title: The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes.
abstract: BACKGROUND
  The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes.
  
  
  METHODS
  The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset.
  
  
  RESULTS
  A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03).
  
  
  CONCLUSIONS
  The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.
authors.affiliation: Department of Paediatrics, Glostrup University Hospital, Denmark. lotbrn01@glo.regionh.dk
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Nielsen
authors.forename: Sven
authors.initials: S
authors.lastname: Pörksen
authors.forename: Marie Louise M
authors.initials: ML
authors.lastname: Andersen
authors.forename: Siri
authors.initials: S
authors.lastname: Fredheim
authors.forename: Jannet
authors.initials: J
authors.lastname: Svensson
authors.forename: Philip
authors.initials: P
authors.lastname: Hougaard
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vanelli
authors.forename: Jan
authors.initials: J
authors.lastname: Åman
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Mortensen
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
mesh_terms: D001323:Autoantibodies / Q000097:blood; D002096:C-Peptide / Q000097:blood; D002648:Child; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics*; D016883:Diabetic Ketoacidosis / Q000209:etiology / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011384:Proinsulin / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012044:Regression Analysis; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D002096:C-Peptide; D011384:Proinsulin; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22