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　　原标题：儿童哮喘的DNA 甲基化：一个表观基因组荟萃分析
　　与儿童哮喘有关的DNA甲基化特征可能为疾病发病机制提供新的见解。我们做了一个表观遗传关联研究来评估甲基化与儿童哮喘的关系。
　　我们在过敏发生机理研究(MeDALL)项目中进行了一项大规模的表观基因组关联研究(EWAS)。
　　我们使用Illumina Infinium人类甲基化450 BeadChips (450K)在全血中检测了207名哮喘患儿和610名4-5岁对照组，以及185名哮喘患儿和546名8岁对照组，采用横断面病例对照设计。在发现分析中鉴定出差异甲基化的CpG位点后，我们在另外6个来自欧洲同期组群儿童(4-16岁; 247例病例和2949例对照)中进行了验证，并对结果进行meta分析。我们接着研究了在脐带血中复制的CpG位点是否能预测1316名儿童日后的哮喘。随后我们研究了嗜酸性粒细胞和呼吸道上皮细胞中CpG位点的细胞特异性甲基化及其相关基因表达特征。我们在通过鼻腔灌洗收集的455例16岁儿童呼吸道上皮样本和在从（16例哮喘，8例对照，年龄2-56岁）血液嗜酸性细胞分离的DNA中研究了被复制的CpG位点与哮喘相关的细胞型的特异性，并与74例哮喘个体和93例对照（1-79岁）的全血DNA样本进行比较。 与复制的CpG位点相关的全血转录情况用通过荧光激活细胞分选术分类的外周血单核细胞子集的RNA-seq数据进行注释。
　　在发现分析中鉴定了27个甲基化的CpG位点。其中的14个CpG位点被复制，经meta-分选后通过全基因组意义(p < 1.14×10 - 7)。在4岁至16岁哮喘患儿中均观察到一致性的低甲基化水平的所有相关位点，但在脐带血中未观察到，在第二次全血DNA复制研究中，发现所有14个CpG位点均与哮喘显著相关。并且与纯化的嗜酸性粒细胞密切相关。与这些CpG位点相关的全血转录特征提示嗜酸性粒细胞、效应和记忆CD8 T细胞和自然杀伤细胞数量的增加和幼稚T细胞数量的下降。14个CpG位点中有5个在呼吸道上皮上与哮喘有关，提示跨组织表观遗传效应。
　　出生后14个CpG位点的全血甲基化降低与儿童哮喘密切相关。这些CpG位点及其相关的转录谱显示了嗜酸性粒细胞和细胞毒性T细胞在儿童哮喘中的激活。我们的发现值得进一步研究表观遗传学在临床环境中的作用
　　延伸阅读


Respiratory
DNA methylation in childhood asthma: an epigenome-wide meta-analysis
DOI: 10.1016/52213-2600（18）30052-3
Abstract:
Background
DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma.
Methods
We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4–5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4–16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated celltype-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2–56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1–79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting.
Findings
27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p＜1.14×10-7）after meta-analysis. consistently low methylation level were observed at all associated loci across childhood from age 4 to 16 years in participant with asthma ,but not in cord blood at birth , All14 CpG site were significantly associated with asthma in the second replication study using whole blood DNA. and were strongly associated with purified eosinophils. Whole- blood d transcriptional signatures associated with these CpG sites indicated increased eosinophils，effector and Memory CD8 T cells and natural killer cell ,and reduced  number of naïve T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelials, indicating cross-tissue epigenetic effects.
Interpretation  
reduced whole-blood methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma . these CpG sites and their associated transcriptional profile indicated activation of eosinophils and cytotoxic Tcell in childhood asthma. our findings merit further investigations of the role of epigenetics in a clinic context.
First Author:
Correspondence:
All Authors:
Cheng-Jian Xu, Cilla Söderhäll, Mariona Bustamante, Nour Baïz, Olena Gruzieva, Ulrike Gehring, Dan Mason, Leda Chatzi, Mikel Basterrechea, Sabrina Llop, Maties Torrent, Francesco Forastiere, Maria Pia Fantini, Karin C Lødrup Carlsen, Tari Haahtela, Andréanne Morin, Marjan Kerkhof, Simon Kebede Merid, Bianca van Rijkom, Soesma A Jankipersadsing, Marc Jan Bonder, Stephane Ballereau, Cornelis J Vermeulen, Raul Aguirre-Gamboa, Johan C de Jongste, Henriette A Smit, Ashish Kumar, Göran Pershagen, Stefano Guerra, Judith Garcia-Aymerich, Dario Greco, Lovisa Reinius, Rosemary R C McEachan, Raf Azad, Vegard Hovland, Petter Mowinckel, Harri Alenius, Nanna Fyhrquist, Nathanaël Lemonnier, Johann Pellet, Charles Auffray, the BIOS Consortium, Pieter van der Vlies, Cleo C van Diemen, Yang Li, Cisca Wijmenga, Mihai G Netea, Miriam F Moffatt, William O C M Cookson, Josep M Anto, Jean Bousquet, Tiina Laatikainen, Catherine Laprise, Kai-Håkon Carlsen, Davide Gori, Daniela Porta, Carmen Iñiguez, Jose Ramon Bilbao, Manolis Kogevinas, John Wright, Bert Brunekreef, Juha Kere, Martijn C Nawijn, Isabella Annesi-Maesano, Jordi Sunyer, Erik Melén*, Gerard H Koppelman*
　　创建过敏性疾病的科研、科普知识交流平台，为过敏患者提供专业诊断、治疗、预防的共享平台。