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

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Abstract

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Benaroya Research Institute
  • Fred Hutchinson Cancer Research Center
  • Technological Educational Institute of Epirus
  • Ionian University
  • Skåne University Hospital
  • Linköping University
  • Karolinska Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Endokrinologi och diabetes
Originalspråkengelska
Sidor (från-till)2523-2535
TidskriftDiabetes
Volym69
Utgåva nummer11
StatusPublished - 2020
PublikationskategoriForskning
Peer review utfördJa

Bibliografisk information

© 2020 by the American Diabetes Association.