Dataset Information

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.

SUBMITTER: Thomas NJ

PROVIDER: S-EPMC9807542 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Thomas Nicholas J NJ Walkey Helen C HC Kaur Akaal A Misra Shivani S Oliver Nick S NS Colclough Kevin K Weedon Michael N MN Johnston Desmond G DG Hattersley Andrew T AT Patel Kashyap A KA

Diabetologia 20221110 2

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>We analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 3 ...[more]

PMID: 36355183

Similar Datasets

Project description:ObjectivesTo describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive.DesignObservational cohort study.Setting146 mainly secondary care centres across England and Wales.Participants3312 people aged ≥5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%.Main outcome measuresAutoantibody status and characteristics at presentation.ResultsThe majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7 kg/m2; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01).ConclusionsMost people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes.Trial registration numberISRCTN66496918; Pre-results.

Project description:Aims/hypothesisIslet autoantibodies can be detected prior to the onset of type 1 diabetes and are important tools for aetiologic studies, prevention trials and disease screening. Current risk stratification models rely on the positivity status of islet autoantibodies alone, but additional autoantibody characteristics may be important for understanding disease onset. This work aimed to determine if a data-driven model incorporating characteristics of islet autoantibody development, including timing, type and titre, could stratify risk for type 1 diabetes onset.MethodsData on autoantibodies against GAD (GADA), tyrosine phosphatase islet antigen-2 (IA-2A) and insulin (IAA) were obtained for 1,415 children enrolled in The Environmental Determinants of Diabetes in the Young study with at least one positive autoantibody measurement from years 1 to 12 of life. Unsupervised machine learning algorithms were trained to identify clusters of autoantibody development based on islet autoantibody timing, type and titre. Risk for type 1 diabetes across each identified cluster was evaluated using time-to-event analysis.ResultsWe identified 2-4 clusters in each year cohort that differed by autoantibody timing, titre and type. During the first 3 years of life, risk for type 1 diabetes onset was driven by membership in clusters with high titres of all three autoantibodies (1-year risk: 20.87-56.25%, 5-year risk: 67.73-69.19%). Type 1 diabetes risk transitioned to type-specific titres during ages 4 to 8, as clusters with high titres of IA-2A (1-year risk: 20.88-28.93%, 5-year risk: 62.73-78.78%) showed faster progression to diabetes compared with high titres of GADA (1-year risk: 4.38-6.11%, 5-year risk: 25.06-31.44%). The importance of high GADA titres decreased during ages 9 to 12, with clusters containing high titres of IA-2A alone (1-year risk: 14.82-30.93%) or both GADA and IA-2A (1-year risk: 8.27-25.00%) demonstrating increased risk.Conclusions/interpretationThis unsupervised machine learning approach provides a novel tool for stratifying risk for type 1 diabetes onset using multiple autoantibody characteristics. These findings suggest that age-dependent changes in IA-2A titres modulate risk for type 1 diabetes onset across 12 years of life. Overall, this work supports incorporation of islet autoantibody timing, type and titre in risk stratification models for aetiologic studies, prevention trials and disease screening.

Project description:AimsThis study aimed to investigate the frequency of islet autoantibody positivity in adult patients with recently diagnosed diabetes in Uganda and its associated characteristics.MethodsAutoantibodies to glutamic acid decarboxylase-65 (GADA), zinc transporter 8 (ZnT8-A), and tyrosine phosphatase (IA-2A) were measured in 534 adult patients with recently diagnosed diabetes. Islet autoantibody positivity was defined based on diagnostic thresholds derived from a local adult population without diabetes. The socio-demographic, clinical, and metabolic characteristics of islet autoantibody-positive and negative participants were then compared. The differences in these characteristics were analysed using the x2 test for categorical data and the Kruskal Wallis test for continuous data. Multivariate analysis was performed to identify predictors of islet autoantibody positivity.ResultsThirty four (6.4%) participants were positive for ≥1 islet autoantibody. GADA, IA-2A and ZnT8-A positivity was detected in 17 (3.2%), 10 (1.9%), and 7 (1.3%) participants, respectively. Compared with those negative for islet autoantibodies, participants positive for islet autoantibodies were more likely to live in a rural area (n = 18, 52.9% Vs n = 127, 25.5%, p = 0.005), to be initiated on insulin therapy (n = 19, 55.9% Vs n = 134, 26.8%, p<0.001), to have a lower median waist circumference (90 [80-99] cm Vs 96 [87-104.8], p = 0.04), waist circumference: height ratio (0.55 [0.50-0.63] vs 0.59 [0.53-0.65], p = 0.03), and fasting C-peptide concentration (0.9 [0.6-1.8] Vs 1.4 [0.8-2.1] ng/ml, p = 0.01). On multivariate analysis, living in a rural area (odds ratio or OR 3.62, 95%CI 1.68-7.80, p = 0.001) and being initiated on insulin therapy (OR 3.61, 95% CI 1.67-7.83, p = 0.001) were associated with islet autoantibody positivity.ConclusionThe prevalence of islet autoantibody positivity was relatively low, suggesting that pancreatic autoimmunity is a rare cause of new-onset diabetes in this adult Ugandan population. Living in a rural area and being initiated on insulin therapy were independently associated with islet autoantibody positivity in this study population.

Project description:Islet autoantibodies are typically associated with type 1 diabetes, but have been found in patients diagnosed with type 2 diabetes in whom they are associated with lower adiposity. The significance of autoantibody positivity in overweight and obese patients is not well understood. The aim of this study was to determine the prevalence and clinical significance of islet autoantibodies in overweight/obese adults diagnosed with type 2 diabetes. This study includes 204 participants at one site of the multicenter Look AHEAD (Action for Health in Diabetes) trial (ClinicalTrials.gov identifier: NCT00017953) which randomized overweight/obese adults diagnosed with type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. We measured antibodies to glutamic acid decarboxylase, insulinoma antigen-2, and zinc transporter 8. Participants with and without autoantibodies were compared with respect to baseline clinical features, and longitudinal changes in weight, hemoglobin A1c, and antihyperglycemic medications. We found that 13 participants (6.4%) were autoantibody positive, including six of 47 participants (12.8%) with BMI ≥40 kg/m2. At baseline, autoantibody positive participants had higher HDL cholesterol (1.27 vs. 1.09 mmol/L, p = .034) and lower fasting C-peptide (0.32 vs. 0.57 nmol/L, p = .049). Over four years, autoantibody positive participants lost 5.1 kg more weight than autoantibody negative participants (p = .056). Longitudinal changes in hemoglobin A1c did not differ by autoantibody status, though autoantibody positive participants were more likely to increase the number of antihyperglycemic medications or initiate insulin (p = .011). In conclusion, islet autoantibodies were present in 6.4% of overweight/obese adults with type 2 diabetes including those with severe obesity, and were associated with distinct clinical features. The effect of autoantibody positivity on weight loss interventions requires further study.

Dataset Information

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

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Publications

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

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