The PTPN22 1858T Gene Variant in Type 1 Diabetes Is Associated With Reduced Residual β-Cell Function and Worse Metabolic Control

Abstract

FOR THE IMMUNOTHERAPY DIABETES (IMDIAB) GROUP 3OBJECTIVE -Evidence has been reported for a new susceptible locus for type 1 diabetes, the protein tyrosine phosphatase nonreceptor type 2 (PTPN22), which encodes a lymphoidspecific phosphatase. The aim of the study was to evaluate the influence of the C1858T variant of the PTPN22 gene on ␤-cell function as measured by C-peptide levels from time of disease diagnosis through 12 months follow-up in a prospective series of 120 consecutive type 1 diabetic subjects.RESEARCH DESIGN AND METHODS -The C1858T polymorphism was genotyped using TaqMan. Fasting C-peptide, A1C, and insulin requirements were determined at diagnosis and every 3 months for 12 months; their change during follow-up was analyzed using the general linear model repeated-measures procedure.RESULTS -Fasting C-peptide levels were significantly lower and A1C levels were significantly higher in subjects carrying the PTPN22 1858T variant than in subjects homozygous for C1858 from time of disease diagnosis through 12 months of intensive insulin therapy follow-up (P ϭ 0.008 and P ϭ 0.01, respectively). These findings were independent of age at onset, sex, and HLA risk groups. The trend in C-peptide and A1C levels in the 12-month period did not differ significantly between subjects with or without the 1858T variant. Insulin dose was similar in the 1858T carriers and noncarriers.CONCLUSIONS -Type 1 diabetic subjects carrying the 1858T variant show significantly lower ␤-cell function and worse metabolic control at diagnosis and throughout the study period than subjects homozygous for C1858; these differences remain unchanged over the course of the first year after diagnosis.

Prevalence of vitamin D receptor gene polymorphisms FokI and BsmI in Brazilian individuals with type 1 diabetes and their relation to β-cell autoimmunity and to remaining β-cell function

“…Associations between genetic factors such as HLA [37,38], PTNP22 gene [26], and C-peptide levels in T1DM patients have already been described. Petrone et al [37] reported that individuals with high-risk HLA DRB1-DQB1 genotypes had lower C-peptide levels at diagnosis.…”

“…Recently the PTNP22 1858T gene variant was found to be associated with reduced ␤-cell function in T1DM patients followed by 12 months after diagnosis. The authors commented that this could be due to a particular insulin therapy approach or to a more aggressive autoimmune process, as this gene encodes a lymphoid tyrosine phosphatase that alter T-regulatory cell function [26]. This was the first study that tried to evaluate the relationship between VDR polymorphisms and residual pancreatic ␤-cell function.…”

“…Recently a variant of PTNP22 gene was found to be associated with lower residual insulin secretion in T1DM patients independently of some clinical variables (i.e., age at onset, gender) and of HLA genotype [26].…”

HLA-haplotypes, anti- beta-cell antibodies: their role in prognostication of type 1 diabetes mellitus (results of 11-year observation)

“…Наибольший вклад среди остальных вносят: гены инсулина, гены CTLA-4, PTPN-22, выполняющие ключевую роль в координации иммун-ного ответа и др. [5] (CTLA-4 играет основную роль в механизме ответа Т-клеток на презентацию антигена, кодирует ко-стимули-рующую молекулу, экспресс ирующуюся на поверхности активи-зированного Т-лимфоцита. PTPN-22 кодирует тирозиновую фосфатазу Т-лимфоцитов, которая является внутриклеточным белком, экспрессия которой специфична для клеток иммунной системы и является одним из «негативных регуляторов» иммун-ной системы).…”

“…Таким образом, среди заболев-ших в 82% случаях определялись гаплотипы высокого риска (ге-нотип DQ2/DQ8 встречался в 18,2%, генотипы DQ2/Х и DQ8/Х -в 63,6% случаев) и только 18,2% заболевших не имели предраспо-лагающих гаплотипов. Полученные данные еще раз подтвердили, что наличие предрасполагающих гаплотипов важно для прогно-зирования заболевания, однако и отсутствие этих гаплотипов не исключает в небольшом проценте развития СД, что может быть обусловлено влиянием других предрасполагающих генов [5]. Таким образом, в наших исследованиях генотипы HLA-DQ2/DQ8; DQ2/X; DQ8/X прогнозируют примерно с 8-процентной веро-ятностью риск развития СД1 на протяжении 11-летнего периода.…”