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

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
Source :
Scientific Reports; 4/23/2021, Vol. 11 Issue 1, p1-19, 19p
Publication Year :
2021

Abstract

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<superscript>−20</superscript>), "DQAA-YYARD" (OR = 3.34, 2.69*10<superscript>−72</superscript>) and "DQDA-YYARD" (OR = 3.71, 1.53*10<superscript>−6</superscript>) 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20452322
Volume :
11
Issue :
1
Database :
Complementary Index
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
149960941
Full Text :
https://doi.org/10.1038/s41598-021-86229-8