Division of Allergy and Immunology, Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital for Children, Boston, Massachusetts.
Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.
Clin Exp Allergy. 2018 Dec;48(12):1654-1664. doi: 10.1111/cea.13249. Epub 2018 Nov 21.
Asthma represents a significant public health burden; however, novel biological therapies targeting immunoglobulin E (IgE)-mediated pathways have widened clinical treatment options for the disease.
In this study, we sought to identify gene transcripts and gene networks involved in the determination of serum IgE levels in people with asthma that can help inform the development of novel therapeutic agents.
We analysed gene expression data from a cross-sectional study of 326 Costa Rican children with asthma, aged 6 to 12 years, from the Genetics of Asthma in Costa Rica Study and 610 young adults with asthma, aged 16 to 25 years, from the Childhood Asthma Management Program trial. We utilized differential gene expression analysis and performed weighted gene coexpression network analysis on 25 060 genes, to identify gene transcripts and network modules associated with total IgE, adjusting for age and gender. We used pathway enrichment analyses to identify key biological pathways underlying significant modules. We compared findings that replicated between both populations.
We identified 31 transcripts associated with total IgE that replicated between the two study cohorts. These results were notable for increased eosinophil-related transcripts (including IL5RA, CLC, SMPD3, CCL23 and CEBPE). Pathway enrichment identified the regulation of T cell tolerance as important in the determination of total IgE levels, supporting a key role for IDO1.
These results provide robust evidence that biologically meaningful gene expression profiles (relating to eosinophilic and regulatory T cell pathways in particular) associated with total IgE levels can be identified in individuals diagnosed with asthma during childhood. These profiles and their constituent genes may represent novel therapeutic targets.
哮喘是一个重大的公共卫生负担；然而，针对免疫球蛋白 E（IgE）介导途径的新型生物疗法拓宽了疾病的临床治疗选择。
本研究旨在鉴定与哮喘患者血清 IgE 水平相关的基因转录本和基因网络，为新型治疗药物的开发提供信息。
我们分析了来自哥斯达黎加哮喘遗传学研究中 326 名 6 至 12 岁的哮喘儿童和儿童哮喘管理计划试验中 610 名 16 至 25 岁的哮喘青年的横断面研究中的基因表达数据。我们利用差异基因表达分析和加权基因共表达网络分析对 25060 个基因进行了分析，以确定与总 IgE 相关的基因转录本和网络模块，同时调整了年龄和性别因素。我们使用通路富集分析来确定显著模块的关键生物学通路。我们比较了两个人群之间复制的结果。
我们鉴定出 31 个与总 IgE 相关的转录本，在两个研究队列中均有复制。这些结果突出了与嗜酸性粒细胞相关的转录本的增加（包括 IL5RA、CLC、SMPD3、CCL23 和 CEBPE）。通路富集分析表明，T 细胞耐受的调节在总 IgE 水平的确定中很重要，这支持了 IDO1 的关键作用。
这些结果提供了有力的证据，表明与总 IgE 水平相关的具有生物学意义的基因表达谱（特别是与嗜酸性粒细胞和调节性 T 细胞途径相关的基因表达谱）可以在儿童期诊断为哮喘的个体中被识别。这些谱及其组成基因可能代表新的治疗靶点。
