全基因组表观遗传分析 DNA 甲基化与儿童哮喘的关系
Epigenome-wide meta-analysis of DNA methylation and childhood asthma.
机构信息
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
出版信息
J Allergy Clin Immunol. 2019 Jun;143(6):2062-2074. doi: 10.1016/j.jaci.2018.11.043. Epub 2018 Dec 21.
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.
背景
表观遗传机制，包括甲基化，可能导致儿童哮喘。鉴定哮喘患者的 DNA 甲基化谱可以为疾病发病机制提供信息。
目的
我们旨在确定与儿童哮喘相关的新生儿和儿童中差异 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新生儿（前瞻性分析）或学龄儿童横断面血液中 CpG 甲基化（Illumina450K）之间的关系进行了全基因组元分析。我们还鉴定了差异甲基化区域。
结果
在新生儿（8 个队列，668 例）中，有 9 个 CpG（和 35 个区域）与哮喘发展相关（全基因组意义，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），我们鉴定出 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，但在鼻呼吸道上皮或嗜酸性粒细胞中，发现的 179 个 CpG 中的大多数都得到了复制。通路分析突出了与哮喘相关的免疫过程的富集，并且在新生儿和儿童中都富集了相同的通路。基因表达与大多数基因座的甲基化相关。功能注释支持在许多与哮喘相关的 CpG 上对基因表达具有调节作用。一些涉及的基因是已批准或实验性药物的靶点，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得到了充分复制。
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