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Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes.

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 an... Full description

Journal Title: Diabetes August 2015, Vol.64(8), pp.3017-3027
Main Author: Brorsson, Caroline A
Other Authors: Onengut, Suna , Chen, Wei-Min , Wenzlau, Janet , Yu, Liping , Baker, Peter , Williams, Alistair J K , Bingley, Polly J , Hutton, John C , Eisenbarth, George S , Concannon, Patrick , Rich, Stephen S , Pociot, Flemming , Brorsson, Caroline A
Format: Electronic Article Electronic Article
Language: English
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ID: E-ISSN: 1939-327X ; DOI: 10.2337/db14-1730
Link: http://search.proquest.com/docview/1698956601/?pq-origsite=primo
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title: Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes.
format: Article
creator:
  • Brorsson, Caroline A
  • Onengut, Suna
  • Chen, Wei-Min
  • Wenzlau, Janet
  • Yu, Liping
  • Baker, Peter
  • Williams, Alistair J K
  • Bingley, Polly J
  • Hutton, John C
  • Eisenbarth, George S
  • Concannon, Patrick
  • Rich, Stephen S
  • Pociot, Flemming
  • Brorsson, Caroline A
subjects:
  • Autoantibodies–Immunology
  • Autoimmunity–Genetics
  • Cross-Sectional Studies–Immunology
  • Diabetes Mellitus, Type 1–Genetics
  • Genetic Association Studies–Immunology
  • Genetic Loci–Immunology
  • Genetic Predisposition to Disease–Immunology
  • Genotype–Immunology
  • Humans–Immunology
  • Abridged
  • Autoantibodies
ispartof: Diabetes, August 2015, Vol.64(8), pp.3017-3027
description: 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.
language: eng
source:
identifier: E-ISSN: 1939-327X ; DOI: 10.2337/db14-1730
fulltext: fulltext
issn:
  • 1939327X
  • 1939-327X
url: Link


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titleNovel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes.
creatorBrorsson, Caroline A ; Onengut, Suna ; Chen, Wei-Min ; Wenzlau, Janet ; Yu, Liping ; Baker, Peter ; Williams, Alistair J K ; Bingley, Polly J ; Hutton, John C ; Eisenbarth, George S ; Concannon, Patrick ; Rich, Stephen S ; Pociot, Flemming ; Brorsson, Caroline A
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ispartofDiabetes, August 2015, Vol.64(8), pp.3017-3027
identifierE-ISSN: 1939-327X ; DOI: 10.2337/db14-1730
subjectAutoantibodies–Immunology ; Autoimmunity–Genetics ; Cross-Sectional Studies–Immunology ; Diabetes Mellitus, Type 1–Genetics ; Genetic Association Studies–Immunology ; Genetic Loci–Immunology ; Genetic Predisposition to Disease–Immunology ; Genotype–Immunology ; Humans–Immunology ; Abridged ; Autoantibodies
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descriptionIslet 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.
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titleNovel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes.
authorBrorsson, Caroline A ; Onengut, Suna ; Chen, Wei-Min ; Wenzlau, Janet ; Yu, Liping ; Baker, Peter ; Williams, Alistair J K ; Bingley, Polly J ; Hutton, John C ; Eisenbarth, George S ; Concannon, Patrick ; Rich, Stephen S ; Pociot, Flemming ; Brorsson, Caroline A
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