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Analysis of critical residues of HLA-DQ6 molecules in insulin-dependent diabetes mellitus

Sanjeevi, C. B.; DeWeese, C.; Landin-Olsson, M. LU ; Kockum, I.; Dahlquist, G.; Lernmark, Å LU and Lybrand, T. P. (1997) In Tissue Antigens 50(1). p.61-65
Abstract

Among DQ6 molecules, DQA1(*)0102-DQB1(*)0602 is negatively associated with insulin-dependent diabetes mellitus (IDDM), but DQA1(*)0102-DQB1(*)0604 shows a neutral to positive association in Swedish children with IDDM. The aim of this study was to identify critical DQB1 residues that may account for the differences in IDDM association observed for these two DQ6 molecules. HLA-DQ genotyping in 425 IDDM patients and 367 matched controls showed DQ6 (B1(*)0602) in 1% of patients and 25% of controls (odds ratio (OR) 0.02). DQ6 (B1(*)0604) alone was neutral (9% of patients and 10% of controls) but in combination with DQ8, was positively associated (5% of patients, 1% of controls, OR 9.49). In both these DQ6 molecules the α-chain is the same... (More)

Among DQ6 molecules, DQA1(*)0102-DQB1(*)0602 is negatively associated with insulin-dependent diabetes mellitus (IDDM), but DQA1(*)0102-DQB1(*)0604 shows a neutral to positive association in Swedish children with IDDM. The aim of this study was to identify critical DQB1 residues that may account for the differences in IDDM association observed for these two DQ6 molecules. HLA-DQ genotyping in 425 IDDM patients and 367 matched controls showed DQ6 (B1(*)0602) in 1% of patients and 25% of controls (odds ratio (OR) 0.02). DQ6 (B1(*)0604) alone was neutral (9% of patients and 10% of controls) but in combination with DQ8, was positively associated (5% of patients, 1% of controls, OR 9.49). In both these DQ6 molecules the α-chain is the same but the β-chain differs at positions 9, 30, 57, 70, 86 and 87. DQB1(*)0602 has F9, Y30, D57, G70, A86 and F87, whereas DQB1(*)0604 has Y9, H30, V57, R70, G86 and Y87. Three-dimensional models of the two DQ6 molecules, based on crystal coordinates of the homologous DR1 molecule, suggest that residue 57β will likely play a critical role in peptide-binding selectivity, whereas residue 70β is probably a major contact site for the T-cell receptor. The effects of these specific polymorphic substitutions in DQ molecules on peptide binding and T-cell receptor recognition may be significant in IDDM susceptibility.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Diabetes, GAD antibody, Genetic susceptibility, HLA, IAA, ICA, IDDM, Major histocompatibility complex, Molecular modeling
in
Tissue Antigens
volume
50
issue
1
pages
61 - 65
publisher
Wiley-Blackwell
external identifiers
  • scopus:0030916513
ISSN
0001-2815
DOI
10.1111/j.1399-0039.1997.tb02836.x
language
English
LU publication?
no
id
e6d26c8e-981b-4b55-ae15-e5917c2df0ba
date added to LUP
2019-06-30 23:47:33
date last changed
2019-08-16 13:17:52
@article{e6d26c8e-981b-4b55-ae15-e5917c2df0ba,
  abstract     = {<p>Among DQ6 molecules, DQA1(*)0102-DQB1(*)0602 is negatively associated with insulin-dependent diabetes mellitus (IDDM), but DQA1(*)0102-DQB1(*)0604 shows a neutral to positive association in Swedish children with IDDM. The aim of this study was to identify critical DQB1 residues that may account for the differences in IDDM association observed for these two DQ6 molecules. HLA-DQ genotyping in 425 IDDM patients and 367 matched controls showed DQ6 (B1(*)0602) in 1% of patients and 25% of controls (odds ratio (OR) 0.02). DQ6 (B1(*)0604) alone was neutral (9% of patients and 10% of controls) but in combination with DQ8, was positively associated (5% of patients, 1% of controls, OR 9.49). In both these DQ6 molecules the α-chain is the same but the β-chain differs at positions 9, 30, 57, 70, 86 and 87. DQB1(*)0602 has F9, Y30, D57, G70, A86 and F87, whereas DQB1(*)0604 has Y9, H30, V57, R70, G86 and Y87. Three-dimensional models of the two DQ6 molecules, based on crystal coordinates of the homologous DR1 molecule, suggest that residue 57β will likely play a critical role in peptide-binding selectivity, whereas residue 70β is probably a major contact site for the T-cell receptor. The effects of these specific polymorphic substitutions in DQ molecules on peptide binding and T-cell receptor recognition may be significant in IDDM susceptibility.</p>},
  author       = {Sanjeevi, C. B. and DeWeese, C. and Landin-Olsson, M. and Kockum, I. and Dahlquist, G. and Lernmark, Å and Lybrand, T. P.},
  issn         = {0001-2815},
  keyword      = {Diabetes,GAD antibody,Genetic susceptibility,HLA,IAA,ICA,IDDM,Major histocompatibility complex,Molecular modeling},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {61--65},
  publisher    = {Wiley-Blackwell},
  series       = {Tissue Antigens},
  title        = {Analysis of critical residues of HLA-DQ6 molecules in insulin-dependent diabetes mellitus},
  url          = {http://dx.doi.org/10.1111/j.1399-0039.1997.tb02836.x},
  volume       = {50},
  year         = {1997},
}