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

Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study 3

¹ Department of Clinical Sciences, Sapienza University, Rome, Italy
² Sandro Pertini Hospital, Rome, Italy
³ Endocrinology, Catholic University, Rome, Italy
⁴ General Medicine, Diabetes and Endocrinology, San Raffaele Vita-Salute University, Milan, Italy
⁵ Department of Endocrinology and Metabolism, University of Cagliari, Cagliari, Italy
⁶ Endocrinology, University Campus Bio-Medico, Rome, Italy
⁷ Department of Internal Medicine, University of Perugia, Perugia, Italy

Address correspondence and reprint requests to Professor Raffaella Buzzetti, Department of Clinical Science, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Rome, Italy. E-mail: raffaella.buzzetti{at}uniroma1.it

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 (32 arbitrary units) or high (>32 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 < 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 < 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.

Abbreviations: GADA, GAD autoantibody • NIRAD, Non Insulin Requiring Autoimmune Diabetes • PTPN22, protein tyrosine phosphatase nonreceptor type 22

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