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: 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
• 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

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.

哮喘影响美国约2300万人，全球约3亿人；它一直是

项目成果

CASTER: Cross-Sectional Asthma STEroid Response Measurement.

• DOI: 10.3390/jpm10030095
• 发表时间: 2020-08-20
• 期刊: Journal of personalized medicine
• 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
• 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

Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept.

• DOI: 10.3390/jpm11040319
• 发表时间: 2021-04-20
• 期刊: Journal of personalized medicine
• 作者: Sordillo JE;Lutz SM;McGeachie MJ;Lasky-Su J;Weiss ST;Celedón JC;Wu AC
• 通讯作者: Wu AC

The Role of SNP Interactions when Determining Independence of Novel Signals in Genetic Association Studies-An Application to ARG1 and Bronchodilator Response.

• DOI: 10.3390/jpm11020145
• 发表时间: 2021-02-19
• 期刊: Journal of personalized medicine
• 作者: Walsh R;Voorhies K;McDonald ML;McGeachie M;Sordillo JE;Lange C;Wu AC;Lutz SM
• 通讯作者: Lutz SM