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

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

I: Scientific Reports, Vol. 11, Nr. 1, 8821, 23.04.2021.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Zhao, LP, Papadopoulos, GK, Moustakas, AK, Bondinas, GP, Carlsson, A, Larsson, HE, Ludvigsson, J, Marcus, C, Persson, M, Samuelsson, U, Wang, R, Pyo, C-W, Geraghty, DE & Lernmark, Å 2021, 'Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden', Scientific Reports, vol. 11, nr. 1, 8821. https://doi.org/10.1038/s41598-021-86229-8

APA

Zhao, L. P., Papadopoulos, G. K., Moustakas, A. K., Bondinas, G. P., Carlsson, A., Larsson, H. E., Ludvigsson, J., Marcus, C., Persson, M., Samuelsson, U., Wang, R., Pyo, C-W., Geraghty, D. E., & Lernmark, Å. (2021). Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden. Scientific Reports, 11(1), [8821]. https://doi.org/10.1038/s41598-021-86229-8

CBE

Zhao LP, Papadopoulos GK, Moustakas AK, Bondinas GP, Carlsson A, Larsson HE, Ludvigsson J, Marcus C, Persson M, Samuelsson U, Wang R, Pyo C-W, Geraghty DE, Lernmark Å. 2021. Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden. Scientific Reports. 11(1):Article 8821. https://doi.org/10.1038/s41598-021-86229-8

MLA

Vancouver

Author

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. / Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden. I: Scientific Reports. 2021 ; Vol. 11, Nr. 1.

RIS

TY - JOUR

T1 - Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden

AU - Zhao, Lue Ping

AU - Papadopoulos, George K

AU - Moustakas, Antonis K

AU - Bondinas, George P

AU - Carlsson, Annelie

AU - Larsson, Helena Elding

AU - Ludvigsson, Johnny

AU - Marcus, Claude

AU - Persson, Martina

AU - Samuelsson, Ulf

AU - Wang, Ruihan

AU - Pyo, Chul-Woo

AU - Geraghty, Daniel E

AU - Lernmark, Åke

PY - 2021/4/23

Y1 - 2021/4/23

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-021-86229-8

DO - 10.1038/s41598-021-86229-8

M3 - Article

C2 - 33893332

VL - 11

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 8821

ER -