miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in context
Summary: Background: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolite...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239642400570X |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846099113760784384 |
|---|---|
| author | Rinku Sharma Kevin Mendez Sofina Begum Su Chu Nicole Prince Julian Hecker Rachel S. Kelly Qingwen Chen Craig E. Wheelock Juan C. Celedón Clary Clish Robert Gertszen Kelan G. Tantisira Scott T. Weiss Jessica Lasky-Su Michael McGeachie |
| author_facet | Rinku Sharma Kevin Mendez Sofina Begum Su Chu Nicole Prince Julian Hecker Rachel S. Kelly Qingwen Chen Craig E. Wheelock Juan C. Celedón Clary Clish Robert Gertszen Kelan G. Tantisira Scott T. Weiss Jessica Lasky-Su Michael McGeachie |
| author_sort | Rinku Sharma |
| collection | DOAJ |
| description | Summary: Background: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma. Methods: We performed miRNAome-metabolome-wide association studies (‘miR-metabo-WAS’) in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (NBaseline = 312 and NEnd of trial = 454). We conducted a meta-analysis of the two cohorts to identify common contemporaneous associations between CAMP and GACRS (false-discovery rate (FDR) = 0.05). We assessed persistent miRNA-metabolome associations using baseline miRNAs and metabolomic profiling in CAMP at the end of the trial. The relation between miRNAs, metabolites and clinical phenotypes, including airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction, were then assessed via. Mediation analysis with 1000 bootstraps at an FDR significance level of 0.05. Findings: The meta-analysis yielded a total of 369 significant contemporaneous associations, involving 133 miRNAs and 60 metabolites. We identified 13 central hub metabolites (taurine, 12,13-diHOME, sebacate, 9-cis-retinoic acid, azelate, asparagine, C5:1 carnitine, cortisol, 3-methyladipate, inosine, NMMA, glycine, and Pyroglutamic acid) and four hub miRNAs (hsa-miR-186-5p, hsa-miR-143-3p, hsa-miR-192-5p, and hsa-miR-223-3p). Nine of these associations, between eight miRNAs and eight metabolites, were persistent in CAMP from baseline to the end of trial. Finally, five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, and 12,13-diHOME) were identified as primary mediators in over 100 significant indirect miRNA-metabolite associations, with a collective influence on peripheral blood eosinophilia, AHR, and airflow obstruction. Interpretation: The robust association between miRNAs and metabolites, along with the substantial indirect impact of miRNAs via 5 hub metabolites on multiple clinical asthma metrics, suggests important integrated effects of miRNAs and metabolites on asthma. These findings imply that the indirect regulation of metabolism and cellular functions by miRNA influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma. 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). |
| format | Article |
| id | doaj-art-bf39df1b12c843ae86dce00b22fb3a80 |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-bf39df1b12c843ae86dce00b22fb3a802025-01-01T05:10:31ZengElsevierEBioMedicine2352-39642025-02-01112105534miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in contextRinku Sharma0Kevin Mendez1Sofina Begum2Su Chu3Nicole Prince4Julian Hecker5Rachel S. Kelly6Qingwen Chen7Craig E. Wheelock8Juan C. Celedón9Clary Clish10Robert Gertszen11Kelan G. Tantisira12Scott T. Weiss13Jessica Lasky-Su14Michael McGeachie15Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Department of Chemistry, Edith Cowan University, Perth, AustraliaChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAUnit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, SwedenDivision of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, PA, USABroad Institute, Cambridge, MA, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USADivision of Pediatric Respiratory Medicine, University of California San Diego and Rady Children’s Hospital, San Diego, CA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Corresponding author.Summary: Background: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma. Methods: We performed miRNAome-metabolome-wide association studies (‘miR-metabo-WAS’) in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (NBaseline = 312 and NEnd of trial = 454). We conducted a meta-analysis of the two cohorts to identify common contemporaneous associations between CAMP and GACRS (false-discovery rate (FDR) = 0.05). We assessed persistent miRNA-metabolome associations using baseline miRNAs and metabolomic profiling in CAMP at the end of the trial. The relation between miRNAs, metabolites and clinical phenotypes, including airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction, were then assessed via. Mediation analysis with 1000 bootstraps at an FDR significance level of 0.05. Findings: The meta-analysis yielded a total of 369 significant contemporaneous associations, involving 133 miRNAs and 60 metabolites. We identified 13 central hub metabolites (taurine, 12,13-diHOME, sebacate, 9-cis-retinoic acid, azelate, asparagine, C5:1 carnitine, cortisol, 3-methyladipate, inosine, NMMA, glycine, and Pyroglutamic acid) and four hub miRNAs (hsa-miR-186-5p, hsa-miR-143-3p, hsa-miR-192-5p, and hsa-miR-223-3p). Nine of these associations, between eight miRNAs and eight metabolites, were persistent in CAMP from baseline to the end of trial. Finally, five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, and 12,13-diHOME) were identified as primary mediators in over 100 significant indirect miRNA-metabolite associations, with a collective influence on peripheral blood eosinophilia, AHR, and airflow obstruction. Interpretation: The robust association between miRNAs and metabolites, along with the substantial indirect impact of miRNAs via 5 hub metabolites on multiple clinical asthma metrics, suggests important integrated effects of miRNAs and metabolites on asthma. These findings imply that the indirect regulation of metabolism and cellular functions by miRNA influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma. 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).http://www.sciencedirect.com/science/article/pii/S235239642400570XmicroRNAMetaboliteEosinophiliaAirway hyper-responsivenessAirflow obstruction |
| spellingShingle | Rinku Sharma Kevin Mendez Sofina Begum Su Chu Nicole Prince Julian Hecker Rachel S. Kelly Qingwen Chen Craig E. Wheelock Juan C. Celedón Clary Clish Robert Gertszen Kelan G. Tantisira Scott T. Weiss Jessica Lasky-Su Michael McGeachie miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in context EBioMedicine microRNA Metabolite Eosinophilia Airway hyper-responsiveness Airflow obstruction |
| title | miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in context |
| title_full | miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in context |
| title_fullStr | miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in context |
| title_full_unstemmed | miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in context |
| title_short | miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthmaResearch in context |
| title_sort | mirnaome metabolome wide association study reveals effects of mirna regulation in eosinophilia and airflow obstruction in childhood asthmaresearch in context |
| topic | microRNA Metabolite Eosinophilia Airway hyper-responsiveness Airflow obstruction |
| url | http://www.sciencedirect.com/science/article/pii/S235239642400570X |
| work_keys_str_mv | AT rinkusharma mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT kevinmendez mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT sofinabegum mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT suchu mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT nicoleprince mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT julianhecker mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT rachelskelly mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT qingwenchen mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT craigewheelock mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT juancceledon mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT claryclish mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT robertgertszen mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT kelangtantisira mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT scotttweiss mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT jessicalaskysu mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext AT michaelmcgeachie mirnaomemetabolomewideassociationstudyrevealseffectsofmirnaregulationineosinophiliaandairflowobstructioninchildhoodasthmaresearchincontext |