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

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 (125)I-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.

Multiple and High‐Titer Single Autoantibodies in Schoolchildren Reflecting the Genetic Predisposition for Type 1 Diabetes

“…AAb‐positive and AAb‐negative probands were recruited from the Karlsburg Type 1 Diabetes Risk Study of a Normal Schoolchild Population, previously published in detail 6,10. In reexamination after primary screening,6 178 (98 f/80 m) probands, representing a general population of 6337 healthy schoolchildren without diabetes heredity, were found to be AAb‐positive for GADA, IA‐2A, and/or IAA at or above the 99th percentile and/or for ICA at or above 20 JDF units 10. For comparison, 339 children were selected at random from the AAb‐negative children as detected in the primary screening.…”

“…The purpose of this study was to compare the HLA‐DRB1 and DQB1 specificities of AAb‐positive and ‐negative healthy schoolchildren from the Karlsburg Type 1 Diabetes Risk Study of a Normal Schoolchild Population6,10 with those of patients with T1D.…”

Targeting Type 1 Diabetes Before and at the Clinical Onset of Disease

“…DQB1*0602 is not present in children with multiple autoantibodies or with GAD65Ab, IA-2Ab, or IAA at levels above the 99.9th percentile. In comparison to children with single autoantibodies, the frequency of associated or protective alleles in children with multiple autoantibodies may be enhanced or diminished [171].…”

“…Thus, it is of critical and timely importance to screen for the disease before clinical onset in the hopes of preventing the disease. Recent studies suggest that it is possible to predict clinical onset of T1D far in advance of clinical symptoms, by combining genetic with autoantibody testing [163,[169][170][171]. The preclinical phase of T1D is identifiable by the presence of autoantibodies [163][164][165][166].…”

“…Currently HLA and autoantibody testing are the best predictors of the disease [163,[169][170][171]. Future hope in preventive strategies lies in utilizing population screening stratagies that depend on markers of islet injury, such as, autoantibodies and markers of genetic susceptibility, such as HLA, in individuals with or without a family history of T1D.…”