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Åke Lernmark

Principal investigator

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Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden

Author

  • Lue Ping Zhao
  • George K Papadopoulos
  • Antonis K Moustakas
  • George P Bondinas
  • Annelie Carlsson
  • Helena Elding Larsson
  • Johnny Ludvigsson
  • Claude Marcus
  • Martina Persson
  • Ulf Samuelsson
  • Ruihan Wang
  • Chul-Woo Pyo
  • Daniel E Geraghty
  • Åke Lernmark

Summary, in English

HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, "DCAA-YSARD" (OR = 2.10, p = 1.96*10-20), "DQAA-YYARD" (OR = 3.34, 2.69*10-72) and "DQDA-YYARD" (OR = 3.71, 1.53*10-6) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (α44, β9, β30, β57 and β70), one was the N-terminal of the alpha chain (αa1), one in the CD4-binding region (β135), one in the putative cognate TCR-induced αβ homodimerization process (α157), and one in the intra-membrane domain of the alpha chain (α196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.

Department/s

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

Publishing year

2021-04-23

Language

English

Publication/Series

Scientific Reports

Volume

11

Issue

1

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Endocrinology and Diabetes
  • Pediatrics

Status

Published

Research group

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

ISBN/ISSN/Other

  • ISSN: 2045-2322