Epigenome-wide meta-analysis of DNA methylation and childhood asthma
Epigenome-wide meta-analysis of DNA methylation and childhood asthma
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DOI：
10.1016/j.jaci.2018.11.043
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发表时间：
2019-06-01
影响因子：
14.2
通讯作者：
London, Stephanie J.
中科院分区：
文献类型：
--
作者：
Reese, Sarah E.;Xu, Cheng-Jian;London, Stephanie J.
背景：表观遗传机制，包括甲基化，可能导致儿童哮喘。识别哮喘患者的 DNA 甲基化谱可以为疾病发病机制提供信息。 目的：我们试图确定新生儿和儿童中与儿童哮喘相关的差异性 DNA 甲基化。方法：在妊娠和儿童表观遗传学联盟中，我们对学龄期哮喘与血液中 CpG 甲基化 (Illumina450K) 的关系进行了表观基因组荟萃分析，这些甲基化在新生儿、前瞻性分析或学龄儿童中进行横断面测量。我们还确定了差异甲基化区域。结果：在新生儿（8 个队列，668 例）中，9 个 CpG（和 35 个区域）存在与哮喘发展相关的差异甲基化（表观基因组范围内的显着性，错误发现率 < 0.05）。在儿童哮喘和甲基化的横断面荟萃分析中（9 个队列，631 例），我们确定了 179 个 CpG（错误发现率 < 0.05）和 36 个差异甲基化区域。在其他组织中甲基化的复制研究中，尽管样本量较小，但血液中发现的 179 个 CpG 中的大多数在鼻呼吸道上皮或嗜酸性粒细胞的研究中得到了复制。通路分析强调了哮喘相关免疫过程的丰富以及新生儿和儿童中丰富的通路的重叠。基因表达与大多数位点的甲基化相关。功能注释支持对许多哮喘相关 CpG 基因表达的调节作用。几个相关基因是已批准或实验药物的靶标，包括 IL5RA 和 KCNH2。结论：新生儿中差异甲基化的新基因座代表了学龄期哮喘风险的潜在生物标志物。儿童的横断面关联可以反映疾病的风险和影响。儿童血液中与哮喘相关的差异甲基化在嗜酸性粒细胞和呼吸道上皮中大量复制。
Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.