title: Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies.
abstract: BACKGROUND
  The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies.
  
  
  METHODS
  We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil).
  
  
  RESULTS
  The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity.
  
  
  CONCLUSIONS
  MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders.
authors.affiliation: Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Heneberg
authors.forename: Milena
authors.initials: M
authors.lastname: Malá
authors.forename: Tohru
authors.initials: T
authors.lastname: Yorifuji
authors.forename: Galia
authors.initials: G
authors.lastname: Gat-Yablonski
authors.forename: Yael
authors.initials: Y
authors.lastname: Lebenthal
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
authors.forename: Viviane
authors.initials: V
authors.lastname: Nogaroto
authors.forename: Blanka
authors.initials: B
authors.lastname: Rypáčková
authors.forename: Lucie
authors.initials: L
authors.lastname: Kocková
authors.forename: Jana
authors.initials: J
authors.lastname: Urbanová
authors.forename: Michal
authors.initials: M
authors.lastname: Anděl
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D001938:Brazil; D018153:Czech Republic; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology*; D007557:Israel; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22