新发胰岛素依赖型糖尿病患者及其亲属中GAD65和IA-2自身抗体与遗传风险标志物的关联。比利时糖尿病登记处。

Associations of GAD65- and IA-2- autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. The Belgian Diabetes Registry.

作者信息

Vandewalle C L, Falorni A, Lernmark A, Goubert P, Dorchy H, Coucke W, Semakula C, Van der Auwera B, Kaufman L, Schuit F C, Pipeleers D G, Gorus F K

机构信息

Diabetes Research Center, Vrije Universiteit Brussel, Belgium.

出版信息

Diabetes Care. 1997 Oct;20(10):1547-52. doi: 10.2337/diacare.20.10.1547.

DOI:10.2337/diacare.20.10.1547

PMID:9314633

Abstract

OBJECTIVE

To investigate the association of GAD (65-kDa) autoantibodies (GAD65-Abs) and IA-2 autoantibodies (IA-2-Abs) with human leukocyte antigen (HLA)-DQ and insulin gene (INS) risk markers in patients with recent-onset IDDM and their siblings.

RESEARCH DESIGN AND METHODS

Blood was sampled from 608 recent-onset IDDM patients and 480 siblings, aged 0-39 years and consecutively recruited by the Belgian Diabetes Registry, to determine GAD65- and IA-2-Ab (radiobinding assay), HLA-DQ- (allele-specific oligonucleotyping), and INS-genotypes (restriction fragment length polymorphism analysis; siblings, n = 439).

RESULTS

At the onset of IDDM, GAD65-Abs were preferentially associated with two populations at genetic risk but only in the 20- to 39-year age-group: 1) their prevalence was higher in carriers of DQA10301-DQB10302 (88 vs. 73% in non[DQA10301-DQB10302], P = 0.001), and 2) an association was found in patients lacking this haplotype but carrying DQA10501-DQB10201, together with INS I/I (87 vs. 54% vs. non[INS I/I], P = 0.003). Siblings of IDDM patients also presented the association of GAD65-Abs with DQA10301-DQB10302 (13 vs. 2% non[DQA10301-DQB10302], P < 0.001), while associations with the second genetic risk group could not yet be assessed. At the onset of IDDM, IA-2-Ab prevalence was higher in carriers of DQA10301-DQB10302 (69 vs. 39% non[DQA10301-DQB10302], P < 0.001) but not of DQA10501-DQB10201 or INS I/I. This association was present in both the 0- to 19- and the 20- to 39-year age-groups. It was also found in siblings of IDDM patients (4 vs. 0% non[DQA10301-DQB10302], P < 0.001).

CONCLUSIONS

Both GAD65- and IA-2-Abs exhibit higher prevalences in presence of HLA-DQ- and/or INS-genetic risk markers. Their respective associations differ with age at clinical onset, suggesting a possible usefulness in the identification of subgroups in this heterogeneous disease.

摘要

目的

研究谷氨酸脱羧酶（65kDa）自身抗体（GAD65-Abs）和胰岛抗原-2自身抗体（IA-2-Abs）与近期发病的1型糖尿病患者及其同胞的人类白细胞抗原（HLA）-DQ和胰岛素基因（INS）风险标志物之间的关联。

研究设计与方法

从比利时糖尿病登记处连续招募的608例0至39岁近期发病的1型糖尿病患者和480例同胞中采集血液，以测定GAD65-Ab和IA-2-Ab（放射结合测定法）、HLA-DQ（等位基因特异性寡核苷酸分型法）以及INS基因型（限制性片段长度多态性分析；同胞，n = 439）。

结果

在1型糖尿病发病时，GAD65-Abs优先与两个具有遗传风险的人群相关，但仅在20至39岁年龄组中：1）DQA10301-DQB10302携带者中其患病率较高（88%对非[DQA10301-DQB10302]者中的73%，P = 0.001）；2）在缺乏该单倍型但携带DQA10501-DQB10201以及INS I/I的患者中发现了关联（87%对非[INS I/I]者中的54%，P = 0.003）。1型糖尿病患者的同胞中也呈现出GAD65-Abs与DQA10301-DQB10302的关联（13%对非[DQA10301-DQB10302]者中的2%，P < 0.001），而与第二个遗传风险组的关联尚未能评估。在1型糖尿病发病时，DQA10301-DQB10302携带者中IA-2-Ab患病率较高（69%对非[DQA10301-DQB10302]者中的39%，P < 0.001），但与DQA10501-DQB10201或INS I/I无关。这种关联在0至19岁和20至39岁年龄组中均存在。在1型糖尿病患者的同胞中也发现了这种关联（4%对非[DQA10301-DQB10302]者中的0%，P < 0.001）。