Genomics and Pharmacogenomics of Symptoms in Asthma

摘要 全球有超过3亿人患有哮喘。失控的哮喘与一种 直接成本增加一倍，错过工作日和旷课；高达80%的哮喘患者 可能在哮喘症状方面失控。循环中的microRNA(MiRNAs)是 稳定的细胞间通信器，起到调节基因表达的作用，并可以作为 症状和疾病的生物标志物。这项研究的总体目标是确定 循环miRNA和miRNA遗传学在控制哮喘症状中的作用。在这场竞争中 更新方案《哮喘症状的基因组学和药物基因组学》，我们假设 循环中的miRNA在功能上与哮喘治疗指南有关- 基于症状控制、症状加重和症状反应 心理治疗。哮喘症状将被定义为控制良好、控制不良和未控制 通过全球哮喘倡议(GINA)指南和严重加重的频率。这个 将通过三个具体目标确定相关的miRNAs。第一个目标是确定 差异表达的miRNA通过miRNA影响哮喘症状控制 对总计超过4000名受试者的多个哮喘队列的血清样本进行测序。十字 部分研究将确定表明受控者之间机制差异的miRNAs 和未控制的哮喘，而药物基因组和纵向研究将识别miRNAs 提供生物洞察力，并可能形成预测生物标记物测试的基础 难治性哮喘的识别与治疗。第二个目标是评估 MiRNA基因在哮喘症状控制中的作用 影响miRNA表达(通过等位基因特异性表达)和那些影响miRNA生物发生的基因。 通过对超过3500名哮喘患者进行全基因组测序，将识别出显著的变异 受试者和通过全基因组计算的全基因组关联数据超过30,000 哮喘受试者。基因变异将与症状控制和评估有关 预测持续症状和药物治疗反应的能力。最终目标将是 在功能上将miRNA与AIMS的miR-130a-3p和let-7b-5p等遗传变体联系起来 1和2人呼吸道上皮细胞的生理性和炎性变化，使用miRNA 模仿、miRNA抑制剂和基于CRISPR的基因编辑。这项提议的成功将 对哮喘症状控制和哮喘发病机制的新认识 恶化，并可能以生物标记物的形式提供直接的未来床边临床转换 加强基于指南的治疗建议和/或基于miRNA的治疗。

ABSTRACT Asthma affects over 300 million individuals worldwide. Uncontrolled asthma is associated with a doubling of direct costs, missed workdays, and school absenteeism; up to 80% of asthma patients may be uncontrolled with regard to asthma symptoms. Circulating microRNAs (miRNAs) are stable intercellular communicators that function to regulate gene expression and can serve as biomarkers for symptoms and disease. The overall objective of this study is to ascertain the role of circulating miRNA and miRNA genetics in control of asthma symptoms. In this competitive renewal proposal, “Genomics and Pharmacogenomics of Symptoms in Asthma”, we hypothesize that circulating miRNAs are functionally associated with asthma treatment guidelines- based symptoms control, symptomatic exacerbations, and symptoms response to therapy. Asthma symptoms will be defined as well-controlled, poorly controlled, and uncontrolled via Global Initiative for Asthma (GINA) guidelines and by frequency of severe exacerbations. The relevant miRNAs will be identified via three specific aims. The first aim seeks to identify differentially expressed miRNAs influencing asthma symptoms control through miRNA sequencing of serum samples from multiple asthma cohorts totaling over 4000 subjects. Cross sectional studies will identify miRNAs indicative of mechanistic differences between the controlled and uncontrolled asthmatic, while pharmacogenomic and longitudinal studies will identify miRNAs that provide biologic insights and may form the basis of a predictive biomarker test for identification and treatment of the difficult to control asthmatic. The second aim evaluates the role of miRNA genetics in asthma symptoms control through identification of polymorphisms that affect miRNA expression (via allele specific expression) and those affecting miRNA biogenesis. The salient variants will be identified via whole genome sequencing in over 3500 asthmatic subjects and through whole genome imputed genome-wide association data in over 30,000 asthmatic subjects. The genetic variants will be associated with symptoms control and assessed for ability to predict ongoing symptoms and drug treatment response. The final aim will functionally link the miRNA and genetic variants, including miR-130a-3p and let-7b-5p, from Aims 1 and 2 with physiologic and inflammatory changes in human airway epithelial cells, using miRNA mimics, miRNA inhibitors, and CRISPR-based gene editing. The success of this proposal will yield novel understanding into the pathogenesis of asthma symptoms control and asthma exacerbations and may provide direct future bedside clinical translation in the form of biomarkers to enhance guidelines based therapeutic recommendations and/or miRNA based therapeutics.