The Protein Tyrosine Phosphatase Nonreceptor 22 (PTPN22) Is Associated With High GAD Antibody Titer in Latent Autoimmune Diabetes in Adults

Abstract

OBJECTIVE -We previously demonstrated the presence of two different populations among individuals with adult-onset autoimmune diabetes: those having either a high titer or a low titer of antibodies to GAD (GADAs). Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) has been identified as a new susceptibility gene for type 1 diabetes and other autoimmune diseases. The aim of the present study was to evaluate whether the phenotypic heterogeneity of adult-onset autoimmune diabetes based on the GADA titer is associated with the PTPN22 C1858T polymorphism.RESEARCH DESIGN AND METHODS -Analysis for the C1858T polymorphism using the TaqMan assay was performed in 250 subjects with adult-onset autoimmune diabetes, divided into two subgroups with low (Յ32 arbitrary units) or high (Ͼ32 arbitrary units) GADA titers and 450 subjects with classic type 2 diabetes (from the Non Insulin Requiring Autoimmune Diabetes [NIRAD] Study cohort of 5,330 subjects with adult-onset diabetes) and in 558 subjects with juvenile-onset type 1 diabetes and 545 normoglycemic subjects.RESULTS -Genotype, allele, and phenotype distributions of the PTPN22 C1858T variant revealed similar frequencies in autoimmune diabetes with high GADA titer and juvenile-onset type 1 diabetes. An increase in TT and CT genotypes was observed in individuals with a high GADA titer compared with a low GADA titer, those with type 2 diabetes, and control subjects (P Ͻ 0.002 for all comparisons). The PTPN22 1858T allele and phenotype frequencies were increased in high GADA titer compared with a low GADA titer, type 2 diabetic, and control subjects (P Ͻ 0.001 for all comparisons, odds ratio 2.6).CONCLUSIONS -In adult-onset autoimmune diabetes, the PTPN22 1858T variant is associated only with a high GADA titer, providing evidence of a genetic background to clinical heterogeneity identified by GADA titer.

Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus

“…In detail, patients with higher anti-GAD65 titres can be described by a more profound autoimmunity, quite marked dependency on insulin, higher levels of serum A1C, and lower both body mass index (BMI) and metabolic syndrome prevalence and, regarding genetic traits, decreased frequency of HLA-DRB1*0403 and HLA-DQB1*0602 and an increased for HLA-DRB1*03 and HLA-DQB1*0201 characterises the patients with higher anti-GAD65 titres [39] . Furthermore, studies from the same nationwide survey revealed that in LADA, the variant PTPN22 1858T is strongly associated with high titres of anti-GAD65 autoantibodies while the low levels are correlated to the T2D genetic variant of susceptibility, TCF7L2 [40,41] . It has also been suggested that the presence of high anti-GAD65 titres and/or anti-GAD65 autoantibodies directed against the C-terminal and not the middle epitopes of the protein can group a LADA subphenotype with many similarities with classic T1D and a high probability to develop insulin deficiency [42] .…”

Genetic Similarities Between Latent Autoimmune Diabetes and Type 1 and Type 2 Diabetes

“…In their LADA patients, they confirmed an increased frequency of type 1 diabetes-associated genetic risk factors including the heterozygous HLA-DQB1*0201/*0302 genotype, insulin AA genotype (rs689), and increased CT and TT genotypes of the PTPN22 gene (rs2476601) (2). Somewhat surprisingly, in LADA patients they also found a higher frequency of the type 2 diabetesassociated CT and TT genotypes of the TCF7L2 gene (rs7903146) (3), therefore concluding that LADA shares genetic features with both type 1 and type 2 diabetes.…”

Type 1 and type 2 diabetes—chalk and cheese?

“…A series of papers over the past decade has shown that individuals with LADA share the HLA, insulin gene and PTPN22 variant associations that are characteristic of type 1 diabetes [8,9,12,24]. These findings establish that the islet autoimmunity of LADA is causal (rather than secondary to exposure to antigens released from islet cells destroyed by other processes).…”

“…With the recent crop of genome-wide association studies taking the tally of loci confidently implicated in the pathogenesis of multifactorial forms of diabetes [3][4][5] to more than 60, it has become possible to use these to explore the 'aetiological architecture' of diabetes. A number of recent papers describe attempts to do just this [6][7][8][9][10][11][12][13][14].…”

“…In this issue of Diabetologia, Raj and colleagues take a panel of variants known to influence individual risk of type 2 diabetes and examine their effects on predisposition to type 1 diabetes [12]. Since the effects of these variants on type 2 diabetes risk are quite modest (odds ratios of 1.1 to 1.4 per allele), an important feature of this study was the use of large sample collections (more than 25,000 individuals).…”