Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study (TWAS) to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study (FHS) across 17,873 mRNA gene-level transcripts. We identified 216 significant transcripts at a false discovery rate (FDR)<0.05. We conducted replication using the meta-analysis of two independent external studies: the Childhood Asthma Management Program (n=610) and the Genetic Epidemiology of Asthma in Costa Rica Study (n=326); we then reversed the discovery and replication cohorts, which revealed 59 significant genes that bi-directionally replicated. Gene ontology analysis revealed that many of these genes were implicated in immune function pathways, including defense response, inflammatory response, and cytokine production. Mendelian randomization (MR) analysis revealed four genes (CLC, CCDC21, S100A13, and GCNT1) as putatively causal (p<0.05) regulators of IgE levels. GCNT1 (beta=1.5, p=0.01), which is a top result in the MR analysis of expression in relation to asthma and allergic diseases, plays a role in regulating T helper type 1 (Th1) cell homing, lymphocyte trafficking, and B cell differentiation. Our findings build upon prior knowledge of IgE regulation and provide a deeper understanding of underlying molecular mechanisms. The IgE-associated genes that we identified, particularly those implicated in MR analysis, can be explored as promising therapeutic targets for asthma and IgE-related diseases.

中文翻译：

---

循环转录IgE水平的全转录组关联研究确定了哮喘和过敏性疾病的新靶标

循环免疫球蛋白E（IgE）浓度的测量有助于诊断和治疗哮喘和过敏性疾病。鉴定与IgE相关的基因表达特征可能阐明了IgE调控的新途径。为此，我们进行了一项发现转录组关联研究（TWAS），以识别来自Framingham心脏研究（FHS）的5,345名参与者的17,873个mRNA基因水平转录本的全血衍生RNA中与循环IgE水平相关的差异表达基因。 。我们以错误发现率（FDR）<0.05鉴定了216个重要转录本。我们使用两项独立的外部研究的荟萃分析进行了复制：儿童哮喘管理计划（n = 610）和哥斯达黎加哮喘的遗传流行病学研究（n = 326）；然后，我们逆转了发现和复制队列，发现了59个双向复制的重要基因。基因本体分析表明，这些基因中有许多与免疫功能通路有关，包括防御反应，炎症反应和细胞因子产生。孟德尔随机（MR）分析揭示了四个基因（CLC，CCDC21，S100A13和GCNT1）作为IgE水平的假定因果调节因子（p <0.05）。GCNT1（beta = 1.5，p = 0.01）是与哮喘和过敏性疾病有关的MR表达分析的最高结果，在调节T辅助1型（Th1）细胞归巢，淋巴细胞运输和B细胞分化。我们的发现基于对IgE调控的先验知识，并提供了对潜在分子机制的更深刻理解。