Asthma Exacerbations and MicroRNA prediction: Treatment Response in an Underserved Ethnicity (AEM-TRUE)

哮喘加重和 MicroRNA 预测：服务不足的种族的治疗反应 (AEM-TRUE)

• 批准号: 9883831
• 负责人: MICHAEL JOHN McGEACHIE
• 金额: $ 85.36万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883831
• 关键词: Address; Adrenal Cortex Hormones; Affect; Affinity; Asthma; Bayesian Network; Biological; Blood; Child; Childhood; Childhood Asthma; Cohort Studies; Cost Savings; Cost of Illness; Costa Rica; Data; Ethnic Origin; Ethnic group; Frequencies; Gene Expression; Genetic; Genetic Transcription; Goals; Hispanic Americans; Hispanics; Immunity; Incidence; Individual; Inflammation; Inflammatory; Inhalation; Knowledge; Linear Regressions; Logistic Regressions; Measures; Messenger RNA; MicroRNAs; Minority; Modeling; Morbidity - disease rate; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacogenetics; Population; Prediction of Response to Therapy; Prevalence; Process; RNA; Respiratory physiology; Risk; Serum; Source; Steroids; Techniques; Testing; Translational Repression; United States; Untranslated RNA; Variant; Whole Blood; asthma exacerbation; asthmatic; circulating microRNA; clinically actionable; cohort; cost; economic cost; endophenotype; genetic variant; genome sequencing; improved; improved outcome; mRNA Expression; mRNA Transcript Degradation; multiple omics; outcome forecast; predictive modeling; programs; response; success; treatment response; whole genome

Asthma affects ~23 million individuals in the United States and ~300 million individuals worldwide;1 it has been estimated that 20% of the subjects with asthma contribute 80% of the economic costs of asthma.2 Ready identification of this subset of at-risk subjects would dramatically decrease overall morbidity and costs of this disease. For asthma control, the most widely prescribed medications are inhaled corticosteroids (ICS). We have previously demonstrated that 25-30% of subjects taking ICS for asthma do not respond to therapy,3 thereby classifying them as moderate to severe asthmatics.4 Given that Hispanics Americans are an underserved group and tend to have greater morbidity from asthma in the US,5 this ethnic group is particularly important to study. Micro ribonucleic acids (miRNAs) are small non-coding RNAs that regulate gene expression by mRNA degradation and/or translational repression.6 Many miRNAs have already been associated with asthma7-10 or regulate pathways of immunity and inflammation,11-13 processes central to asthma. We have demonstrated that miRs have associations with asthma exacerbation, response to steroids, and can predict asthma remission14 in the Childhood Asthma Management Program (CAMP)15,16 cohort. It is critical to extend these results to other populations, particularly ethnicities with high asthma prevalence and morbidity. This proposal aims to investigate the microRNA underpinnings of asthma exacerbations on and off ICS in a Hispanic population with high incidence of asthma, ICS, and exacerbations: the Genetics of Asthma in Costa Rica study (GACRS) cohort of 1165 childhood asthmatics.17,18 Crucially, GACRS contains many additional omics data available at no cost to the proposal, which provides an excellent opportunity to study microRNA’s interaction with messenger RNA expression and whole-genome sequencing in relation to exacerbation. We will measure asthma control on and off ICS by exacerbations and a steroid responsiveness endophenotype (SRE).19 We hypothesize that miRNAs impacting exacerbation in CAMP will replicate in GACRS, that we may identify further critical miRs, and that predictive models of asthma exacerbations and SRE in the GACRS cohort will replicate in CAMP. Using available serum we will sequence whole blood microRNAs using miR-Seq in GACRS. We will 1) use miRNA-Seq to sequencing miRNAs from serum of 1165 GACRS children, and replicate our associations of miR-206 with ICS response. We then 2) will use whole-genome sequencing data to identify the effects of rare and common variants on miR expression levels and their interaction with exacerbation and ICS response. Finally 3) we will replicate our existing miR model of steroid response in GACRS, and use additionally identified miRs and genomic variants to build stronger predictive models of ICS response and SRE. All of these results will be validated in the CAMP cohort. By completing these objectives, we will have advanced knowledge of ICS treatment response in asthma, while building clinically actionable predictive models of exacerbation and SRE in childhood asthma.

哮喘在美国影响约2300万个体，在全世界影响约3亿个体;1 据估计，20%的哮喘患者贡献了80%的哮喘经济成本。 识别这一亚组的高危受试者将显著降低总体发病率和成本， 疾病对于哮喘控制，最广泛的处方药物是吸入性皮质类固醇（ICS）。我们 先前已经证明，25-30%服用ICS治疗哮喘的受试者对治疗无反应，3 从而将他们归类为中度至重度哮喘。4鉴于西班牙裔美国人是一个 在美国，这是一个服务水平低下的群体，哮喘的发病率往往更高，5这个种族群体特别 重要的是学习。微小核糖核酸（microribonucleicacids，miRNAs）是一类非编码小分子RNA，在基因表达调控中起重要作用 通过mRNA降解和/或翻译抑制表达。6许多miRNA已经被发现 与哮喘相关7 -10或调节免疫和炎症的途径，11-13 哮喘我们已经证明miR与哮喘恶化、对类固醇的反应、 并且可以预测儿童哮喘管理项目（CAMP）15，16队列中的哮喘缓解14。是 将这些结果扩展到其他人群，特别是哮喘患病率高的种族， 发病率该提案旨在研究哮喘急性发作的microRNA基础， 西班牙裔人群中哮喘、ICS和急性发作发病率高的患者停用ICS： 哥斯达黎加哮喘研究（GACRS）1165例儿童哮喘患者队列。17，18至关重要的是，GACRS包含 许多额外的组学数据是免费提供的，这提供了一个很好的机会， 研究microRNA与信使RNA表达相互作用和全基因组测序 恶化。我们将通过急性发作和类固醇来衡量ICS治疗和非ICS治疗对哮喘的控制 反应性内表型（SRE）。19我们假设影响CAMP恶化的miRNA 将在GACRS中复制，我们可以识别更多的关键miR，以及哮喘的预测模型 GACRS队列中的急性加重和SRE将在CAMP中复制。使用可用的血清，我们将 在GACRS中使用miR-Seq对全血microRNA进行测序。我们将1）使用miRNA-Seq进行测序 来自1165名GACRS儿童血清的miRNA，并复制了我们的miR-206与ICS的关联 反应然后，我们将使用全基因组测序数据来确定罕见和常见的影响。 对miR表达水平的影响及其与急性加重和ICS反应的相互作用。（3）我们 将在GACRS中复制我们现有的类固醇反应miR模型，并使用额外鉴定的miR 和基因组变异，以建立更强的ICS反应和SRE预测模型。所有这些结果将 在CAMP队列中得到验证。通过完成这些目标，我们将对ICS有更深入的了解 哮喘的治疗反应，同时建立急性发作的临床可行的预测模型， 儿童哮喘的SRE。