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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

From The First Department of Internal Medicine, Kyoto Prefectural University of Medicine (H.O., G.H., M.F., K.K., A.K., M.O., H.S., T.K., Y.K., K.N., N.N.), Kyoto 602-0841; Kyoto Microbiological Institute (H.O.), Kyoto; Department of Clinical Research Center, Utano National Hospital (M.N., M.O.), Kyoto; and Department of Clinical Chemistry, Kobe Pharmaceutical University (M.O.), Kobe, Japan

Address correspondence and requests for reprints to: Dr. Goji Hasegawa, The First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-0841, Japan. E-mail: goji{at}koto.kpu-m.ac.jp

Recently, several studies have demonstrated that tumor necrosis factor microsatellite polymorphism (TNFa) contributes to the susceptibility of type 1 diabetes. This study investigates the influence of TNFa on the predisposition to insulin dependency in adult-onset diabetic patients with type 1 diabetes-protective human leukocyte antigen haplotypes. The TNFa of three groups of DRB1_*1502-DQB1_*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 TNFa13 allele. DRB1_*1502-DQB1_*0601 was strongly associated with the TNFa12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFa12 and non-TNFa13 in group B reacted with GAD65 protein by Western blot. These results suggest that TNFa is associated with a predisposition to progression to insulin dependency in GADab/DRB1_*1502-DQB1_*0601-positive diabetic patients initially diagnosed with type 2 diabetes and that determination of these patients’ TNFa genotype may allow for better prediction of their clinical course.

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