Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma

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

doi:10.1016/j.ebiom.2024.105025

Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma

EBioMedicine. 2024 Apr:102:105025. doi: 10.1016/j.ebiom.2024.105025. Epub 2024 Mar 7.

Authors

Kevin M Mendez¹, Sofina Begum², Anshul Tiwari³, Rinku Sharma², Qingwen Chen², Rachel S Kelly², Nicole Prince², Mengna Huang², Priyadarshini Kachroo², Su H Chu², Yulu Chen², Kathleen Lee-Sarwar⁴, David I Broadhurst⁵, Stacey N Reinke⁵, Robert Gerszten⁶, Clary Clish⁷, Lydiana Avila⁸, Juan C Celedón⁸, Craig E Wheelock⁹, Scott T Weiss², Michael McGeachie², Jessica A Lasky-Su¹⁰

Affiliations

¹ 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.
² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ 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.
⁴ 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.
⁵ Centre for Integrative Metabolomics & Computational Biology, School of Science, Edith Cowan University, Perth, Australia.
⁶ Department of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁷ Broad Institute, Cambridge, MA, USA.
⁸ Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: rejas@channing.harvard.edu.

Abstract

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 (PC_LF) 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 PC_LF 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, PC_LF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PC_LF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PC_LF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PC_LF 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).

Keywords: Asthma; Genomics; Lung function trajectories; Metabolomics; MicroRNAs.

Publication types

Meta-Analysis

MeSH terms

Asthma*
Child
Cross-Sectional Studies
Humans
Lung / metabolism
Metabolomics
MicroRNAs* / metabolism

Substances

MicroRNAs
MIRN143 microRNA, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding