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

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. Graphical abstract

The phenotype of type 1 diabetes in sub-Saharan Africa

“…This significant reduction was not observed in the white population. Given that atypical diabetes presentations are common in black Africans, the older peak age of onset of diabetes and the reduction of the positivity rate of GAD65 autoantibody may suggest non-autoimmune diabetes in these younger black adults -a finding that has been recently demonstrated in older adults diagnosed with T1D in Europe, where a reduction in islet antibody prevalence with older age in clinically diagnosed T1D appears to reflect misclassification (74,75). Another recent study in Ethiopia amongst a group of carefully selected patients with young-onset diabetes requiring insulin treatment at diagnosis showed that the median age was 21 years.…”

“…The commonest autoantibody markers present in T1D are insulin autoantibodies (IAA), glutamic acid decarboxylase (GAD) autoantibodies, islet antigen 2 (IA-2) autoantibodies and variants of the zinc transporter 8 (ZnT8) autoantibodies (85,86). Usually, at least one autoantibody is present in over 90% of cases with T1D at the time of diagnosis (75,86,87). In clinically suspected T1D, a positive islet antibody will confirm the diagnosis, although the absence of the autoimmune markers does not rule out the presence of the condition (88).…”

Type 1 diabetes: A new vision of the disease based on endotypes

“…Studies have speculated that patients who fall into the T1DE5 endotype (low GAD, high C‐peptide LADA patients) may simply be a subset of misdiagnosed T2D patients 71,111 . Although false positive LADA patients do exist, the study by Andersen et al.…”

Prevalence, clinical characteristics and HLA genotypes of idiopathic type 1 diabetes: A cross‐sectional study

“…Several studies have reported the clinical features of idiopathic T1D, including older age, higher body mass index (BMI), and milder onset symptoms. [13][14][15] However, the results of these studies were contradictory. For example, Luong et al reported that the majority of T1D patients with diabetic ketoacidosis (DKA) were autoantibody negative.…”

“…Several studies have reported the clinical features of idiopathic T1D, including older age, higher body mass index (BMI), and milder onset symptoms 13–15 . However, the results of these studies were contradictory.…”