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.
Asthma exacerbation on and off of typical treatment with inhaled corticosteroids represents a critical source of morbidity and expense in the treatment of asthma. Genetic variants and microRNA levels have been associated with exacerbation frequency and ICS treatment response, and preliminary models show some efficacy in predicting exacerbation prognosis in childhood asthmatics. These biological associations and models can be improved by comprehensive sequencing of miRNA levels from total serum RNA, which goes beyond existing studies by completely characterizing the species of short RNA in the blood. Existing miRNAs studies have shown particular affinities of miRs for asthma and related inflammatory conditions, and this sequencing will allow a complete look at the ways miRs interact to influence steroid treatment response and exacerbation in asthma. Combining this with available whole-genome sequencing and blood messenger RNA expression provides an opportunity to identify integrative effects between genetic variants and miRNA expression levels and targeting proclivities that influence asthma morbidity and treatment success. We will use these results to build on existing prognostic models of exacerbation and steroid treatment response to identify cost-saving and outcome-improving treatment options for childhood asthmatics.
|McGeachie, Michael J; Clemmer, George L; Hayete, Boris et al. (2018) Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator. J Allergy Clin Immunol 142:1479-1488.e12|