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)

基本信息

批准号：
10323038
负责人：
MICHAEL JOHN McGEACHIE
金额：
$ 85.99万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323038
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 Drug Prescriptions Ethnic Origin Ethnic group Frequencies Gene Expression Genetic Genetic Transcription Goals Hispanic Americans Hispanic Populations Immunity Incidence Individual Inflammation Inflammatory Inhalation Knowledge Linear Regressions Logistic Regressions Measures Messenger RNA MicroRNAs Minority Groups Modeling Morbidity - disease rate Outcome Pathway interactions Pharmacogenetics Population Prediction of Response to Therapy Prevalence Process Prognosis RNA Risk Serum Source Steroids Techniques Testing Translational Repression Underserved Population 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 predictive modeling prognostic model programs pulmonary function response success treatment response whole genome

项目摘要

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2300万人，在全球范围内约有3亿个人；估计有20％的哮喘受试者占哮喘经济成本的80％。2 识别该子风险受试者的子仪，急剧降低了整体病情及其成本疾病。哮喘控制最广泛的药物是吸入的皮质类固醇（ICS）以前已经证明，哮喘的受试者中有25-30％对治疗没有反应，3 从而将它们归类为中度至严重的哮喘患者。4鉴于西班牙裔美国人是一个服务欠佳的群体，在美国哮喘病往往会造成更大的病态，5这个族群尤其是重要的是研究微核酸（miRNA）是小的非编码RNA 通过mRNA降解和/或翻译纠正的表达。6许多miRNA被验与哮喘7-10相关或调节免疫力和炎症途径，11-13的过程与哮喘。并可以预测儿童哮喘管理计划（CAMP）15,16队列中的哮喘缓解14。将结果扩展到其他受欢迎程度，尤其是哮喘患病率和发病率。在具有哮喘，ICS和ADACERBECTIONS的骨化人群中脱离IC：哥斯达黎加研究（GACRS）1165童年哮喘患者的哮喘。17,18至关重要的是，GACR包含该提案无需提供许多其他的OMIC数据，这提供了一个绝佳的机会在关系中研究MicroRNA与Messenger RNA Express和全基因组测序的相互作用为了加剧。响应性内表型（SRE）.19我们假设miRNA会影响cAMP的加剧将在GACRS中复制，我们可以确定进一步的关键mir，并且哮喘的预测模型 GACRS队列中的加剧和SRE将在营地中复制。使用mir-seq的序列全血元素，我们将使用miRNA-seq进行测序来自1165个GACRS儿童血清的miRNA，并复制我们与IC的miR-206的关联响应。 Mir Express水平的变体以及与加剧和ICS响应的相互作用将复制我们现有的MIR在GACR中的类固醇反应的MIR模型，并另外识别的miRS 以及基因组学变体对ICS响应和SRE的构建器预测模型。在营地队列中得到验证。哮喘的治疗反应，同时构建临床可行的恶化预测模型和童年时期的SRE。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CASTER: Cross-Sectional Asthma STEroid Response Measurement.

DOI：
10.3390/jpm10030095
发表时间：
2020-08-20
期刊：
Journal of personalized medicine
影响因子：
0
作者：
Kho AT;Sordillo J;Wu AC;Cho MH;Sharma S;Tiwari A;Lasky-Su J;Weiss ST;Tantisira KG;McGeachie MJ
通讯作者：
McGeachie MJ

Plasmalogens Mediate the Effect of Age on Bronchodilator Response in Individuals With Asthma.

缩醛磷脂介导年龄对哮喘患者支气管扩张剂反应的影响。

DOI：
10.3389/fmed.2020.00038
发表时间：
2020
期刊：
Frontiers in medicine
影响因子：
3.9
作者：
Sordillo,JoanneE;Lutz,SharonM;Kelly,RachelS;McGeachie,MichaelJ;Dahlin,Amber;Tantisira,Kelan;Clish,Clary;Lasky-Su,Jessica;Wu,AnnChen
通讯作者：
Wu,AnnChen

Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator.

DOI：
10.1016/j.jaci.2017.11.059
发表时间：
2018-11
期刊：
The Journal of allergy and clinical immunology
影响因子：
0
作者：
McGeachie MJ;Clemmer GL;Hayete B;Xing H;Runge K;Wu AC;Jiang X;Lu Q;Church B;Khalil I;Tantisira K;Weiss S
通讯作者：
Weiss S

Genetic Association Study Advances Idiopathic Pulmonary Fibrosis Pathophysiology and Health Equity.