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.
Journal
Diabetes
ISSN: 1939-327X
Titre abrégé: Diabetes
Pays: United States
ID NLM: 0372763
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
13
03
2019
accepted:
21
05
2019
pubmed:
28
5
2019
medline:
12
2
2020
entrez:
26
5
2019
Statut:
ppublish
Résumé
Next-generation targeted sequencing of HLA-DRB1 and HLA-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), and ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity as a result of high polymorphisms and extended linkage disequilibrium among the DR loci, we applied a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease-associated DR sequences and identifies 11 residues of DRB1, sequences of which retain all significant associations observed by DR genes. Furthermore, all 11 residues locate under/adjoining the peptide-binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. The 15 residues of DRB345, located respectively in the β49-55 homodimerization patch and on the 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 that DRB1 residues significantly associated with ZnT8A and DRB345 residues with GADA. The strongest association is between four residues (β14, β25, β71, and β73) and IA-2A, in which the sequence ERKA confers a risk association (odds ratio 2.15,
Identifiants
pubmed: 31127057
pii: db19-0273
doi: 10.2337/db19-0273
pmc: PMC6692811
doi:
Substances chimiques
HLA-DRB1 Chains
0
HLA-DRB3 Chains
0
HLA-DRB4 Chains
0
HLA-DRB5 Chains
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1692-1704Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK026190
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK117276
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK063861
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK063861
Pays : United States
Informations de copyright
© 2019 by the American Diabetes Association.
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