在 DPT-1 和 TN07 临床试验中,1 型糖尿病的进展与 HLA-DQA1-B1 异源二聚体中的特定残基密切相关。

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Diabetologia Pub Date : 2024-11-01 Epub Date: 2024-10-01 DOI:10.1007/s00125-024-06274-6
Lue Ping Zhao, George K Papadopoulos, Jay S Skyler, Alberto Pugliese, Hemang M Parikh, William W Kwok, Terry P Lybrand, George P Bondinas, Antonis K Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C Nelson, Daniel E Geraghty, Åke Lernmark
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引用次数: 0

摘要

目的/假设:本研究旨在探索HLA-DQA1-DQB1的分子氨基酸(AAs)和相关结构对1型糖尿病从1期或2期发展到3期的影响:利用糖尿病预防试验-1型和糖尿病预防试验中1216名参与者的高分辨率DQA1和DQB1基因型,我们应用分层组织单倍型关联分析(HOH)来解读哪些AAs有助于DQ与疾病的关联及其结构特性。单倍型关联分析依靠 Cox 回归来量化 DQ 与 1 型糖尿病发病时间的关联:通过计算α链和β链的所有可能的DQ异二聚体,我们发现异二聚体增加了细胞水平的遗传多样性,从43种经验观察到的单倍型增加到186种可能的异二聚体。异源二聚化将几种中性单倍型(DQ2.2、DQ2.3 和 DQ4.4)转化为风险单倍型(DQ2.2/2.3-DQ4.4 和 DQ4.4-DQ2.2)。HOH发现了α链上的8个AA(-16α、-13α、-6α、α22、α23、α44、α72、α157)和β链上的6个AA(-18β、β9、β13、β26、β57、β135),这些AA导致了DQ与1型糖尿病进展的关联。具体的 AAs 涉及信号肽(负号,可能与表达水平有关)、α1β1 结构域抗原结合沟中的袋 1、袋 4 和袋 9 以及αβ异二聚体的假定同源二聚化:这些结果揭示了DQ在单个残基和相关蛋白结构上对1型糖尿病进展的贡献,揭示了其免疫学机制,并为制定治疗策略提供了新线索:临床试验数据和生物样本可通过美国国家糖尿病和消化道及肾脏疾病研究所中央存储库门户网站 ( https://repository.niddk.nih.gov/studies ) 获取。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Progression to type 1 diabetes in the DPT-1 and TN07 clinical trials is critically associated with specific residues in HLA-DQA1-B1 heterodimers.

Progression to type 1 diabetes in the DPT-1 and TN07 clinical trials is critically associated with specific residues in HLA-DQA1-B1 heterodimers.

Aims/hypothesis: The aim of this work was to explore molecular amino acids (AAs) and related structures of HLA-DQA1-DQB1 that underlie its contribution to the progression from stages 1 or 2 to stage 3 type 1 diabetes.

Methods: Using high-resolution DQA1 and DQB1 genotypes from 1216 participants in the Diabetes Prevention Trial-Type 1 and the Diabetes Prevention Trial, we applied hierarchically organised haplotype association analysis (HOH) to decipher which AAs contributed to the associations of DQ with disease and their structural properties. HOH relied on the Cox regression to quantify the association of DQ with time-to-onset of type 1 diabetes.

Results: By numerating all possible DQ heterodimers of α- and β-chains, we showed that the heterodimerisation increases genetic diversity at the cellular level from 43 empirically observed haplotypes to 186 possible heterodimers. Heterodimerisation turned several neutral haplotypes (DQ2.2, DQ2.3 and DQ4.4) to risk haplotypes (DQ2.2/2.3-DQ4.4 and DQ4.4-DQ2.2). HOH uncovered eight AAs on the α-chain (-16α, -13α, -6α, α22, α23, α44, α72, α157) and six AAs on the β-chain (-18β, β9, β13, β26, β57, β135) that contributed to the association of DQ with progression of type 1 diabetes. The specific AAs concerned the signal peptide (minus sign, possible linkage to expression levels), pockets 1, 4 and 9 in the antigen-binding groove of the α1β1 domain, and the putative homodimerisation of the αβ heterodimers.

Conclusions/interpretation: These results unveil the contribution made by DQ to type 1 diabetes progression at individual residues and related protein structures, shedding light on its immunological mechanisms and providing new leads for developing treatment strategies.

Data availability: Clinical trial data and biospecimen samples are available through the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository portal ( https://repository.niddk.nih.gov/studies ).

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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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