DNA甲基化和儿童哮喘的表观基因组Meta分析
2019/01/09
摘要
背景：表观遗传机制，包括甲基化，可能导致儿童哮喘。鉴定哮喘中的DNA甲基化谱可能为疾病发病机制提供信息。
目的：鉴定新生儿和儿童相关儿童哮喘的DNA甲基化差异。
方法：在妊娠和儿童表观遗传学（PACE）联盟中，我们对学龄期哮喘进行了表观基因组荟萃分析，前瞻性分析新生儿、横断面分析学龄期儿童血液中CpG甲基化（Illumina450K）情况。我们还鉴定了差异甲基化区域（DMR）。
结果：在新生儿（8个队列，668个病例）中，有9个CpG（和35个区域）与哮喘发展存在甲基化差异（表观基因组显著性，FDR <0.05）。在儿童（9个队列，631例）哮喘和甲基化的横断面荟萃分析中，我们确定了179个CpG（FDR <0.05）和36个差异甲基化区域。其他组织中类似的甲基化研究中，血液中发现的179个CpGs大多数可在在鼻腔呼吸道上皮细胞或嗜酸性粒细胞的研究中得到证实，尽管样本量较小。通路分析强调了哮喘相关免疫途径的富集以及新生儿和儿童中富集途径存在重叠。基因表达与大多数基因座的甲基化相关。功能注释也表明许多哮喘相关CpG在基因表达调控中发挥影响。几个涉及的基因是批准的或实验性药物的靶标，包括IL5RA和KCNH2。
结论：新基因座在新生儿中差异甲基化是学龄期发生哮喘风险的潜在生物标志物。儿童中横断面关联可能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基本上与在嗜酸性粒细胞和呼吸道上皮细胞中一致。
Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma.
Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, et al.
Abstract
BACKGROUND:Epigenetic mechanisms, including methylation, may contribute to childhood asthma. Identifying DNA methylation profiles in asthma may inform disease pathogenesis.
OBJECTIVE:To identify differential DNA methylation in newborns and children related to childhood asthma.
METHODS:Within the Pregnancy And Childhood Epigenetics (PACE) 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-age children. We also identified differentially methylated regions (DMRs).
RESULTS:In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<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 regulatory impact on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.
CONCLUSIONS:Novel loci differentially methylated in newborns represent potential biomarkers of risk of developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children 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。鉴定哮喘中的DNA甲基化谱可能为疾病发病机制提供信息。
目的：鉴定新生儿和儿童相关儿童哮喘的DNA甲基化差异。
方法：在妊娠和儿童表观遗传学（PACE）联盟中，我们对学龄期哮喘进行了表观基因组荟萃分析，前瞻性分析新生儿、横断面分析学龄期儿童血液中CpG甲基化（Illumina450K）情况。我们还鉴定了差异甲基化区域（DMR）。
结果：在新生儿（8个队列，668个病例）中，有9个CpG（和35个区域）与哮喘发展存在甲基化差异（表观基因组显著性，FDR <0.05）。在儿童（9个队列，631例）哮喘和甲基化的横断面荟萃分析中，我们确定了179个CpG（FDR <0.05）和36个差异甲基化区域。其他组织中类似的甲基化研究中，血液中发现的179个CpGs大多数可在在鼻腔呼吸道上皮细胞或嗜酸性粒细胞的研究中得到证实，尽管样本量较小。通路分析强调了哮喘相关免疫途径的富集以及新生儿和儿童中富集途径存在重叠。基因表达与大多数基因座的甲基化相关。功能注释也表明许多哮喘相关CpG在基因表达调控中发挥影响。几个涉及的基因是批准的或实验性药物的靶标，包括IL5RA和KCNH2。
结论：新基因座在新生儿中差异甲基化是学龄期发生哮喘风险的潜在生物标志物。儿童中横断面关联可能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基本上与在嗜酸性粒细胞和呼吸道上皮细胞中一致。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2018 Dec 20. pii: S0091-6749(18)32788-X.)
(J Allergy Clin Immunol. 2018 Dec 20. pii: S0091-6749(18)32788-X.)
Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma.
Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, et al.
Abstract
BACKGROUND:Epigenetic mechanisms, including methylation, may contribute to childhood asthma. Identifying DNA methylation profiles in asthma may inform disease pathogenesis.
OBJECTIVE:To identify differential DNA methylation in newborns and children related to childhood asthma.
METHODS:Within the Pregnancy And Childhood Epigenetics (PACE) 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-age children. We also identified differentially methylated regions (DMRs).
RESULTS:In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, FDR<0.05) in relation to asthma development. In cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (FDR<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 regulatory impact on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.
CONCLUSIONS:Novel loci differentially methylated in newborns represent potential biomarkers of risk of developing asthma by school age. Cross-sectional associations in children may reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children substantially replicated in eosinophils and respiratory epithelium.
