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Next Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes

Zhao, Lue Ping ; Papadopoulos, George K ; Kwok, William W ; Moustakas, Antonis K ; Bondinas, George P ; Carlsson, Annelie LU orcid ; Larsson, Helena Elding LU ; Ludvigsson, Johnny ; Marcus, Claude and Samuelsson, Ulf , et al. (2020) In Diabetes 69(11). p.2523-2535
Abstract

HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif "DAAFYDG", "DAAYHDG" and "DAAYYDR" have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a... (More)

HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif "DAAFYDG", "DAAYHDG" and "DAAYYDR" have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a change of a single residue from the motif "DAAYH
D
G" to "DAAYH
S
G" (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10-15) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher's p-value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, pMHCII complex stability, β167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
69
issue
11
pages
2523 - 2535
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:32868339
  • scopus:85093875702
ISSN
1939-327X
DOI
10.2337/db20-0374
project
Better Diabetes Diagnosis (BDD)
language
English
LU publication?
yes
additional info
© 2020 by the American Diabetes Association.
id
e94df8db-3e57-429e-b8a7-ff0f4c84dd14
date added to LUP
2020-09-06 17:08:15
date last changed
2024-05-29 20:12:41
@article{e94df8db-3e57-429e-b8a7-ff0f4c84dd14,
  abstract     = {{<p>HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values&gt;0.05), and one motif has 7 copies observed among controls only. The motif "DAAFYDG", "DAAYHDG" and "DAAYYDR" have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a change of a single residue from the motif "DAAYH <br>
 D<br>
 G" to "DAAYH <br>
 S<br>
 G" (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10-15) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher's p-value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, pMHCII complex stability, β167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.</p>}},
  author       = {{Zhao, Lue Ping and Papadopoulos, George K and Kwok, William W and Moustakas, Antonis K and Bondinas, George P and Carlsson, Annelie and Larsson, Helena Elding and Ludvigsson, Johnny and Marcus, Claude 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}},
  number       = {{11}},
  pages        = {{2523--2535}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Next Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes}},
  url          = {{http://dx.doi.org/10.2337/db20-0374}},
  doi          = {{10.2337/db20-0374}},
  volume       = {{69}},
  year         = {{2020}},
}