a Channing Division of Network Medicine, Department of Medicine , Brigham and Women's Hospital, Harvard Medical School , Boston , MA , USA.
b The Generation R Study Group, Erasmus MC , University Medical Center Rotterdam , Rotterdam , the Netherlands.
Epigenetics. 2019 May;14(5):445-466. doi: 10.1080/15592294.2019.1590085. Epub 2019 Mar 28.
Epigenetic mechanisms integrate both genetic variability and environmental exposures. However, comprehensive epigenome-wide analysis has not been performed across major childhood allergic phenotypes. We examined the association of epigenome-wide DNA methylation in mid-childhood peripheral blood (Illumina HumanMethyl450K) with mid-childhood atopic sensitization, environmental/inhalant and food allergen sensitization in 739 children in two birth cohorts (Project Viva-Boston, and the Generation R Study-Rotterdam). We performed covariate-adjusted epigenome-wide association meta-analysis and employed pathway and regional analyses of results. Seven-hundred and five methylation sites (505 genes) were significantly cross-sectionally associated with mid-childhood atopic sensitization, 1411 (905 genes) for environmental and 45 (36 genes) for food allergen sensitization (FDR<0.05). We observed differential methylation across multiple genes for all three phenotypes, including genes implicated previously in innate immunity (DICER1), eosinophilic esophagitis and sinusitis (SIGLEC8), the atopic march (AP5B1) and asthma (EPX, IL4, IL5RA, PRG2, SIGLEC8, CLU). In addition, most of the associated methylation marks for all three phenotypes occur in putative transcription factor binding motifs. Pathway analysis identified multiple methylation sites associated with atopic sensitization and environmental allergen sensitization located in/near genes involved in asthma, mTOR signaling, and inositol phosphate metabolism. We identified multiple differentially methylated regions associated with atopic sensitization (8 regions) and environmental allergen sensitization (26 regions). A number of nominally significant methylation sites in the cord blood analysis were epigenome-wide significant in the mid-childhood analysis, and we observed significant methylation - time interactions among a subset of sites examined. Our findings provide insights into epigenetic regulatory pathways as markers of childhood allergic sensitization.
表观遗传机制整合了遗传变异性和环境暴露。然而，尚未对主要儿童过敏表型进行全基因组范围的表观基因组分析。我们在两个出生队列（波士顿的 Project Viva 和鹿特丹的 Generation R 研究）的 739 名儿童中检查了儿童中期外周血（Illumina HumanMethyl450K）中全基因组范围的 DNA 甲基化与儿童中期特应性致敏、环境/吸入性和食物过敏原致敏之间的关联。我们进行了协变量调整的全基因组关联元分析，并对结果进行了途径和区域分析。705 个甲基化位点（505 个基因）与儿童中期特应性致敏显著相关，1411 个（905 个基因）与环境和 45 个（36 个基因）与食物过敏原致敏相关（FDR<0.05）。我们观察到所有三种表型的多个基因中存在差异甲基化，包括先前涉及固有免疫（DICER1）、嗜酸性食管炎和鼻窦炎（SIGLEC8）、特应性进展（AP5B1）和哮喘（EPX、IL4、IL5RA、PRG2、SIGLEC8、CLU）的基因。此外，所有三种表型的关联甲基化标记大多发生在假定的转录因子结合基序中。途径分析确定了与特应性致敏和环境过敏原致敏相关的多个甲基化位点，这些位点位于/附近参与哮喘、mTOR 信号和肌醇磷酸盐代谢的基因中。我们确定了与特应性致敏（8 个区域）和环境过敏原致敏（26 个区域）相关的多个差异甲基化区域。在脐带血分析中，一些名义上显著的甲基化位点在儿童中期分析中具有全基因组显著意义，并且我们观察到检查的一部分位点之间存在显著的甲基化-时间相互作用。我们的研究结果为儿童过敏致敏的表观遗传调控途径提供了见解。
