全基因组 DNA 甲基化关联研究表明，循环 IgE 水平与哮喘的发生存在关联，并鉴定出哮喘的新靶点。

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma.

机构信息

The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; The Framingham Heart Study, Framingham, MA 01702, USA.

Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA 02115, USA.

出版信息

EBioMedicine. 2023 Sep;95:104758. doi: 10.1016/j.ebiom.2023.104758. Epub 2023 Aug 18.

DOI:10.1016/j.ebiom.2023.104758

PMID:37598461

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10462855/

Abstract

BACKGROUND

Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.

METHODS

We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables.

FINDINGS

We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P < 7.94E-04) that can be explored as potential therapeutic targets.

INTERPRETATION

By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels.

FUNDING

US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.

摘要

背景

鉴定与血清免疫球蛋白 E（IgE）相关的新型表观遗传特征，可能有助于我们深入了解哮喘和 IgE 介导疾病的分子机制。

方法

我们对弗雷明汉心脏研究（FHS；n=3471，46%女性）参与者的全血进行了全基因组关联研究，并使用儿童哮喘管理计划（CAMP；n=674，39%女性）和哥斯达黎加哮喘遗传流行病学研究（CRA；n=787，41%女性）进行了验证。我们使用与每个 IgE 相关 CpG 最近的基因，突出了 IgE 调节的潜在生物学途径，并分析了与 IgE 相关 CpG 相关的转录模式（表达数量性状甲基化位点；eQTMs）。使用先前的英国生物库哮喘和过敏全基因组关联研究的汇总数据，我们使用来自 FHS 的与 IgE 相关的 CpG 作为工具变量，对孟德尔随机化（MR）进行因果推断测试。

结果

我们在 FHS 中发现了 490 个与 IgE 相关的统计学上显著差异甲基化 CpG，其中 193 个（39.3%）在 CAMP 和 CRA 中得到复制（FDR<0.05）。基因本体分析显示，与转录因子结合、哮喘和其他免疫过程相关的途径富集。eQTM 分析确定了 106 个表达基因的 124 个顺式-eQTM（FDR<0.05）。MR 结合药物靶标分析显示，CTSB 和 USP20 可能是 IgE 水平的因果调节因子（经 Bonferroni 校正的 P<7.94E-04），可作为潜在的治疗靶点进行探索。