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Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM

Sanjeevi, C. B. ; Lybrand, T. P. ; Deweese, C. ; Landin-Olsson, M. LU ; Kockum, I. ; Dahlquist, G. ; Sundkvist, G. LU ; Stenger, D. and Lernmark, A. LU orcid (1995) In Diabetes 44(1). p.125-131
Abstract

The association between human leukocyte antigen (HLA) insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp- 57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQS) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the β- chain, but DQ8 was... (More)

The association between human leukocyte antigen (HLA) insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp- 57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQS) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the β- chain, but DQ8 was positively (odds ratio 8.07; P < 0.001) and DQ7 negatively (odds ratio 0.38; P < 0.001) associated with the disease. Molecular modeling was used to determine whether physicochemical properties such as steric factors and surface electrostatic potentials also differ in a systematic way for various DQ molecules. Amino acids were substituted systematically at the four polymorphic sites, and the solvent-accessible surfaces and electrostatic potentials were computed for each molecule. Dramatic alterations in electrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1. The variation of physicochemical properties due to polymorphic substitutions may be significant to the mechanism of HLA-DQ association with insulin-dependent diabetes, via the effect these property variations have on peptide antigen binding selectivity and subsequent interactions with specific T-cell receptors.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
44
issue
1
pages
125 - 131
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:0028890395
  • pmid:7813806
ISSN
0012-1797
DOI
10.2337/diab.44.1.125
language
English
LU publication?
yes
id
d5ba7925-2a94-455a-ad1f-e8f0106d8ccb
date added to LUP
2019-09-11 08:59:55
date last changed
2024-03-13 08:21:07
@article{d5ba7925-2a94-455a-ad1f-e8f0106d8ccb,
  abstract     = {{<p>The association between human leukocyte antigen (HLA) insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp- 57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQS) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the β- chain, but DQ8 was positively (odds ratio 8.07; P &lt; 0.001) and DQ7 negatively (odds ratio 0.38; P &lt; 0.001) associated with the disease. Molecular modeling was used to determine whether physicochemical properties such as steric factors and surface electrostatic potentials also differ in a systematic way for various DQ molecules. Amino acids were substituted systematically at the four polymorphic sites, and the solvent-accessible surfaces and electrostatic potentials were computed for each molecule. Dramatic alterations in electrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1. The variation of physicochemical properties due to polymorphic substitutions may be significant to the mechanism of HLA-DQ association with insulin-dependent diabetes, via the effect these property variations have on peptide antigen binding selectivity and subsequent interactions with specific T-cell receptors.</p>}},
  author       = {{Sanjeevi, C. B. and Lybrand, T. P. and Deweese, C. and Landin-Olsson, M. and Kockum, I. and Dahlquist, G. and Sundkvist, G. and Stenger, D. and Lernmark, A.}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{125--131}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM}},
  url          = {{http://dx.doi.org/10.2337/diab.44.1.125}},
  doi          = {{10.2337/diab.44.1.125}},
  volume       = {{44}},
  year         = {{1995}},
}