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Åke Lernmark

Principal investigator

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Next Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes

Author

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

Summary, in English

HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif "DAAFYDG", "DAAYHDG" and "DAAYYDR" have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a change of a single residue from the motif "DAAYH
D
G" to "DAAYH
S
G" (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10-15) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher's p-value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, pMHCII complex stability, β167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.

Department/s

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

Publishing year

2020

Language

English

Pages

2523-2535

Publication/Series

Diabetes

Volume

69

Issue

11

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