Metabolite Signatures Associated with Microrna Mir-143-3p Serve As Drivers of Poor Lung Function Trajectories in Childhood Asthma

Summary: Background: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. Methods: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. Findings: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10−5), SLC8A1 (P-value = 3.9 × 10−5); and TENM4 (P-value = 4.9 × 10−5). Interpretation: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. Funding: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).