OBJECTIVE To explore associations of HLA class II genes (HLAII) with the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Next-generation targeted sequencing was used to genotype eight HLAII genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1) in 1,216 participants from the Diabetes Prevention Trial-1 and Randomized Diabetes Prevention Trial with Oral Insulin sponsored by TrialNet. By the linkage disequilibrium, DQA1 and DQB1 are haplotyped to form DQ haplotypes; DP and DR haplotypes are similarly constructed. Together with available clinical covariables, we applied the Cox regression model to assess HLAII immunogenic associations with the disease progression. RESULTS 1) The current investigation updated the previously reported genetic associations of DQA1*03:01-DQB1*03:02 (hazard ratio [HR] = 1.25, P = 3.50*10−3) and DQA1*03:03-DQB1*03:01 (HR = 0.56, P = 1.16*10−3), and also uncovered a risk association with DQA1*05:01-DQB1*02:01 (HR = 1.19, P = 0.041). 2) After adjusting for DQ, DPA1*02:01-DPB1*11:01 and DPA1*01:03-DPB1*03:01 were found to have opposite associations with progression (HR = 1.98 and 0.70, P = 0.021 and 6.16*10−3, respectively). 3) DRB1*03:01-DRB3*01:01 and DRB1*03:01-DRB3*02:02, sharing the DRB1*03:01, had opposite associations (HR = 0.73 and 1.44, P = 0.04 and 0.019, respectively), indicating a role of DRB3. Meanwhile, DRB1*12:01-DRB3*02:02 and DRB1*01:03 alone were found to associate with progression (HR = 2.6 and 2.32, P = 0.018 and 0.039, respectively). 4) Through enumerating all heterodimers, it was found that both DQ and DP could exhibit associations with disease progression. CONCLUSIONS These results suggest that HLAII polymorphisms influence progression from islet autoimmunity to T1D among at-risk subjects with islet autoantibodies.

中文翻译：

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HLA II 类（DR、DQ、DP）基因分别与两项糖尿病预防试验（DPT-1 和 TN07）参与者中从血清转化到 1 型糖尿病发病的进展相关

目的 探讨 HLA II 类基因 (HLAII) 与胰岛自身免疫从无症状进展为有症状 1 型糖尿病 (T1D) 的关系。研究设计和方法 使用下一代靶向测序对来自糖尿病预防试验 1 和口服糖尿病随机预防试验的 1,216 名参与者的 8 个 HLAII 基因（DQA1、DQB1、DRB1、DRB3、DRB4、DRB5、DPA1、DPB1）进行基因分型胰岛素由 TrialNet 赞助。通过连锁不平衡，DQA1和DQB1被单倍型化，形成DQ单倍型； DP 和 DR 单倍型的构建类似。结合可用的临床协变量，我们应用 Cox 回归模型来评估 HLAII 免疫原性与疾病进展的关联。结果 1) 当前的研究更新了之前报道的 DQA1*03:01-DQB1*03:02（风险比 [HR] = 1.25，P = 3.50*10−3）和 DQA1*03:03-DQB1* 的遗传关联03:01（HR = 0.56，P = 1.16*10−3），并且还发现了与 DQA1*05:01-DQB1*02:01（HR = 1.19，P = 0.041）的风险关联。 2) 调整 DQ 后，发现 DPA1*02:01-DPB1*11:01 和 DPA1*01:03-DPB1*03:01 与进展具有相反的相关性（HR = 1.98 和 0.70，P = 0.021 和 6.16） *10−3，分别）。 3) DRB1*03:01-DRB3*01:01 和 DRB1*03:01-DRB3*02:02 共享 DRB1*03:01，具有相反的关联（HR = 0.73 和 1.44，P = 0.04 和 0.019，分别），表明 DRB3 的作用。同时，发现 DRB1*12:01-DRB3*02:02 和 DRB1*01:03 单独与进展相关（HR = 2.6 和 2.32，P = 0.018 和 0.039，分别）。 4)通过列举所有异源二聚体，发现DQ和DP均与疾病进展相关。结论 这些结果表明，HLAII 多态性影响具有胰岛自身抗体的高危受试者从胰岛自身免疫到 T1D 的进展。