Tumor Necrosis Factor Microsatellite Polymorphism Influences the Development of Insulin Dependency in Adult-Onset Diabetes Patients with the DRB1∗1502-DQB1∗0601 Allele and Anti-Glutamic Acid Decarboxylase Antibodies

Abstract

Recently, several studies have demonstrated that tumor necrosis factor microsatellite polymorphism (TNFalpha) contributes to the susceptibility of type 1 diabetes. This study investigates the influence of TNFalpha on the predisposition to insulin dependency in adult-onset diabetic patients with type 1 diabetes-protective human leukocyte antigen haplotypes. The TNFalpha of three groups of DRB1*1502DQB1*0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 yr was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 yr of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 yr. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1*1502-DQB1*0601 was strongly associated with the TNFalpha13 allele. DRB1*1502-DQB1*0601 was strongly associated with the TNFalpha12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFalpha12 and non-TNFalpha13 in group B reacted with GAD65 protein by Western blot. These results suggest that TNFalpha is associated with a predisposition to progression to insulin dependency in GADab/DRB1*1502DQB1*0601-positive diabetic patients initially diagnosed with type 2 diabetes and that determination of these patients' TNFalpha genotype may allow for better prediction of their clinical course.

Polymorphisms of TNF microsatellite marker a and HLA-DR-DQ in diabetes mellitus—a study in 609 Swedish subjects

“…Moreover, TNFa12 has been demonstrated to be associated to LADA in the Japanese population [33]. In contrary to our findings, none of the TNFa alleles manifested an association to type 1 diabetes in an Italian population [11].…”

Susceptible and Protective Human Leukocyte Antigen Class II Alleles and Haplotypes in Bahraini Type 2 (Non-Insulin-Dependent) Diabetes Mellitus Patients

“…Although the DQB1 region was examined in some of the studies on the relationship with autoimmune markers (4,15,32) and in some family studies (21,26), direct comparison was not possible, despite the fact that a few studies have examined DQB1*0201 (8,20,26,32) or DQB1*0601 (15,20,22). This is so because these studies reported on genotype combinations (see below) and not on the frequency of the specific genotype.…”

“…Of interest was the increased prevalence of the DRB1*150101-DQB1*060101 haplotype among Bahraini patients with type 2 diabetes. Previous studies which looked into the possible role of DQB1*0601 reported that in GAD-positive, DRB1*1502-QB1*0601-positive patients initially diagnosed as having type 2 diabetes, tumor necrosis factor alpha was associated with predisposition to subsequent insulin dependency (19,22). In the Finnish study (8), the frequency of the "type I protective alleles" HLA-DQB1*0602 and *0603 was similar in control subjects and GAD-positive and GADnegative type 2 diabetes patients, but lower in type 1 diabetes subjects.…”

“…Increased frequency of HLA-DRB1*1502 was also seen in anti-GAD-positive patients who remained well controlled on oral antidiabetic drugs (7). Furthermore, tumor necrosis factor alpha was associated with predisposition to subsequent insulin dependency in GAD-positive HLA-DRB1*1502-DQB1*0602 (22) or DQB1*02 (19) type 2 diabetes patients, suggesting an interplay between HLA genotypes and other polymorphic markers in dictating the progression of type 2 diabetes. Others failed to link HLA class II (DQA1 and DQB1) with type 2 diabetes (4, 5), and it would appear that the association between HLA class II and type 2 diabetes is racially and geographically restricted.…”

Clinical and genetic characteristics of diabetic patients with high-titer (>10,000U/ml) of antibodies to glutamic acid decarboxylase

“…However, the age of onset of type 1 diabetes is variable and it has been reported that the frequencies of some type 1 diabetes susceptibility HLA class II alleles and/or haplotypes may vary depending on the age of disease onset [1,2]. It has also been reported that several polymorphisms of MHC classes I and III genes and interleukin genes are associated with the age at onset of type 1 diabetes [3][4][5][6][7][8][9].…”