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

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...

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Bibliographic Details
Published in:Scientific reports Vol. 11; no. 1; pp. 8821 - 19
Main Authors: Zhao, Lue Ping, Papadopoulos, George K., Moustakas, Antonis K., Bondinas, George P., Carlsson, Annelie, Larsson, Helena Elding, Ludvigsson, Johnny, Marcus, Claude, Persson, Martina, Samuelsson, Ulf, Wang, Ruihan, Pyo, Chul-Woo, Geraghty, Daniel E., Lernmark, Åke
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 23.04.2021
Nature Publishing Group
Nature Portfolio
Subjects:
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631/250
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Autoimmunity
CD4 antigen
Clinical Medicine
Deep learning
Diabetes
Diabetes mellitus (insulin dependent)
Endocrinology and Diabetes
Endokrinologi och diabetes
Histocompatibility antigen HLA
Humanities and Social Sciences
Immunological tolerance
Klinisk medicin
Medical and Health Sciences
Medicin och hälsovetenskap
multidisciplinary
Pediatrics
Pediatrik
Residues
Science
Science (multidisciplinary)
T cell receptors
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-86229-8