哮喘的表观遗传特征:DNA 甲基化和临床标记的综合研究。

IF 4.8 2区 医学 Q1 GENETICS & HEREDITY
Austin J Van Asselt, Jeffrey J Beck, Casey T Finnicum, Brandon N Johnson, Noah Kallsen, Sarah Viet, Patricia Huizenga, Lannie Ligthart, Jouke-Jan Hottenga, René Pool, Anke H Maitland-van der Zee, S J Vijverberg, Eco de Geus, Dorret I Boomsma, Erik A Ehli, Jenny van Dongen
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引用次数: 0

摘要

背景:哮喘是一种复杂的呼吸系统疾病,表现为肺部、血液和其他组织的炎症症状。我们研究了 DNA 甲基化与 35 种哮喘临床指标之间的关系:方法:使用 Illumina Infinium EPIC v1 甲基化阵列评估了来自 94 个家庭的 319 名参与者全血中的 742,442 个 CpGs。他们是荷兰双胞胎登记册的一部分,来自至少有一名成员患有严重哮喘的家庭。182 人在 10 年后重复采集了血液样本。对临床哮喘标志物进行主成分分析后得出了十个主成分,解释了总方差的 92.8%。我们对十个主成分中的每一个进行了表观全基因组关联研究(EWAS),并对家族结构和其他协变量进行了校正。结果发现:经过 Bonferroni 校正后,221 个独特的 CpGs 在时间点 1 达到了全基因组显著性。PC7 与嗜酸性粒细胞计数和免疫球蛋白水平的负荷相关,占关联的绝大部分(204 个)。通过 EWAS Atlas 进行的富集分析发现,这些 CpGs 中有 190 个曾在哮喘和哮喘相关性状的 EWAS 中被鉴定过。与先前确定的与哮喘相关的 SNPs 的邻近性评估发现,在 221 个 CpGs 中,有 17 个独特的 SNPs 位于两个 CpGs 的 1 MB 范围内。在第二个时间点对 182 个具有表观遗传学数据的个体进行的 EWAS 发现了 49 个重要的 CpGs。EWAS 图集富集分析表明,这 49 个基因中有 4 个以前与哮喘或哮喘相关性状有关。比较两个时间点发现的所有重要关联的估计值,得出的相关性为 0.81:我们发现了 270 个独特的 CpGs,这些 CpGs 与 35 个哮喘临床标记物产生的 PC 评分(无论是横截面还是 10 年后)相关。两个时间点的效应大小之间存在很强的相关性。大多数关联是在 PC7 中发现的,PC7 反映了血液中嗜酸性粒细胞计数和免疫球蛋白水平,其中许多 CpGs 以前在哮喘和哮喘相关特征的早期研究中就有关联。研究结果表明,稳健的 DNA 甲基化特征是哮喘的一种新的、稳定的生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Epigenetic signatures of asthma: a comprehensive study of DNA methylation and clinical markers.

Background: Asthma, a complex respiratory disease, presents with inflammatory symptoms in the lungs, blood, and other tissues. We investigated the relationship between DNA methylation and 35 clinical markers of asthma.

Methods: The Illumina Infinium EPIC v1 methylation array was used to evaluate 742,442 CpGs in whole blood from 319 participants from 94 families. They were part of the Netherlands Twin Register from families with at least one member suffering from severe asthma. Repeat blood samples were taken after 10 years from 182 individuals. Principal component analysis on the clinical asthma markers yielded ten principal components (PCs) that explained 92.8% of the total variance. We performed epigenome-wide association studies (EWAS) for each of the ten PCs correcting for familial structure and other covariates.

Results: 221 unique CpGs reached genome-wide significance at timepoint 1 after Bonferroni correction. PC7, which correlated with loadings of eosinophil counts and immunoglobulin levels, accounted for the majority of associations (204). Enrichment analysis via the EWAS Atlas identified 190 of these CpGs to be previously identified in EWASs of asthma and asthma-related traits. Proximity assessment to previously identified SNPs associated with asthma identified 17 unique SNPs within 1 MB of two of the 221 CpGs. EWAS in 182 individuals with epigenetic data at a second timepoint identified 49 significant CpGs. EWAS Atlas enrichment analysis indicated that 4 of the 49 were previously associated with asthma or asthma-related traits. Comparing the estimates of all the significant associations identified across the two time points yielded a correlation of 0.81.

Conclusion: We identified 270 unique CpGs that were associated with PC scores generated from 35 clinical markers of asthma, either cross-sectionally or 10 years later. A strong correlation was present between effect sizes at the 2 timepoints. Most associations were identified for PC7, which captured blood eosinophil counts and immunoglobulin levels and many of these CpGs have previous associations in earlier studies of asthma and asthma-related traits. The results point to a robust DNA methylation profile as a new, stable biomarker for asthma.

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来源期刊
自引率
5.30%
发文量
150
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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