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Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden

Zhao, Lue Ping ; Papadopoulos, George K ; Moustakas, Antonis K ; Bondinas, George P ; Carlsson, Annelie LU orcid ; Larsson, Helena Elding LU orcid ; Ludvigsson, Johnny ; Marcus, Claude ; Persson, Martina LU and Samuelsson, Ulf , et al. (2021) In Scientific Reports 11(1).
Abstract

HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, "DCAA-YSARD" (OR = 2.10, p = 1.96*10-20), "DQAA-YYARD" (OR = 3.34, 2.69*10-72) and "DQDA-YYARD" (OR = 3.71, 1.53*10-6) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with... (More)

HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, "DCAA-YSARD" (OR = 2.10, p = 1.96*10-20), "DQAA-YYARD" (OR = 3.34, 2.69*10-72) and "DQDA-YYARD" (OR = 3.71, 1.53*10-6) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (α44, β9, β30, β57 and β70), one was the N-terminal of the alpha chain (αa1), one in the CD4-binding region (β135), one in the putative cognate TCR-induced αβ homodimerization process (α157), and one in the intra-membrane domain of the alpha chain (α196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
11
issue
1
article number
8821
publisher
Nature Publishing Group
external identifiers
  • scopus:85104863802
  • pmid:33893332
ISSN
2045-2322
DOI
10.1038/s41598-021-86229-8
project
Better Diabetes Diagnosis (BDD)
language
English
LU publication?
yes
id
d1c10df1-8cd4-4fa9-98ea-207019750bb1
date added to LUP
2021-04-28 10:36:08
date last changed
2025-02-10 12:16:49
@article{d1c10df1-8cd4-4fa9-98ea-207019750bb1,
  abstract     = {{<p>HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, "DCAA-YSARD" (OR = 2.10, p = 1.96*10-20), "DQAA-YYARD" (OR = 3.34, 2.69*10-72) and "DQDA-YYARD" (OR = 3.71, 1.53*10-6) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (α44, β9, β30, β57 and β70), one was the N-terminal of the alpha chain (αa1), one in the CD4-binding region (β135), one in the putative cognate TCR-induced αβ homodimerization process (α157), and one in the intra-membrane domain of the alpha chain (α196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.</p>}},
  author       = {{Zhao, Lue Ping and Papadopoulos, George K and Moustakas, Antonis K and Bondinas, George P and Carlsson, Annelie and Larsson, Helena Elding and Ludvigsson, Johnny and Marcus, Claude and Persson, Martina and Samuelsson, Ulf and Wang, Ruihan and Pyo, Chul-Woo and Geraghty, Daniel E and Lernmark, Åke}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-86229-8}},
  doi          = {{10.1038/s41598-021-86229-8}},
  volume       = {{11}},
  year         = {{2021}},
}