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Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4 and 5 Include Potentially "Causal Residues" Responsible for the Risk of Childhood Type 1 Diabetes

Zhao, Lue Ping; Papadopoulos, George K; Kwok, Bill; Xu, Bryan; Kong, Matthew; Moustakas, Antonis K; Bondinas, George P; Carlsson, Annelie LU ; Elding-Larsson, Helena LU and Ludvigsson, Johnny, et al. (2019) In Diabetes 68(8). p.1692-1704
Abstract

Next generation targeted sequencing of HLA-DRB1, -DRB3, -DRB4 and -DRB5 (abbreviated as DRB345) provides high resolution of functional variant positions to investigate their associations with type 1 diabetes risk and with autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (IA-2A) or ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity due to high polymorphisms and extended linkage-disequilibrium among the DR loci, we apply a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease associated DR sequences down and identifies eleven residues of DRB1, sequences of which retain all significant associations observed by DR genes. Further, all eleven residues locate under/adjoining... (More)

Next generation targeted sequencing of HLA-DRB1, -DRB3, -DRB4 and -DRB5 (abbreviated as DRB345) provides high resolution of functional variant positions to investigate their associations with type 1 diabetes risk and with autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (IA-2A) or ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity due to high polymorphisms and extended linkage-disequilibrium among the DR loci, we apply a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease associated DR sequences down and identifies eleven residues of DRB1, sequences of which retain all significant associations observed by DR genes. Further, all eleven residues locate under/adjoining the peptide binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. In addition, 15 residues of DRB345, located respectively in the β50-55 homodimerization patch and in face of the molecule shown to interact with and bind to the accessory molecule CD4, retain their significant disease associations. Further ROR analysis of DR associations with autoantibodies finds DRB1 residues significantly associated with ZnT8A and DRB345-residues with GADA. The strongest association is between four residues (χ14, β25, β71 and β73) and IA-2A, in which a sequence "ERKA" confers a risk association (OR=2.15, p-value=10-18), and another sequence "ERKG" confers a protective association (OR=0.59, p-value=10-11), despite a difference of only one amino acid. As motifs of identified residues capture potentially causal DR associations with type 1 diabetes, this list of residuals is expected to include corresponding causal residues in this study population.

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Contribution to journal
publication status
published
subject
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Diabetes
volume
68
issue
8
pages
1692 - 1704
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85070185002
ISSN
1939-327X
DOI
10.2337/db19-0273
language
English
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yes
id
091e7853-a95c-420b-a795-cbd81fafe1ef
date added to LUP
2019-06-25 13:08:59
date last changed
2019-09-25 03:00:15
@article{091e7853-a95c-420b-a795-cbd81fafe1ef,
  abstract     = {<p>Next generation targeted sequencing of HLA-DRB1, -DRB3, -DRB4 and -DRB5 (abbreviated as DRB345) provides high resolution of functional variant positions to investigate their associations with type 1 diabetes risk and with autoantibodies against insulin (IAA), GAD65 (GADA), IA-2 (IA-2A) or ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity due to high polymorphisms and extended linkage-disequilibrium among the DR loci, we apply a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease associated DR sequences down and identifies eleven residues of DRB1, sequences of which retain all significant associations observed by DR genes. Further, all eleven residues locate under/adjoining the peptide binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. In addition, 15 residues of DRB345, located respectively in the β50-55 homodimerization patch and in face of the molecule shown to interact with and bind to the accessory molecule CD4, retain their significant disease associations. Further ROR analysis of DR associations with autoantibodies finds DRB1 residues significantly associated with ZnT8A and DRB345-residues with GADA. The strongest association is between four residues (χ14, β25, β71 and β73) and IA-2A, in which a sequence "ERKA" confers a risk association (OR=2.15, p-value=10-18), and another sequence "ERKG" confers a protective association (OR=0.59, p-value=10-11), despite a difference of only one amino acid. As motifs of identified residues capture potentially causal DR associations with type 1 diabetes, this list of residuals is expected to include corresponding causal residues in this study population.</p>},
  author       = {Zhao, Lue Ping and Papadopoulos, George K and Kwok, Bill and Xu, Bryan and Kong, Matthew and Moustakas, Antonis K and Bondinas, George P and Carlsson, Annelie and Elding-Larsson, Helena and Ludvigsson, Johnny and Marcus, Claude and Persson, Martina and Samuelsson, Ulf and Wang, Ruihan and Pyo, Chul-Woo and Nelson, Wyatt C and Geraghty, Daniel E and Lernmark, Åke},
  issn         = {1939-327X},
  language     = {eng},
  month        = {05},
  number       = {8},
  pages        = {1692--1704},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4 and 5 Include Potentially "Causal Residues" Responsible for the Risk of Childhood Type 1 Diabetes},
  url          = {http://dx.doi.org/10.2337/db19-0273},
  volume       = {68},
  year         = {2019},
}