The relationship between islet autoantibody status and the genetic risk of type 1 diabetes in adult-onset type 1 diabetes

Nicholas J Thomas, Helen C Walkey, Akaal Kaur, Shivani Misra, Nick S Oliver, Kevin Colclough, Michael N Weedon, Desmond G Johnston, Andrew T Hattersley, Kashyap A Patel, Nicholas J Thomas, Helen C Walkey, Akaal Kaur, Shivani Misra, Nick S Oliver, Kevin Colclough, Michael N Weedon, Desmond G Johnston, Andrew T Hattersley, Kashyap A Patel

Abstract

Aims/hypothesis: The reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults.

Methods: We analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants.

Results: The T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m2) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p<0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies (p>0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p=0.4).

Conclusions/interpretation: The inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice.

Keywords: Adult onset; Diabetes classification; Islet autoantibodies; Type 1 diabetes; Type 2 diabetes.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
T1DGRS by islet autoantibody status in clinician-diagnosed adult- and childhood-onset type 1 diabetes (T1D). Individuals with type 2 diabetes (T2D) were from the Wellcome Trust Case Control Consortium [29]. Individuals with childhood-onset diabetes were those diagnosed at p<0.001
Fig. 2
Fig. 2
HLA and non-HLA T1DGRS by islet autoantibody status in clinician-diagnosed adult- and childhood-onset type 1 diabetes. Individuals with type 2 diabetes (T2D) were from the Wellcome Trust Case Control Consortium [29]. Non-HLA and HLA T1DGRS were scaled to have a mean of 0 and SD of 1 for ease of representation. Individuals with childhood-onset diabetes were those diagnosed at

Fig. 3

The frequencies of type 1…

Fig. 3

The frequencies of type 1 diabetes risk-increasing HLA genotypes and protective HLA genotypes…

Fig. 3
The frequencies of type 1 diabetes risk-increasing HLA genotypes and protective HLA genotypes by islet autoantibody status in clinician-diagnosed adult- and childhood-onset type 1 diabetes. (a) Age ≥18 years; (b) age <18 years. Neutral X/X represents any HLA other than DR3-DQ2, DR4-DQ8 or DR15-DQ6. DR3-DQ2/X or DR4-DQ8/X represents one of the following: DR3-DQ2/X, DR3-DQ2/DR3-DQ2, DR4-DQ8/X or DR4-DQ8/DR4-DQ8. DR15-DQ6/X represents DR15-DQ6/X or DR15-DQ6/DR15-DQ6. T2D, type 2 diabetes. ***p<0.001
Fig. 3
Fig. 3
The frequencies of type 1 diabetes risk-increasing HLA genotypes and protective HLA genotypes by islet autoantibody status in clinician-diagnosed adult- and childhood-onset type 1 diabetes. (a) Age ≥18 years; (b) age <18 years. Neutral X/X represents any HLA other than DR3-DQ2, DR4-DQ8 or DR15-DQ6. DR3-DQ2/X or DR4-DQ8/X represents one of the following: DR3-DQ2/X, DR3-DQ2/DR3-DQ2, DR4-DQ8/X or DR4-DQ8/DR4-DQ8. DR15-DQ6/X represents DR15-DQ6/X or DR15-DQ6/DR15-DQ6. T2D, type 2 diabetes. ***p<0.001

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