原標題：兒童哮喘的DNA 甲基化：一個表觀基因組薈萃分析
　　與兒童哮喘有關的DNA甲基化特征可能為疾病發(fā)病機制提供新的見解。我們做了一個表觀遺傳關聯研究來評估甲基化與兒童哮喘的關系。
　　我們在過敏發(fā)生機理研究(MeDALL)項目中進行了一項大規(guī)模的表觀基因組關聯研究(EWAS)。
　　我們使用Illumina Infinium人類甲基化450 BeadChips (450K)在全血中檢測了207名哮喘患兒和610名4-5歲對照組，以及185名哮喘患兒和546名8歲對照組，采用橫斷面病例對照設計。在發(fā)現分析中鑒定出差異甲基化的CpG位點后，我們在另外6個來自歐洲同期組群兒童(4-16歲; 247例病例和2949例對照)中進行了驗證，并對結果進行meta分析。我們接著研究了在臍帶血中復制的CpG位點是否能預測1316名兒童日后的哮喘。隨后我們研究了嗜酸性粒細胞和呼吸道上皮細胞中CpG位點的細胞特異性甲基化及其相關基因表達特征。我們在通過鼻腔灌洗收集的455例16歲兒童呼吸道上皮樣本和在從（16例哮喘，8例對照，年齡2-56歲）血液嗜酸性細胞分離的DNA中研究了被復制的CpG位點與哮喘相關的細胞型的特異性，并與74例哮喘個體和93例對照（1-79歲）的全血DNA樣本進行比較。 與復制的CpG位點相關的全血轉錄情況用通過熒光激活細胞分選術分類的外周血單核細胞子集的RNA-seq數據進行注釋。
　　在發(fā)現分析中鑒定了27個甲基化的CpG位點。其中的14個CpG位點被復制，經meta-分選后通過全基因組意義(p < 1.14×10 - 7)。在4歲至16歲哮喘患兒中均觀察到一致性的低甲基化水平的所有相關位點，但在臍帶血中未觀察到，在第二次全血DNA復制研究中，發(fā)現所有14個CpG位點均與哮喘顯著相關。并且與純化的嗜酸性粒細胞密切相關。與這些CpG位點相關的全血轉錄特征提示嗜酸性粒細胞、效應和記憶CD8 T細胞和自然殺傷細胞數量的增加和幼稚T細胞數量的下降。14個CpG位點中有5個在呼吸道上皮上與哮喘有關，提示跨組織表觀遺傳效應。
　　出生后14個CpG位點的全血甲基化降低與兒童哮喘密切相關。這些CpG位點及其相關的轉錄譜顯示了嗜酸性粒細胞和細胞毒性T細胞在兒童哮喘中的激活。我們的發(fā)現值得進一步研究表觀遺傳學在臨床環(huán)境中的作用
　　延伸閱讀


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 na?ve 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 S?derh?ll, Mariona Bustamante, Nour Ba?z, Olena Gruzieva, Ulrike Gehring, Dan Mason, Leda Chatzi, Mikel Basterrechea, Sabrina Llop, Maties Torrent, Francesco Forastiere, Maria Pia Fantini, Karin C L?drup 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, G?ran Pershagen, Stefano Guerra, Judith Garcia-Aymerich, Dario Greco, Lovisa Reinius, Rosemary R C McEachan, Raf Azad, Vegard Hovland, Petter Mowinckel, Harri Alenius, Nanna Fyhrquist, Nathana?l 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-H?kon Carlsen, Davide Gori, Daniela Porta, Carmen I?iguez, Jose Ramon Bilbao, Manolis Kogevinas, John Wright, Bert Brunekreef, Juha Kere, Martijn C Nawijn, Isabella Annesi-Maesano, Jordi Sunyer, Erik Melén*, Gerard H Koppelman*
　　創(chuàng)建過敏性疾病的科研、科普知識交流平臺，為過敏患者提供專業(yè)診斷、治療、預防的共享平臺。