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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
Organisations
External organisations
  • Fred Hutchinson Cancer Research Center
  • Benaroya Research Institute
  • University of California, Berkeley
  • Carnegie Mellon University
  • Ionian University
  • Technological Educational Institute of Epirus
  • Skåne University Hospital
  • Linköping University
  • Karolinska Institutet
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)1692-1704
JournalDiabetes
Volume68
Issue number8
Early online date2019 May 24
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes