The PTPN22C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

Abstract

BackgroundThe 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.MethodsThe 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.ResultsA 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).ConclusionsThe T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

A systematic review of non‐genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis

“…The association remains significant after adjusting for insulin dose, gender, age at onset, and diabetes duration, but this finding has not been replicated yet. The Protein Tyrosine Phosphatase Non‐receptor type 22 (PTPN22) T1D risk allele was associated with HbA1c level, but this finding was not replicated in an independent study that used the insulin dose‐adjusted HbA1c measure (IDAAC), defined by Mortensen et al in 2009 . Associations reported for the candidate genes interleukin‐6 (IL‐6), T lymphocyte‐associated antigen‐4 (CTLA4), and tumour necrosis factor‐Alpha (TNF‐α) genes did not remain significant after correcting for multiple testing.…”

CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients

“…Several T1D candidate genes have been implicated in β-cell function and survival (28,(30)(31)(32), but to our knowledge, this study is the first demonstration that a genome-wide association study-identified genetic variation affects β-cell function in both model systems and human T1D. Thus, this study strengthens CTSH as a causal risk gene in T1D and reinforces the concept that candidate genes for T1D may affect disease progression by modulating survival and function of the pancreatic β-cells (33).…”

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

“…The disease risk is transmitted through the altered antigen-presenting function of dendritic cells (that express high levels of LYP), the altered activation of helper T cells and likely also via the decreased function of self-reactive regulatory T cells [48]. The c.1858C>T polymorphism of PTPN22 is associated with decreased residual β-cell function at the onset of T1DM [49,50]. The recent discovery of the expression of islet cell autoantibodies in 17-25% of MODY patients of Czech, German and Austrian origin [29,30,31] raises the question of whether the islet cell autoantibodies are present in a fraction of MODY patients because of their susceptibility to autoimmune disorders or whether these autoantibodies appear physiologically only as a transient result of β-cell destruction.…”