Allele-specific methylation of type 1 diabetes susceptibility genes

被引：27
|
作者：
Kindt, Alida S. D. [1 ]
Fuerst, Rainer W. [2 ]
Knoop, Jan [2 ]
Laimighofer, Michael [1 ]
Telieps, Tanja [3 ]
Hippich, Markus [2 ]
Woerheide, Maria A. [1 ]
Wahl, Simone [4 ,5 ,6 ]
Wilson, Rory [4 ,5 ]
Sedlmeier, Eva-Maria [2 ]
Hommel, Angela [7 ]
Todd, John A. [8 ]
Krumsiek, Jan [1 ,6 ]
Ziegler, Anette-G. [2 ,9 ]
Bonifacio, Ezio [3 ,7 ,9 ]
机构：
[1] Helmholtz Zentrum Munchen, Inst Computat Biol, Neuherberg, Germany
[2] Helmholtz Zentrum Munchen, Inst Diabet Res, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany
[3] Helmholtz Zentrum Munchen, Inst Diabet & Obes, Neuherberg, Germany
[4] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany
[5] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany
[6] German Ctr Diabet Res DZD, Neuherberg, Germany
[7] Tech Univ, Fac Med Carl Gustav Carus, Ctr Regenerat Therapies Dresden, Dresden, Germany
[8] Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, JDRF Wellanne Trust Diabet & Inflammat Lab, Oxford, England
[9] Forschergrp Diabet eV, Neuherberg, Germany
来源：
JOURNAL OF AUTOIMMUNITY | 2018年 / 89卷
关键词：
Epigenetics; Autoimmunity; HLA; Insulin autoantibodies; Insulin gene; Lactate dehydrogenase C; ALPHA-BETA-HETERODIMER; HLA-DQ ALLELES; CLASS-II GENES; CELIAC-DISEASE; DNA METHYLATION; ISLET AUTOANTIBODIES; IMMUNE-RESPONSES; WIDE ASSOCIATION; GERMAN BABYDIAB; RISK;
D O I：
10.1016/j.jaut.2017.11.008
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
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.
引用
收藏
页码：63 / 74
页数：12
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