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

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...

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Autores principales: 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
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Publicado: Nature Portfolio 2021
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spelling oai:doaj.org-article:74813d36caef4a368c740f9032ef08092021-12-02T18:27:49ZNine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden10.1038/s41598-021-86229-82045-2322https://doaj.org/article/74813d36caef4a368c740f9032ef08092021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86229-8https://doaj.org/toc/2045-2322Abstract 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.Lue Ping ZhaoGeorge K. PapadopoulosAntonis K. MoustakasGeorge P. BondinasAnnelie CarlssonHelena Elding LarssonJohnny LudvigssonClaude MarcusMartina PerssonUlf SamuelssonRuihan WangChul-Woo PyoDaniel E. GeraghtyÅke LernmarkNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
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
Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden
description 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*10−20), “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.
format article
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
author_facet 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
author_sort Lue Ping Zhao
title Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden
title_short Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden
title_full Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden
title_fullStr Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden
title_full_unstemmed Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden
title_sort nine residues in hla-dq molecules determine with susceptibility and resistance to type 1 diabetes among young children in sweden
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/74813d36caef4a368c740f9032ef0809
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