摘要
背景：miRNA与代谢物之间存在重要的相互作用：各种代谢刺激可诱导miRNA表达改变，而miRNA也可以调控细胞代谢过程。虽然已发现特定的miRNA和代谢物与儿童哮喘有关，但尚未有研究系统评估二者在儿童哮喘中的协同作用。
方法：本研究在两个儿童哮喘队列中进行miRNA组-代谢组广泛关联研究（miR-metabo-WAS），以评估miRNA-代谢物的同时性和持久性关联：1）哮喘遗传流行病学研究（GACRS）（N=1121）；2）儿童哮喘管理项目（CAMP）（NBaseline=312，NEnd of trial=454）。对这两个队列进行Meta分析，以识别CAMP与GACRS之间的同时性关联（伪发现率（FDR）=0.05）。在CAMP中，利用基线miRNA与试验结束时的代谢组数据评估持久性关联。通过介导分析（1000次自举法，FDR显著性水平为0.05）探究miRNA、代谢物与临床表型（包括气道高反应性、外周血嗜酸性粒细胞增多及气流阻塞）的关系。
结果：Meta分析共发现369个显著关联（133个miRNA和60种代谢物）。鉴定出13种核心枢纽代谢物（牛磺酸、12,13-二羟基十三烯酸、癸二酸、9－顺式维甲酸、壬二酸、天冬氨酸、C5:1肉毒碱、皮质醇、3-甲基戊二酸、肌苷、NMMA、甘氨酸和吡咯谷氨酸）和4个枢纽miRNA（hsa-miR-186-5p、hsa-miR-143-3p、hsa-miR-192-5p和hsa-miR-223-3p）。其中9个关联（8个miRNA与8种代谢物）在CAMP队列中，从基线到试验结束全程持续存在。5种中心枢纽代谢物（9－顺式维甲酸、牛磺酸、癸二酸、壬二酸和12,13-二羟基十三烯酸）通过100余条间接通路共同影响外周血嗜酸性粒细胞增多、AHR和气流阻塞。
结论：miRNA与代谢物的强关联，以及miRNA通过5种枢纽代谢物对哮喘临床指标的间接影响，表明二者通过整合机制影响哮喘进程。这些发现提示miRNA可能通过调节代谢和细胞功能间接影响儿童哮喘Th2炎症、气道高反应性和气流阻塞。
关键词： miRNA；代谢物；嗜酸性粒细胞增多；气道高反应性；气流阻塞
文献来源：(Sharma R, Mendez K, Begum S, et al. miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthma[J]. Ebiomedicine, 2025, 112: 105534. DOI: 10.1016/j.ebiom.2024.105534.)
Abstract
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.
Results：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.
Conclusion：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.
Key words：microRNA ; Metabolite; Eosinophilia; Airway hyper-responsiveness; Airflow obstruction
背景：miRNA与代谢物之间存在重要的相互作用：各种代谢刺激可诱导miRNA表达改变，而miRNA也可以调控细胞代谢过程。虽然已发现特定的miRNA和代谢物与儿童哮喘有关，但尚未有研究系统评估二者在儿童哮喘中的协同作用。
方法：本研究在两个儿童哮喘队列中进行miRNA组-代谢组广泛关联研究（miR-metabo-WAS），以评估miRNA-代谢物的同时性和持久性关联：1）哮喘遗传流行病学研究（GACRS）（N=1121）；2）儿童哮喘管理项目（CAMP）（NBaseline=312，NEnd of trial=454）。对这两个队列进行Meta分析，以识别CAMP与GACRS之间的同时性关联（伪发现率（FDR）=0.05）。在CAMP中，利用基线miRNA与试验结束时的代谢组数据评估持久性关联。通过介导分析（1000次自举法，FDR显著性水平为0.05）探究miRNA、代谢物与临床表型（包括气道高反应性、外周血嗜酸性粒细胞增多及气流阻塞）的关系。
结果：Meta分析共发现369个显著关联（133个miRNA和60种代谢物）。鉴定出13种核心枢纽代谢物（牛磺酸、12,13-二羟基十三烯酸、癸二酸、9－顺式维甲酸、壬二酸、天冬氨酸、C5:1肉毒碱、皮质醇、3-甲基戊二酸、肌苷、NMMA、甘氨酸和吡咯谷氨酸）和4个枢纽miRNA（hsa-miR-186-5p、hsa-miR-143-3p、hsa-miR-192-5p和hsa-miR-223-3p）。其中9个关联（8个miRNA与8种代谢物）在CAMP队列中，从基线到试验结束全程持续存在。5种中心枢纽代谢物（9－顺式维甲酸、牛磺酸、癸二酸、壬二酸和12,13-二羟基十三烯酸）通过100余条间接通路共同影响外周血嗜酸性粒细胞增多、AHR和气流阻塞。
结论：miRNA与代谢物的强关联，以及miRNA通过5种枢纽代谢物对哮喘临床指标的间接影响，表明二者通过整合机制影响哮喘进程。这些发现提示miRNA可能通过调节代谢和细胞功能间接影响儿童哮喘Th2炎症、气道高反应性和气流阻塞。
关键词： miRNA；代谢物；嗜酸性粒细胞增多；气道高反应性；气流阻塞
文献来源：(Sharma R, Mendez K, Begum S, et al. miRNAome-metabolome wide association study reveals effects of miRNA regulation in eosinophilia and airflow obstruction in childhood asthma[J]. Ebiomedicine, 2025, 112: 105534. DOI: 10.1016/j.ebiom.2024.105534.)
（南方医科大学南方医院 黄海伦 龚钊乾 赵文驱 赵海金）
Abstract
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.
Results：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.
Conclusion：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.
Key words：microRNA ; Metabolite; Eosinophilia; Airway hyper-responsiveness; Airflow obstruction
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