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

Brorsson, Caroline; Hansen, Niclas Tue; Bergholdt, Regine; Brunak, Soren and Pociot, Flemming LU (2010) In PLoS ONE 5(3).
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
5
issue
3
publisher
Public Library of Science
external identifiers
  • wos:000275197200019
  • scopus:77949683112
ISSN
1932-6203
DOI
10.1371/journal.pone.0009576
language
English
LU publication?
yes
id
9e9df15b-baeb-410c-989e-bc30bf329086 (old id 1589351)
date added to LUP
2010-04-20 11:30:28
date last changed
2018-07-08 03:47:46
@article{9e9df15b-baeb-410c-989e-bc30bf329086,
  abstract     = {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.},
  author       = {Brorsson, Caroline and Hansen, Niclas Tue and Bergholdt, Regine and Brunak, Soren and Pociot, Flemming},
  issn         = {1932-6203},
  language     = {eng},
  number       = {3},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {The Type 1 Diabetes - HLA Susceptibility Interactome - Identification of HLA Genotype-Specific Disease Genes for Type 1 Diabetes},
  url          = {http://dx.doi.org/10.1371/journal.pone.0009576},
  volume       = {5},
  year         = {2010},
}