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

Strebelow, M.; Schlosser, Michael; Ziegler, B; Rjasanowski, I; Ziegler, M.

doi:10.1007/s001250051213

Cited by 75 publications

(79 citation statements)

References 29 publications

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“…Nevertheless, approximately 90% of children diagnosed with type 1 diabetes have no first-degree relatives with the disease [18][19][20]. The intent of the present study was therefore to extend our previous findings in relatives to schoolchildren from the general population.…”

Section: Introductionmentioning

confidence: 78%

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GAD autoantibody affinity in schoolchildren from the general population

Bender

Schlosser²,

Christen

et al. 2014

Diabetologia

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Aims/hypothesis Subtyping GAD autoantibody (GADA) responses using affinity measurement allows the identification of GADA-positive children with a family history of type 1 diabetes who are at risk of developing diabetes. Here, we asked whether GADA affinity is a useful marker to stratify the risk of type 1 diabetes in GADA-positive schoolchildren from the general population. Methods GADA affinity was measured by competitive binding experiments with [ 125

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Section: Introductionmentioning

confidence: 78%

“…Islet autoantibody measurements Levels of GADA, IA-2A and IAA were measured by radiobinding assays using [ 125 I]-labelled recombinant human 65 kDa isoform of GAD (GAD65), IA-2 and insulin as previously described [20,21]. A cut-off level at or above the 98th percentile was used for all autoantibodies [21].…”

Section: Methodsmentioning

confidence: 99%

GAD autoantibody affinity in schoolchildren from the general population

Bender

Schlosser²,

Christen

et al. 2014

Diabetologia

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“…Importantly, the INS locus influenced the development of IAA in all three HLA risk groups. Although the INS locus is associated with disease risk, the effect of INS on the emergence of IAA seems to be a genuine one, since IAA as such are not associated with particularly high diabetes risk [1,4,36].…”

Section: Discussionmentioning

confidence: 99%

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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“…Subjects and samples Samples were obtained from the Karlsburg Type 1 Diabetes Risk Study of a Normal Schoolchild Population [8,9]. A total of 11 840 children aged 6-17 years were screened for IAA using the polyethylene glycol IAA method, as well as for GAD, IA-2 and islet cell antibodies.…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

In insulin-autoantibody-positive children from the general population, antibody affinity identifies those at high and low risk

et al. 2005

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Aims/hypothesis: Insulin autoantibodies (IAA) precede and predict the onset of type 1 diabetes, but not all children with IAA develop the disease. In affected families, IAA affinity can identify IAA-positive children who are more likely to progress to diabetes. The purpose of this study was to determine whether affinity is a useful marker to stratify type 1 diabetes risk in IAA-positive children from the general population. Methods: IAA affinity was determined by competitive binding to 125 Iinsulin with increasing concentrations of cold insulin and with cold proinsulin in sera from 46 IAA-positive children identified in the Karlsburg Type 1 Diabetes Risk Study of a Normal Schoolchild Population in north-eastern Germany. Results: IAA affinity ranged between 5×10 6 and 1.2×10 11 l/mol. IAA affinity was higher in 24 children who developed multiple islet autoantibodies or diabetes (median 3.5×10 9 l/mol; interquartile range [IQR] 2.1×10 9 to 2.1×10 10 l/mol) than in 22 children who did not develop multiple islet autoantibodies or diabetes (median 1.3×10 8 l/mol; IQR 3.8×10 7 to 7.2×10 8 l/mol; p<0.0001). Using a threshold of ≥10 9 l/mol, 22 of the 24 children who developed multiple islet autoantibodies or diabetes were correctly identified by high-affinity IAA and 18 of 22 who did not develop multiple islet autoantibodies or diabetes were correctly identified by low-affinity IAA. IAA affinity was significantly higher in samples with proinsulin reactive IAA (p<0.0001). Conclusions/interpretation: IAA affinity measurement provides robust identification of IAA associated with high diabetes risk.

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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

Cited by 75 publications

References 29 publications

GAD autoantibody affinity in schoolchildren from the general population

GAD autoantibody affinity in schoolchildren from the general population

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

In insulin-autoantibody-positive children from the general population, antibody affinity identifies those at high and low risk

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