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Åke Lernmark

Principal investigator

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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

Author

  • Lue Ping Zhao
  • George K Papadopoulos
  • Bill Kwok
  • Bryan Xu
  • Matthew Kong
  • Antonis K Moustakas
  • George P Bondinas
  • Annelie Carlsson
  • Helena Elding-Larsson
  • Johnny Ludvigsson
  • Claude Marcus
  • Martina Persson
  • Ulf Samuelsson
  • Ruihan Wang
  • Chul-Woo Pyo
  • Wyatt C Nelson
  • Daniel E Geraghty
  • Åke Lernmark

Summary, in English

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.

Department/s

  • PediatricCeliaki/Diabetes
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Paediatric Endocrinology
  • Diabetes and Celiac Unit

Publishing year

2019-05-24

Language

English

Pages

1692-1704

Publication/Series

Diabetes

Volume

68

Issue

8

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • PediatricCeliaki/Diabetes
  • Paediatric Endocrinology
  • Diabetes and Celiac Unit

ISBN/ISSN/Other

  • ISSN: 1939-327X