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.
EBioMedicine. 2023 Sep;95:104758. doi: 10.1016/j.ebiom.2023.104758. Epub 2023 Aug 18.
Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.
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.
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.
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.
US NIH/NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.
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。
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。
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。
通过在一般和临床哮喘人群中整合 eQTM 和 MR 分析，我们的研究结果提供了对 DNA 甲基化、基因表达和 IgE 水平多维相互关系的更深入理解。
美国 NIH/NHLBI 拨款：P01HL132825、K99HL159234、N01-HC-25195 和 HHSN268201500001I。
