronakos C (2005) Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study. J Med Genet 42:266–270PubMedCrossRef

13.

Onengut-Gumuscu S, Ewens KG, Spielman RS, Concannon P (2004) A functional polymorphism (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families. Genes Immun 5:678–680PubMedCrossRef

14.

Criswell LA, Pfeiffer KA, Lum RF et al (2005) 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 76:561–571PubMedCrossRef

15.

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

16.

Zheng W, She JX (2005) Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes. Diabetes 54:906–908PubMedCrossRef

17.

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

18.

Kyogoku C, Langefeld CD, Ortmann WA et al (2004) Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 75:504–507PubMedCrossRef

19.

Begovich AB, Carlton VE, Honigberg LA et al (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75:330–337PubMedCrossRef

20.

Velaga MR, Wilson V, Jennings CE et al (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 89:5862–5865PubMedCrossRef

21.

Gjorloff-Wingren A, Saxena M, Williams S, Hammi D, Mustelin T (1999) Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur J Immunol 29:3845–3854PubMedCrossRef

22.

Cloutier JF, Veillette A (1999) Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med 189:111–121PubMedCrossRef

23.

Gepts W (1965) Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619–633PubMed

24.

Roep BO, Arden SD, de Vries RR, Hutton JC (1990) T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins. Nature 345:632–634PubMedCrossRef

25.

Ziegler AG, Hummel M, Schenker M, Bonifacio E (1999) Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 48:460–468PubMedCrossRef

26.

Kukko M, Kimpimaki T, Korhonen S et al (2005) Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population. J Clin Endocrinol Metab 90:2712–2717PubMedCrossRef

27.

LaGasse JM, Brantley MS, Leech NJ et al (2002) Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study. Diabetes Care 25:505–511PubMedCrossRef

28.

Vandewalle CL, Falorni A, Lernmark A et al (1997) Associations of GAD65- and IA-2- autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. The Belgian Diabetes Registry. Diabetes Care 20:1547–1552PubMedCrossRef

29.

Sabbah E, Savola K, Kulmala P et al (1999) Disease-associated autoantibodies and HLA-DQB1 genotypes in children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). The Childhood Diabetes in Finland Study Group. Clin Exp Immunol 116:78–83PubMedCrossRef

30.

Graham J, Hagopian WA, Kockum I et al (2002) Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 51:1346–1355PubMedCrossRef

31.

Genovese S, Bonfanti R, Bazzigaluppi E et al (1996) Association of IA-2 autoantibodies with HLA DR4 phenotypes in IDDM. Diabetologia 39:1223–1226PubMedCrossRef

32.

Hermann R, Laine AP, Veijola R et al (2005) The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity. Diabetologia 48:1766–1775PubMedCrossRef

33.

Kupila A, Muona P, Simell T et al (2001) Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort. Diabetologia 44:290–297PubMedCrossRef

34.

Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553PubMedCrossRef

35.

Kiviniemi M, Nurmi J, Turpeinen H, Lovgren T, Ilonen J (2003) A homogeneous high-throughput genotyping method based on competitive hybridization. Clin Biochem 36:633–640PubMedCrossRef

36.

Sjoroos M, Iitia A, Ilonen J, Reijonen H, Lovgren T (1995) Triple-label hybridization assay for type-1 diabetes-related HLA alleles. Biotechniques 18:870–877PubMed

37.

Nejentsev S, Sjoroos M, Soukka T et al (1999) Population-based genetic screening for the estimation of type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci. Diabet Med 16:985–992PubMedCrossRef

38.

Laaksonen M, Pastinen T, Sjoroos M et al (2002) HLA class II associated risk and protection against multiple sclerosis—a Finnish family study. J Neuroimmunol 122:140–145PubMedCrossRef

39.

Haller K, Kisand K, Nemvalts V, Laine AP, Ilonen J, Uibo R (2004) Type 1 diabetes is insulin −2221 MspI and CTLA−4 +49 A/G polymorphism dependent. Eur J Clin Invest 34:543–548PubMedCrossRef

40.

Kimpimaki T, Kulmala P, Savola K et al (2002) Natural history of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes recruited from the general population. J Clin Endocrinol Metab 87:4572–4579PubMedCrossRef

41.

Ronkainen MS, Hamalainen AM, Koskela P, Akerblom HK, Knip M (2001) Pregnancy induces nonimmunoglobulin insulin-binding activity in both maternal and cord blood serum. Clin Exp Immunol 124:190–196PubMedCrossRef

42.

Williams AJ, Bingley PJ, Bonifacio E, Palmer JP, Gale EA (1997) A novel micro-assay for insulin autoantibodies. J Autoimmun 10:473–478PubMedCrossRef

43.

Savola K, Sabbah E, Kulmala P, Vahasalo P, Ilonen J, Knip M (1998) Autoantibodies associated with type I diabetes mellitus persist after diagnosis in children. Diabetologia 41:1293–1297PubMedCrossRef

44.

Savola K, Bonifacio E, Sabbah E et al (1998) IA-2 antibodies—a sensitive marker of IDDM with clinical onset in childhood and adolescence. Childhood Diabetes in Finland Study Group. Diabetologia 41:424–429PubMedCrossRef

45.

Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121PubMedCrossRef

46.

Undlien DE, Friede T, Rammensee HG et al (1997) HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection. Diabetes 46:143–149PubMedCrossRef

47.

Walter M, Albert E, Conrad M et al (2003) IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of type 1 diabetes and associated autoimmunity. Diabetologia 46:712–720PubMedCrossRef

48.

Van der Auwera BJ, Vandewalle CL, Schuit FC et al (1997) CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry. Clin Exp Immunol 110:98–103PubMedCrossRef

49.

Hermann R, Bartsocas CS, Soltesz G et al (2004) Genetic screening for individuals at high risk for type 1 diabetes in the general population using HLA Class II alleles as disease markers. A comparison between three European populations with variable rates of disease incidence. Diabetes Metab Res Rev 20:322–329PubMedCrossRef

50.

Cucca F, Goy JV, Kawaguchi Y et al (1998) A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nat Genet 19:301–302PubMedCrossRef

Titel: Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes
verfasst von: R. Hermann
K. Lipponen
M. Kiviniemi
T. Kakko
R. Veijola
O. Simell
M. Knip
J. Ilonen
Publikationsdatum: 01.06.2006
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 6/2006
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0225-4

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Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes

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Results

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