Epidemiology and Immunogenetic Background of Islet Cell Antibody–Positive Nondiabetic Schoolchildren: Ulm-Frankfurt Population Study

Boehm, B. O.; Manfras, Burkhard; Seißler, Jochen; Schöffling, Κ.; Glück, Michael; Holzberger, G; Seidl, S.; Kühnl, P.; Trucco, Massimo; Scherbaum, W. A.

doi:10.2337/diab.40.11.1435

Cited by 41 publications

(32 citation statements)

References 6 publications

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“…No difference was seen in these comparisons. This and others' findings indicate that low ICA titres show no association with HLA, whereas children with multiple autoantibodies or high titres of ICA show a HLA genotype distribution resembling that seen in patients with type 1 diabetes [42][43][44][45]. This implies that the appearance of low-titre ICA alone may represent harmless immune phenomena unrelated to the diabetes-specific disease process.…”

Section: Discussionmentioning

confidence: 76%

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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Aims/hypothesis: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. Subjects and methods: We analysed the effect of HLA class II, insulin (INS; −23 HphI variant) and cytotoxic T-lymphocyteassociated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies ). Those who developed betacell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). Results: IAA emerged at a higher rate in children with the −23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. Conclusions/interpretation: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.

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Section: Discussionmentioning

confidence: 76%

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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“…HLA susceptibility for Type 1 diabetes in Caucasian individuals has been described for HLA DR3, DR4 and a nonAsp genotype at position 57 of the HLA DQ ~ chain [1,2]. Recently we reported an association of ICA positivity in non-diabetic subj ects with HLA DR3 and DR4 and a nonAsp haplotype [12]. In this study we showed for the first time that in a population of ICA positive individuals there is a significant correlation between the appearance of 64KA, CF-ICA and CIAA with HLA DR4 and the non Asp DQ [3 allele.…”

Section: Discussionmentioning

confidence: 89%

“…HLA analysis of our ICA positive individuals and a control population has been published recently [12]. HLA DR typing was performed by the two colour fluorescence technique.…”

Section: Methodsmentioning

confidence: 99%

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Antibodies to the Mr 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired Beta-cell function

et al. 1992

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Summary.A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the Mr 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6 %). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50 % of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p < 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ 13 chain (p < 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type i (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies. We conclude that 64K antibodies, complement-fixing islet cell antibodies and insulin autoantibodies represent sensitive serological markers in assessing high risk for a progression to Type 1 diabetes in islet cell antibody positive non-diabetic individuals.

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“…Thus, studies are currently in progress to examine whether the occurrence of multiple autoantibodies in schoolchildren is associated with Type I diabetes-associated alleles [34]. This ongoing follow-up study will enable us to evaluate the risk of developing Type I diabetes depending on immunological and genetic markers in a general population of schoolchildren.…”

Section: Discussionmentioning

confidence: 99%

Karlsburg Type I diabetes risk study of a general population: frequencies and interactions of the four major Type I diabetes-associated autoantibodies studied in 9419 schoolchildren

et al. 1999

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Epidemiology and Immunogenetic Background of Islet Cell Antibody–Positive Nondiabetic Schoolchildren: Ulm-Frankfurt Population Study

Cited by 41 publications

References 6 publications

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

Antibodies to the Mr 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired Beta-cell function

Karlsburg Type I diabetes risk study of a general population: frequencies and interactions of the four major Type I diabetes-associated autoantibodies studied in 9419 schoolchildren

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