Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.
Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.
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DOI：
10.1038/s41598-021-86229-8
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发表时间：
2021-04-23
影响因子：
4.6
通讯作者：
Lernmark Å
中科院分区：
文献类型：
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作者：
Zhao LP;Papadopoulos GK;Moustakas AK;Bondinas GP;Carlsson A;Larsson HE;Ludvigsson J;Marcus C;Persson M;Samuelsson U;Wang R;Pyo CW;Geraghty DE;Lernmark Å
HLA-DQ分子占1型糖尿病（T1 D）遗传风险的50%以上，但对相关残基知之甚少。通过下一代靶向测序技术和DQ残基序列的深度学习，目的是发现与T1 D相关的关键残基及其基序。我们的分析揭示了HLA-DQ分子上的（αa1，α44，α157，α196）和（β9，β30，β57，β70，β135）。他们的基序捕获了所有已知的易感性和耐药T1 D协会。三个基序，“DCAA-YSARD”（OR = 2.10，p = 1.96*10−20），“DQAA-YYARD”（OR = 3.34，2.69*10−72）和“DQDA-YYARD”（OR = 3.71，1.53*10−6）对应于与易感性相关的DQ 2.5和DQ 8.1（后两个基序）。10个基序与T1 D抗性显著相关。总的来说，纯合DQ风险基序占DQ-T1 D风险的43%，而纯合DQ抗性基序占DQ-T1 D风险的25%。在鉴定的9个残基中，5个位于抗原肽的锚定口袋内或附近（α44、β9、β30、β57和β70），1个位于α链的N末端（αa1），1个位于CD 4结合区（β135），1个位于推定的同源TCR诱导的αβ同源二聚化过程（α157），1个位于α链的膜内结构域（α196）。找到这些关键的残基，应允许调查的基本性质的宿主免疫耐受性的基础，以自身和器官特异性自身免疫。
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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影响因子：
32.4
作者：
Cochran, JR;Cameron, TO;Stern, LJ
通讯作者：
Stern, LJ
影响因子：
7.7
作者：
Ilonen, Jorma;Hammais, Anna;Knip, Mikael
通讯作者：
Knip, Mikael
影响因子：
64.8
作者：
CAMMAROTA, G;SCHEIRLE, A;SINIGAGLIA, F
通讯作者：
SINIGAGLIA, F
影响因子：
7.7
作者：
Delli AJ;Vaziri-Sani F;Lindblad B;Elding-Larsson H;Carlsson A;Forsander G;Ivarsson SA;Ludvigsson J;Kockum I;Marcus C;Samuelsson U;Örtqvist E;Groop L;Bondinas GP;Papadopoulos GK;Lernmark Å;Better Diabetes Diagnosis Study Group
通讯作者：
Better Diabetes Diagnosis Study Group
DOI：
10.4049/jimmunol.1901079
发表时间：
2020-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
通讯作者：
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