Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes
| Autor: | Brorsson, C.A., Onengut, S., Chen, W.M., Wenzlau, J., Yu, L.P., Baker, P., Williams, A.J.K., Bingley, P.J., Hutton, J.C., Eisenbarth, G.S., Concannon, P., Rich, S.S., Pociot, F., Type 1 Diabetes Genetics Consortiu |
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| Rok vydání: | 2015 |
| Předmět: |
Genotype
Endocrinology Diabetes and Metabolism Autoimmunity 030209 endocrinology & metabolism medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Antigen Thyroid peroxidase Diabetes mellitus Internal Medicine medicine Humans Genetic Predisposition to Disease Genetic Association Studies Autoantibodies 030304 developmental biology Genetic association 0303 health sciences Type 1 diabetes biology Autoantibody Genetics/Genomes/Proteomics/Metabolomics medicine.disease 3. Good health Cross-Sectional Studies Diabetes Mellitus Type 1 Genetic Loci Immunology biology.protein |
| Zdroj: | Diabetes Diabetes, 64(8), 3017-3027 |
| ISSN: | 1939-327X 0012-1797 3017-3027 |
| DOI: | 10.2337/db14-1730 |
| Popis: | Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes–affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, for IA-2A with 1q23/FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1. The 3q28 locus showed association after only 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13, and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity. |
| Databáze: | OpenAIRE |
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