HLA-DR 3 is associated with a more slowly progressive form of Type 1 (insulin-dependent) diabetes

Ludvigsson, Johnny; Samuelsson, Ulf; Beauforts, C.; Deschamps, I; Dorchy, Harry; Drash, Allan L.; François, R; Herz, G.; New, Maria I.; Schober, Edith

doi:10.1007/bf00454876

Cited by 95 publications

(56 citation statements)

References 9 publications

(9 reference statements)

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“…Because ICA512/IA-2A has been shown to predict type 1 diabetes, most likely as a marker of ongoing ␤-cell destruction, we speculate that this process may be decelerated in DQ2 individuals because of a reduced immune response to ICA512/IA-2. This speculation is consistent with the observation that DQ2-DR3 patients have higher C-peptide levels at the time of clinical diagnosis (44,45).…”

Section: Discussionsupporting

confidence: 91%

“…In the exploratory analysis, the unadjusted frequency of IAA increased with the number of class I alleles of INS VNTR: 15% of III/III patients (95% CI 0 -30), 30% of I/III patients (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), and 40% of I/I patients (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) were positive for IAA. Unadjusted frequencies of IAA were higher in DQ8-positive than in DQ8-negative patients: 27% of patients with no DQ8 haplotypes (95% CI 20 -34), 41% of patients with one DQ8 haplotype (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), and 42% of patients with two DQ8 haplotypes (26 -57) were positive for IAA. Finally, the unadjusted frequencies in Table 5 support numerous observations that IAAs are more common in younger than in older patients.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

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

et al. 2002

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“…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]. Nevertheless, progression to diabetes in antibody-positive carriers of DQ2 remains low in the absence of IA-2A.…”

Section: Discussionsupporting

confidence: 89%

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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“…In multivariate analysis, the persistence of antibodies was primarily related to the respective levels at diagnosis, which is in agreement with previous observations for ICA (11). The additional association of persisting GADA levels with the absence of HLA DQA1*0301-DQB1*0302 and residual C-peptide levels 2 years after diagnosis is indicative of a less aggressive form of the disease (27,28). Likewise, persisting IA-2-A levels were associated with older age and the absence of HLA DQA1*0501-DQB1*0201, which is consistent with previous correlations at clinical onset (20,22,29).…”

supporting

confidence: 89%

High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry.

et al. 2000

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OBJECTIVE -To study the presence and levels of GAD65 antibodies (GADA), IA-2 antibodies (IA-2-A), and islet cell antibodies (ICA) during the first years after clinical onset of type 1 diabetes in relation to age at diagnosis.RESEARCH DESIGN AND METHODS -Type 1 diabetic patients (n = 194) Ͻ40 years of age were consecutively recruited at the time of diagnosis by the Belgian Diabetes Registry and followed during the first 4 years of insulin treatment. ICA were determined by indirect immunofluorescence assay and IA-2-A, GADA, and insulin autoantibodies by a radioligand assay.RESULTS -Overall, 94% of initially antibody-positive patients (n = 180) remained positive for at least 1 antibody type 4 years after diagnosis. In the case of diagnosis after 7 years of age, GADA, IA-2-A, and ICA persisted in 91, 88, and 71%, respectively, of the initially antibody-positive patients. Antibody persistence was lower in those diagnosed at Ͻ7 years of age, amounting to 60% for GADA, 71% for IA-2-A, and 39% for ICA. In 57% of the initially antibody-positive patients, at least 1 type of autoantibody reached peak values after diagnosis. This occurred more frequently for clinical onset after 7 years of age and more often for GADA (49%) than for IA-2-A (29%) or ICA (19%). Of the patients, 24% that were negative for GADA at onset became GADApositive during the following 4 years. Among the 7% initially antibody-negative patients, 2 of 14 subjects developed antibodies after clinical onset.CONCLUSIONS -In particular, for diagnosis after 7 years of age, islet cell-specific autoantibodies generally persist for many years after diagnosis. There is also a high frequency of increasing antibody levels and of conversion to antibody positivity in the first 4 years after diagnosis and start of insulin treatment. Thus, determination of antibodies at diagnosis can underestimate the number of cases with autoimmune type 1 diabetes, in particular with assays of lower sensitivity. The divergent temporal patterns of ICA, GADA, and IA-2-A suggest that the ICA test recognizes other antibody specificities besides GADA and IA-2-A and reflects other autoimmune processes; it also indicates that GADA assays have a higher diagnostic sensitivity in the period after clinical onset.

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HLA-DR 3 is associated with a more slowly progressive form of Type 1 (insulin-dependent) diabetes

Cited by 95 publications

References 9 publications

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

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

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

High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry.

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