Associations of GAD65- and IA-2-Autoantibodies With Genetic Risk Markers in New-Onset IDDM Patients and Their Siblings. The Belgian Diabetes Registry

Vandewalle, Christina; Falorni, Alberto; Lernmark, Åke; Goubert, Patrick; Dorchy, Harry; Coucke, Willy; Semakula, Crispin; Auwera, Bart Van Der; Kaufman, Léon; Schuit, Frans; Pipeleers, Daniël; Gorus, Frans

doi:10.2337/diacare.20.10.1547

Cited by 72 publications

(67 citation statements)

References 32 publications

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“…In the DQA1* 05-DQB1*02/Y group, GADA were the most frequent autoantibody reactivity detected. These observations are in line with findings by ourselves and other groups that indicate that the two major disease-associated HLA class II haplotypes could mediate alternative, although probably related pathways in the emergence of beta-cell-specific autoimmunity [5][6][7][8].…”

Section: Discussionsupporting

confidence: 92%

“…Although cellular immunity is perceived to play a central role in the effector phase of islet destruction, a combination of humoral markers (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies [IA-2A]) has proved to be a useful tool for monitoring the development of islet autoimmunity and for prediction of progression to clinical disease [1][2][3][4]. Although the association of certain HLA haplotypes with the appearance of IAA, GADA and IA-2A seems to be consistent in various studies [5][6][7][8], it is still unclear at what stage of the autoimmune process the HLA genes exert their effect.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

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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“…In the absence of IA-2A, the presence of at least one other antibody type (IAA, ICA or GADA) did confer a significantalbeit low risk of diabetes. This risk increased with the number of antibodies present, as indicated by both survival analysis and Cox regression, and in carriers of HLA DQ2, regardless of DQ8 status, it is consistent with the reported preferential association of GADA with DQ2 in new-onset patients [31][32][33]. The differential HLA DQ enhancement of progression to diabetes according to IA-2A status supports previous suggestions that different diabetogenic pathways may converge to the same clinical endpoint of immune-mediated type 1 diabetes [35,36].…”

Section: Discussionsupporting

confidence: 89%

“…In IA-2A-positive relatives carrying DQ2/DQ8, progression to diabetes averaged 84% within 5 years, in line with the preferential association of DQ2/DQ8 with early-onset type 1 diabetes [3,17,18]; hence, simultaneous positivity for both markers can almost be considered a diagnostic criterion for diabetes long before glycaemia starts to rise, and defines a group of relatives at homogeneously high risk of type 1 diabetes. Carriers of DQ8 in combination with a haplotype other than DQ2 also tended to progress more rapidly to diabetes than DQ8-negative relatives, thereby confirming the preferential association of IA-2A and DQ8/DR4 in new-onset patients [31][32][33]. Recently, the strong diabetes-predictive value of IA-2A, especially in cases where there are high levels and specific subclasses, was independently confirmed in persistently antibody-positive relatives [34].…”

Section: Discussionmentioning

confidence: 64%

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Decochez

Truyen²,

Auwera

et al. 2005

Diabetologia

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Aims/hypothesis: Prevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset. Methods: Antibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40. Results: On first sampling, 11.1% of the siblings presented at least one antibody type (p<0.001 vs other relatives). During follow-up (median 52 months) 43 subjects developed type 1 diabetes (31 siblings, ten offspring of a diabetic father, two offspring of a diabetic mother). Using Kaplan-Meier survival analysis and Cox regression, IA-2A conferred the highest 5-year diabetes risk (>50%) irrespective of the number of antibodies present. In initially IA-2A-positive relatives (n=58) progression to hyperglycaemia depended more on HLA DQ status than on type of kinship (84% progression in the presence of DQ2/DQ8 vs 32% in its absence; p<0.003). In IA-2A-negative relatives (n=4,531) 5-year progression to diabetes increased with the number of other antibodies (ICA, GADA and/or IAA) (p<0.001) but overall did not exceed 10% even for two or more antibodies. Among relatives initially positive for one or more antibody type other than IA-2A (n=315), there was significantly more progression to diabetes (overall still <10%) in carriers of DQ2 (p<0.001 vs no DQ2), regardless of DQ8 status. Conclusions/interpretation: These observations suggest that the HLA-DQ-inferred risk of diabetes can proceed through two distinct pathways distinguished by IA-2A status. Combined positivity for DQ2/DQ8 and IA-2A defines a more homogeneous high-risk population for prevention trials than those used so far.

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“…Previous studies have established that the frequency of immune markers, such as IAAs, GADAs, and IA-2As, at clinical onset varies with age (9,10). Autoantibodies to the ICA512/IA-2 autoantigen (11,12) are associated with HLA-DQ8 in patients (13) and are of particular interest because they may better predict type 1 diabetes in first-degree relatives (14,15). IAAs, widely known to be markedly affected by age at clinical onset (10,16), have been reported to be associated with HLA-DQ8, but only in patients who are younger than 10 years (9).…”

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confidence: 99%

Genetic Effects on Age-Dependent Onset and Islet Cell Autoantibody Markers in Type 1 Diabetes

et al. 2002

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Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0 -34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P ‫؍‬ 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P ‫؍‬ 0.03) and with INS VNTR (P ‫؍‬ 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P ‫؍‬ 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P ‫؍‬ 0.04), and all four autoantibody markers (P ‫؍‬ 0.004). The CTLA-4 3 end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development. Diabetes 51: 1346 -1355, 2002

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Associations of GAD65- and IA-2-Autoantibodies With Genetic Risk Markers in New-Onset IDDM Patients and Their Siblings. The Belgian Diabetes Registry

Abstract: Both GAD65- and IA-2-Abs exhibit higher prevalences in presence of HLA-DQ- and/or INS-genetic risk markers. Their respective associations differ with age at clinical onset, suggesting a possible usefulness in the identification of subgroups in this heterogeneous disease.

Cited by 72 publications

References 32 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

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Genetic Effects on Age-Dependent Onset and Islet Cell Autoantibody Markers in Type 1 Diabetes

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