Allele-specific methylation of type 1 diabetes susceptibility genes
Allele-specific methylation of type 1 diabetes susceptibility genes
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DOI：
10.1016/j.jaut.2017.11.008
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发表时间：
2018-05-01
影响因子：
12.8
通讯作者：
Bonifacio, Ezio
中科院分区：
文献类型：
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作者：
Kindt, Alida S. D.;Fuerst, Rainer W.;Bonifacio, Ezio
自身免疫性疾病的易感性受编码主要组织相容性复合体(MHC)蛋白的基因影响。通过检测脐带血样本的表观遗传甲基化图谱，我们发现1型糖尿病风险单倍型HLA-DRB1*03-DQA1*0501-DQB1*0201(DR3-DQ2)和HLA-DRB1*04-DQA1*0301-DQB1*0302(DR4-DQ8)携带者的MHC基因CpG位点甲基化状态(cis-metQTL)存在显著差异。这些差异在儿童和成人中发现，并伴随着Eila-DR3-DQ2单倍型免疫细胞中HIA-DR蛋白表达的减少。在本研究分析的所有45个免疫性和非免疫性1型糖尿病易感基因中都发现了广泛的顺式-MetQTL。我们观察并验证了LDHC基因内CpG位点的甲基化状态与儿童早期胰岛素自身抗体的发展之间的一种新的关联，这些儿童是1型糖尿病风险最高的基因携带者。易感基因功能相关的表观遗传学改变可能代表1型糖尿病的治疗靶点。(C)2017年作者。爱思唯尔有限公司出版。
The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HIA-DR protein expression in immune cells with the EILA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes. (C) 2017 The Authors. Published by Elsevier Ltd.