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The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes

BACKGROUND: The individual contribution of genes in the HLA region to the risk of developing type 1 diabetes (T1D) is confounded by the high linkage disequilibrium (LD) in this region. Using a novel approach we have combined genetic association data with information on functional protein-protein int...

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Autores principales: Brorsson, Caroline, Tue Hansen, Niclas, Bergholdt, Regine, Brunak, Søren, Pociot, Flemming
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832689/
https://www.ncbi.nlm.nih.gov/pubmed/20221424
http://dx.doi.org/10.1371/journal.pone.0009576
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author Brorsson, Caroline
Tue Hansen, Niclas
Bergholdt, Regine
Brunak, Søren
Pociot, Flemming
author_facet Brorsson, Caroline
Tue Hansen, Niclas
Bergholdt, Regine
Brunak, Søren
Pociot, Flemming
author_sort Brorsson, Caroline
collection PubMed
description BACKGROUND: The individual contribution of genes in the HLA region to the risk of developing type 1 diabetes (T1D) is confounded by the high linkage disequilibrium (LD) in this region. Using a novel approach we have combined genetic association data with information on functional protein-protein interactions to elucidate risk independent of LD and to place the genetic association into a functional context. METHODOLOGY/PRINCIPAL FINDINGS: Genetic association data from 2300 single nucleotide polymorphisms (SNPs) in the HLA region was analysed in 2200 T1D family trios divided into six risk groups based on HLA-DRB1 genotypes. The best SNP signal in each gene was mapped to proteins in a human protein interaction network and their significance of clustering in functional network modules was evaluated. The significant network modules identified through this approach differed between the six HLA risk groups, which could be divided into two groups based on carrying the DRB1*0301 or the DRB1*0401 allele. Proteins identified in networks specific for DRB1*0301 carriers were involved in stress response and inflammation whereas in DRB1*0401 carriers the proteins were involved in antigen processing and presentation. CONCLUSIONS/SIGNIFICANCE: In this study we were able to hypothesise functional differences between individuals with T1D carrying specific DRB1 alleles. The results point at candidate proteins involved in distinct cellular processes that could not only help the understanding of the pathogenesis of T1D, but also the distinction between individuals at different genetic risk for developing T1D.
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spelling pubmed-28326892010-03-11 The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes Brorsson, Caroline Tue Hansen, Niclas Bergholdt, Regine Brunak, Søren Pociot, Flemming PLoS One Research Article BACKGROUND: The individual contribution of genes in the HLA region to the risk of developing type 1 diabetes (T1D) is confounded by the high linkage disequilibrium (LD) in this region. Using a novel approach we have combined genetic association data with information on functional protein-protein interactions to elucidate risk independent of LD and to place the genetic association into a functional context. METHODOLOGY/PRINCIPAL FINDINGS: Genetic association data from 2300 single nucleotide polymorphisms (SNPs) in the HLA region was analysed in 2200 T1D family trios divided into six risk groups based on HLA-DRB1 genotypes. The best SNP signal in each gene was mapped to proteins in a human protein interaction network and their significance of clustering in functional network modules was evaluated. The significant network modules identified through this approach differed between the six HLA risk groups, which could be divided into two groups based on carrying the DRB1*0301 or the DRB1*0401 allele. Proteins identified in networks specific for DRB1*0301 carriers were involved in stress response and inflammation whereas in DRB1*0401 carriers the proteins were involved in antigen processing and presentation. CONCLUSIONS/SIGNIFICANCE: In this study we were able to hypothesise functional differences between individuals with T1D carrying specific DRB1 alleles. The results point at candidate proteins involved in distinct cellular processes that could not only help the understanding of the pathogenesis of T1D, but also the distinction between individuals at different genetic risk for developing T1D. Public Library of Science 2010-03-05 /pmc/articles/PMC2832689/ /pubmed/20221424 http://dx.doi.org/10.1371/journal.pone.0009576 Text en Brorsson et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Brorsson, Caroline
Tue Hansen, Niclas
Bergholdt, Regine
Brunak, Søren
Pociot, Flemming
The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes
title The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes
title_full The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes
title_fullStr The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes
title_full_unstemmed The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes
title_short The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes
title_sort type 1 diabetes - hla susceptibility interactome - identification of hla genotype-specific disease genes for type 1 diabetes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832689/
https://www.ncbi.nlm.nih.gov/pubmed/20221424
http://dx.doi.org/10.1371/journal.pone.0009576
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