Dataset Information

Role of Type 1 Diabetes-Associated SNPs on Autoantibody Positivity in the Type 1 Diabetes Genetics Consortium: Overview.

ABSTRACT: Type 1 diabetes (T1D) arises from the autoimmune destruction of the ?-cells of the pancreas, resulting in dependence on exogenously administered insulin for survival. Key biomarkers of the autoimmune process in T1D are the occurrence of autoantibodies directed against ?-cells and other antigens. The Type 1 Diabetes Genetics Consortium (T1DGC) assembled collections to 1) discover genes that modify the risk of T1D, 2) conduct phenotyping related to risk, and 3) make available biologic and genetic resources for research. The goal of the T1DGC Autoantibody Workshop was to use T1DGC phenotypic, genotypic, and autoantibody data on affected sibling pair (ASP) families to discover genes accounting for variation in presence of autoantibodies.The T1DGC provided the working groups with autoantibody and genetic data on 9,976 subjects from 2,321 ASP families. Data were distributed to numerous working groups for analyses of specific autoantibody subsets and targets.Seven groups analyzed the joint autoantibody and genetic data within the ASP families. Six reports are provided in this collection, ranging from candidate gene analyses of selected autoantibodies to evaluation of regions of genetic variants associated with autoimmunity on the collection of autoantibodies.Although selected variants in the available genes remain important genetic predictors for prevalence of T1D, other genes and nongenetic factors are expected to contribute to the initiation of islet autoimmunity, the first step in the pathogenesis of T1D.

SUBMITTER: Rich SS

PROVIDER: S-EPMC4582912 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Role of Type 1 Diabetes-Associated SNPs on Autoantibody Positivity in the Type 1 Diabetes Genetics Consortium: Overview.

Rich Stephen S SS Concannon Patrick P

Diabetes care 20151001

<h4>Objective</h4>Type 1 diabetes (T1D) arises from the autoimmune destruction of the β-cells of the pancreas, resulting in dependence on exogenously administered insulin for survival. Key biomarkers of the autoimmune process in T1D are the occurrence of autoantibodies directed against β-cells and other antigens. The Type 1 Diabetes Genetics Consortium (T1DGC) assembled collections to 1) discover genes that modify the risk of T1D, 2) conduct phenotyping related to risk, and 3) make available bio ...[more]

PMID: 26405066

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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.

Project description:Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers.In this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years.Methods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences.A total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances.The chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required.High-resolution HLA genotyping can be performed in multiple laboratories using standard equipment, reagents, protocols, software, and communication to produce consistent and reproducible data with minimal systematic error. Many of the strategies used in this study are generally applicable to other large multi-center studies.

Dataset Information

Role of Type 1 Diabetes-Associated SNPs on Autoantibody Positivity in the Type 1 Diabetes Genetics Consortium: Overview.

Publications

Role of Type 1 Diabetes-Associated SNPs on Autoantibody Positivity in the Type 1 Diabetes Genetics Consortium: Overview.

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