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The Karlsburg Type 1 Diabetes Risk Study of a Normal Schoolchild Population: Association of ß-Cell Autoantibodies and Human Leukocyte Antigen-DQB1 Alleles in Antibody-Positive Individuals

Institute of Pathophysiology (M.Sc., M.St., B.Z., M.Z.), Ernst Moritz Arndt University of Greifswald, Karlsburg D-17495, Germany; Surgery Hospital (M.Sc.), Ernst Moritz Arndt University of Greifswald, Greifswald D-17487, Germany; Institute for Clinical Immunology (R.W., M.-L.A., I.B.), Friedrich Alexander University Erlangen-Nürnberg, Erlangen D-91054, Germany; and Centre of Diabetes and Metabolic Disorders (I.R.), Karlsburg D-17495, Germany

Address all correspondence to: Dr. Manfred Ziegler, Institute of Pathophysiology, Universitiy of Greifswald, Greifswalder Strasse 11b, Karlsburg D-17495, Germany. E-mail: . ziegler{at}mail.uni-greifswald.de

Abstract

The intent of this study was to analyze the prevalence of diabetes-associated autoantibodies (AAbs) at or above the 99^th percentile as well as their association with human leukocyte antigen (HLA)-DQB1 alleles in a normal population of 6,337 schoolchildren. AAbs against glutamic acid decarboxylase (GADA), tyrosine phosphatase IA-2 (IA-2A), and/or insulin (IAA) were detected by ¹²⁵I-antigen binding and islet cell antibodies (ICA) immunohistochemically in 181 (2.86%) schoolchildren. HLA-DQB1 alleles were analyzed in 178/181 children and subsequently compared with 119 controls. 2.37% (150/6,337) possessed only one AAb, whereas 0.49% (31/6,337) had multiple AAbs but at increased levels (P < 0.001). Subjects with GADA, IA-2A, or IAA revealed an increased frequency of the diabetes-associated HLA-DQB1 alleles *0302 and/or *02 (P = 0.001–0.006) as well as a decreased frequency in the protective allele *0602 (P < 0.001–0.022). DQB1*0602 was completely absent within children with multiple AAbs or with GADA, IA2-A, or IAA at or above the 99.9^th percentile. In comparison to children with single AAbs, the frequency of associated/protective alleles of children with multiple AAbs was enhanced/diminished (P = 0.004–0.009). The study shows that also in the general population the multiple AAbs or high level single AAbs predict rather certainly a HLA-DQB1-mediated diabetes susceptibility as shown for first degree relatives of type 1 diabetic patients.

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