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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
Fred Hutchinson Canc Res Ctr, WA 98104 USA.
Technol Educ Inst Epirus, Greece; Univ Ioannina, Greece.
Benaroya Res Inst Virginia Mason, WA USA.
Univ Calif Berkeley, CA 94720 USA.
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2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 8, p. 1692-1704Article in journal (Refereed) Published
Abstract [en]

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 beta 49-55 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 (beta 14, beta 25, beta 71, and beta 73) and IA-2A, in which the sequence ERKA confers a risk association (odds ratio 2.15, P = 10(-18)), and another sequence, ERKG, confers a protective association (odds ratio 0.59, P = 10(-11)), despite a difference of only one amino acid. Because 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.

Place, publisher, year, edition, pages
Arlington, VA, United States: American Diabetes Association , 2019. Vol. 68, no 8, p. 1692-1704
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:liu:diva-159562DOI: 10.2337/db19-0273ISI: 000476794600015PubMedID: 31127057Scopus ID: 2-s2.0-85070185002OAI: oai:DiVA.org:liu-159562DiVA, id: diva2:1342470
Note

Funding Agencies|National Institute of Diabetes and Digestive and Kidney Diseases [R56-DK-117276, R01-DK-117276, DK-63861, DK-26190]; European Foundation for the Study of Diabetes Clinical Research Grants Programme 2013; Swedish Child Diabetes Foundation (Barndiabetesfonden); Swedish Research Council; Skane County Council for Research and Development; Swedish Association of Local Authorities and Regions; Forskningsradet om Halsa, Arbetsliv och Valfard; European Union [MIS 91949]

Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-19Bibliographically approved

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Ludvigsson, JohnnySamuelsson, Ulf
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Division of Children's and Women's healthFaculty of Medicine and Health SciencesH.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus
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