Accelerated Progression to Type 1 Diabetes in the Presence of HLA-A*24 and -B*18 Is Restricted to Multiple Islet Autoantibody–Positive Individuals With Distinct HLA-DQ and Autoantibody Risk Profiles,Diabetes Care

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Accelerated Progression to Type 1 Diabetes in the Presence of HLA-A*24 and -B*18 Is Restricted to Multiple Islet Autoantibody–Positive Individuals With Distinct HLA-DQ and Autoantibody Risk Profiles
Diabetes Care ( IF 16.2 ) Pub Date : 2018-05-01 , DOI: 10.2337/dc17-2462
Else M. Balke ₁ , Eric V. Balti _{1,

2} , Bart Van der Auwera ₁ , Ilse Weets _{1,

2} , Olivier Costa _{1,

2} , Simke Demeester _{1,

2} , Pascale Abrams _{1,

3} , Kristina Casteels _{1,

4} , Marina Coeckelberghs _{1,

5} , Sylvie Tenoutasse _{1,

6} , Bart Keymeulen _{1,

7} , Daniel G. Pipeleers ₁ , Frans K. Gorus _{1,

2} ,

Affiliation

OBJECTIVE We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS A registry-based group of siblings/offspring (aged 0–39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A*24, -B*18, and -B*39 status. Genetic markers were determined by PCR sequence-specific oligotyping.

RESULTS Unlike HLA-B*18 or -B*39, HLA-A*24 was associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurred independently from older age (P < 0.001) and absence of HLA-DQ2/DQ8 or -DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A*24 was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects were restricted to HLA-DQ8⁺ relatives with IA-2 or zinc transporter 8 autoantibodies (P = 0.002). HLA-B*18, but not -B*39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004).

CONCLUSIONS HLA-A*24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A*24 and -B*18 are associated with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.

中文翻译：

在HLA-A * 24和-B * 18存在的情况下向1型糖尿病的加速进展仅限于具有不同HLA-DQ和自身抗体风险特征的多岛型自身抗体阳性个体

目的我们研究了HLA I类风险等位基因对1型糖尿病患者一级亲属亚临床胰岛自身免疫各个阶段疾病进展的影响。

研究设计和方法从单抗体抗体阳性到多抗体抗体阳性（n = 267），从多抗体抗体阳性到临床发作（n = 252），对一个基于注册表的兄弟姐妹/后代组（年龄为0-39岁）进行了监测。到HLA-DQ，-A * 24，-B * 18和-B * 39状态。通过PCR序列特异性寡聚确定遗传标记。

结果与HLA-B * 18或-B * 39不同，HLA-A * 24与单抗体阳性向多抗体阳性的进展延迟有关（P = 0.009），但与1型糖尿病无关。这种情况独立于老年（P <0.001）和HLA-DQ2 / DQ8或-DQ8的缺失（分别为P <0.001和P = 0.003），并且仅在GAD自身抗体存在的情况下发生。相比之下，HLA-A * 24与多抗体阳性到临床发作的加速进展相关（P = 0.006），但其作用仅限于HLA-DQ8 ⁺携带IA-2或锌转运蛋白8个自身抗体的亲戚（P = 0.002）。HLA-B * 18（而非-B * 39）也与更快的进展相关，但仅在对GAD和胰岛素自身抗体具有双重阳性的HLA-DQ2携带者中（P = 0.004）。