Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthmaResearch in context
Kevin M. Mendez,
Sofina Begum,
Anshul Tiwari,
Rinku Sharma,
Qingwen Chen,
Rachel S. Kelly,
Nicole Prince,
Mengna Huang,
Priyadarshini Kachroo,
Su H. Chu,
Yulu Chen,
Kathleen Lee-Sarwar,
David I. Broadhurst,
Stacey N. Reinke,
Robert Gerszten,
Clary Clish,
Lydiana Avila,
Juan C. Celedón,
Craig E. Wheelock,
Scott T. Weiss,
Michael McGeachie,
Jessica A. Lasky-Su
Affiliations
Kevin M. Mendez
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Centre for Integrative Metabolomics & Computational Biology, School of Science, Edith Cowan University, Perth, Australia
Sofina Begum
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Anshul Tiwari
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
Rinku Sharma
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Qingwen Chen
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Rachel S. Kelly
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Nicole Prince
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Mengna Huang
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Priyadarshini Kachroo
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Su H. Chu
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Yulu Chen
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Kathleen Lee-Sarwar
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
David I. Broadhurst
Centre for Integrative Metabolomics & Computational Biology, School of Science, Edith Cowan University, Perth, Australia
Stacey N. Reinke
Centre for Integrative Metabolomics & Computational Biology, School of Science, Edith Cowan University, Perth, Australia
Robert Gerszten
Department of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
Clary Clish
Broad Institute, Cambridge, MA, USA
Lydiana Avila
Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
Juan C. Celedón
Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
Craig E. Wheelock
Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
Scott T. Weiss
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Michael McGeachie
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Jessica A. Lasky-Su
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Corresponding author. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.
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).
