Format

Send to

Choose Destination
Diabetes. 2019 May 24. pii: db190273. doi: 10.2337/db19-0273. [Epub ahead of print]

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.

Author information

1
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA lzhao@fredhutch.org papadopg@gmail.com ake.lernmark@med.lu.se.
2
Laboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, GR47100 Arta, GREECE lzhao@fredhutch.org papadopg@gmail.com ake.lernmark@med.lu.se.
3
Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
4
College of Letters and Sciences, University of California, Berkeley, CA, USA.
5
Department of Computer Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
6
Department of Food Science and Technology, Ionian University, GR28100 Argostoli, Cephallonia, GREECE.
7
Laboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, GR47100 Arta, GREECE.
8
Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden.
9
Department of Pediatrics, Lund University, Lund, Sweden.
10
Crown Princess Victoria Children's Hospital, Region Östergötland and Div of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
11
Department of Clinical Science and Education Karolinska Institutet and Institution of Medicine, Clinical Epidemiology, Karolinska Institutet.
12
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
13
Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden lzhao@fredhutch.org papadopg@gmail.com ake.lernmark@med.lu.se.

Abstract

Next generation targeted sequencing of HLA-DRB1, -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) or ZnT8 (ZnT8A). To overcome exceptional DR sequence complexity due to high polymorphisms and extended linkage-disequilibrium among the DR loci, we apply a novel recursive organizer (ROR) to discover disease-associated amino acid residues. ROR distills disease associated DR sequences down and identifies eleven residues of DRB1, sequences of which retain all significant associations observed by DR genes. Further, all eleven residues locate under/adjoining the peptide binding groove of DRB1, suggesting a plausible functional mechanism through peptide binding. In addition, 15 residues of DRB345, located respectively in the β50-55 homodimerization patch and in 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 DRB1 residues significantly associated with ZnT8A and DRB345-residues with GADA. The strongest association is between four residues (χ14, β25, β71 and β73) and IA-2A, in which a sequence "ERKA" confers a risk association (OR=2.15, p-value=10-18), and another sequence "ERKG" confers a protective association (OR=0.59, p-value=10-11), despite a difference of only one amino acid. As motifs of identified residues capture potentially causal DR associations with type 1 diabetes, this list of residuals is expected to include corresponding causal residues in this study population.

PMID:
31127057
DOI:
10.2337/db19-0273

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center