Evidence That HLA Class I and II Associations With Type 1 Diabetes, Autoantibodies to GAD and Autoantibodies to IA-2, Are Distinct
Evidence That HLA Class I and II Associations With Type 1 Diabetes, Autoantibodies to GAD and Autoantibodies to IA-2, Are Distinct
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DOI：
10.2337/db11-0131
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发表时间：
2011-10-01
期刊：
影响因子：
7.7
通讯作者：
Todd, John A.
中科院分区：
文献类型：
--
作者：
Howson, Joanna M. M.;Stevens, Helen;Todd, John A.
1型糖尿病的一个主要特征是在诊断前出现胰岛自身抗体。然而，尽管1型糖尿病的遗传学研究取得了进展，但胰岛自身抗体的遗传学还需要进一步研究。1型糖尿病的主要易感基因位点，即HLA I类和II类基因，被认为决定了对胰岛抗原的自身免疫应答的特异性和程度。我们研究了谷氨酸脱羧酶自身抗体（GADA）和胰岛素瘤相关抗原-2自身抗体（IA-2A）与HLA区域的相关性。在2,531名儿童期发病病例受试者中分析了HLA-DRB 1、HLA-DQB 1、HLA-B、HLA-C、HLA-A、云母和3,779个单核苷酸多态性（SNP）（自诊断以来的中位时间为5年）。所有的分析都校正了诊断时的年龄和糖尿病的持续时间，GADA和IA-2A与诊断时的年龄相关（P < 10（-19））。对于GADA，主要与HLA-DQB 1相关（P = 9.00 × 10（-18）），有证据表明HLA I类区域的SNP rs 9266722（P = 2.84 × 10（-6））具有第二个独立效应。HLA-DRB 1与IA-2A的相关性最强（P = 1.94 × 10 - 41），HLA-A*24增加了这种相关性，尽管是负相关的（P = 1.21 × 10- 19）。没有证据表明1A-2A或GADA与高度1型糖尿病易感基因型HLA-DRB 1 *03/04相关。结论尽管1型糖尿病与胰岛自身抗体定位于相同的HLA-DRB 1和HLA-DQB 1的遗传相关性，但II类等位基因和基因型的影响是完全不同的。因此，自身抗体的存在不太可能是因果关系，其在发病机制中的作用仍有待确定。糖尿病60：2635-2644，2011
OBJECTIVE-A major feature of type 1 diabetes is the appearance of islet autoantibodies before diagnosis. However, although the genetics of type 1 diabetes is advanced, the genetics of islet autoantibodies needs further investigation. The primary susceptibility loci in type 1 diabetes, the HLA class I and II genes, are believed to determine the specificity and magnitude of the autoimmune response to islet antigens. We investigated the association of glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen-2 autoantibodies (IA-2A) with the HLA region.RESEARCH DESIGN AND METHODS-Associations of GADA and IA-2A with. HLA-DRB1, HLA-DQB1, HLA-B, HLA-C, HLA-A, MICA, and 3,779 single nucleotide polymorphisms (SNPs) were analyzed in 2,531 childhood-onset case subjects (median time since diagnosis 5 years). All analyses were adjusted for age-at-diagnosis and duration of diabetes.RESULTS-GADA and IA-2A were associated with an older age-at-diagnosis (P < 10(-19)). For GADA, the primary association was with HLA-DQB1 (P = 9.00 X 10(-18)), with evidence of a second independent effect in the HLA class I region with SNP, rs9266722 (P = 2.84 x 10(-6)). HLA-DRB1 had the strongest association with IA-2A (P = 1.94 X 10(-41)), with HLA-A*24 adding to the association, albeit negatively (P = 1.21 X 10-(19)). There was no evidence of association of either 1A-2A or GADA with the highly type 1 diabetes predisposing genotype, HLA-DRB1*03/04.CONCLUSIONS-Despite genetic association of type 1 diabetes and the islet autoantibodies localizing to the same HLA class II genes, HLA-DRB1 and HLA-DQB1, the effects of the class II alleles and genotypes involved are quite different. Therefore, the presence of autoantibodies is unlikely to be causal, and their role in pathogenesis remains to be established. Diabetes 60:2635-2644, 2011