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.