Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Laboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta, Greece
Diabetes. 2020 Jul;69(7):1573-1587. doi: 10.2337/db20-0075. Epub 2020 Apr 3.
HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next-generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1- to 18 year-old patients ( = 962) and control subjects ( = 636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically organized haplotype (HOH) association analysis allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues α44Q (odds ratio [OR] 3.29, = 2.38 * 10) and β57A (OR 3.44, = 3.80 * 10) to be associated with T1D in the DQ8/9 cluster representing all ten residues (α22, α23, α44, α49, α51, α53, α54, α73, α184, β57) due to complete linkage disequilibrium (LD) of α44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found α44C and β135D to share the risk for T1D (OR 2.10, = 1.96 * 10). The motif "QAD" of α44, β57, and β135 captured the T1D risk association of DQ8.1 (OR 3.44, = 3.80 * 10), and the corresponding motif "CAD" captured the risk association of DQ2.5 (OR 2.10, = 1.96 * 10). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56, = 6.35 * 10) but negatively with IA-2A (OR 0.59, = 6.55 * 10). QAD was negatively associated with GADA (OR 0.88; = 3.70 * 10) but positively with IA-2A (OR 1.64; = 2.40 * 10), despite a single difference at α44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AAs (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.
HLA-DQA1 和 -DQB1 与 1 型糖尿病（T1D）密切相关，DQ8.1 和 DQ2.5 是主要的风险单倍型。在瑞典新诊断的 1 至 18 岁患者（n=962）和对照受试者（n=636）中，使用 HLA-DQA1 和 -DQB1 的下一代靶向测序来构建缩写的 DQ 单倍型，将其转化为氨基酸（AA）残基，并评估它们与 T1D 的关联。层次组织的单倍型（HOH）关联分析允许将 45 个独特的 DQ 单倍型分为七个簇。DQ8/9 簇包括两个 DQ8.1 风险和 DQ9 抗性单倍型，而 DQ2 簇包括 DQ2.5 风险和 DQ2.2 抗性单倍型。在每个簇中，由于α44 与八个这样的残基完全连锁不平衡（LD），HOH 发现残基α44Q（优势比 [OR] 3.29， = 2.38 * 10）和β57A（OR 3.44， = 3.80 * 10）与 T1D 相关在代表所有十个残基（α22、α23、α44、α49、α51、α53、α54、α73、α184、β57）的 DQ8/9 簇中。在 DQ2 簇中，由于 LD，HOH 分析发现α44C 和β135D 共享 T1D 的风险（OR 2.10， = 1.96 * 10）。α44、β57 和β135 的“QAD”基序捕获了 DQ8.1 的 T1D 风险关联（OR 3.44， = 3.80 * 10），而相应的“CAD”基序捕获了 DQ2.5 的风险关联（OR 2.10， = 1.96 * 10）。两个风险关联与 GAD65 自身抗体（GADA）和 IA-2 自身抗体（IA-2A）有关，但方向相反。CAD 与 GADA 呈正相关（OR 1.56， = 6.35 * 10），但与 IA-2A 呈负相关（OR 0.59， = 6.55 * 10）。QAD 与 GADA 呈负相关（OR 0.88； = 3.70 * 10），但与 IA-2A 呈正相关（OR 1.64； = 2.40 * 10），尽管在α44 处存在单个差异。这些残基位于锚定口袋 1 和 9 内和周围，作为潜在的 T 细胞受体接触部位，在 CD4 结合和假定同源二聚体形成的区域。鉴定出三个 HLA-DQ AA（α44、β57、β135）赋予 T1D 风险，应使功能和转化研究更加精确。
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