维生素A和D对成人及儿童哮喘患者肺功能和表观遗传调控的影响
2026/07/31
摘要
背景：维生素A和D通过相互交叉的代谢通路调控众多基因，从而影响肺发育和哮喘。本研究旨在考察维生素A和D对哮喘儿童及成人肺功能、表观遗传衰老和表观遗传调控的影响。
方法：纳入两项哮喘队列：哥斯达黎加哮喘遗传流行病学研究（GACRS；1,165名儿童）和哮喘纵向肺功能组学决定因素研究（ODOLLFA；1,041名成人）。检测血清miRNA谱、血液DNA甲基化，以及血浆/血清维生素A和D水平；评估维生素水平与肺功能〔1秒用力呼气容积（FEV1）、用力肺活量（FVC）及FEV1/FVC〕、miRNA表达和DNA甲基化之间的关联。在成人中，采用中介分析评估甲基化状态和miRNA是否介导维生素与肺功能或表观遗传衰老之间的关系。
结果：在儿童中，较高的维生素A水平与较高的FEV1（β=2.5，p=4.9 × 10⁻³）和FVC（β=7.6，p=7.7 × 10⁻¹⁴）相关，但与较低的FEV1/FVC（β=-3.9，p=2.0 × 10⁻¹⁶）相关；维生素D未见相关性。在成人中，两种维生素均与FEV1呈正相关〔维生素A：β=4.7，p=9.3 × 10⁻³；维生素D：β=0.16，p=8.6 × 10⁻³〕，并与FVC呈正相关〔维生素A：β=3.4，p=3.0 × 10⁻²；维生素D：β=0.18，p=4.6 × 10⁻⁴〕；仅维生素A与FEV1/FVC相关（β=2.5，p=3.9 × 10⁻²）。成人维生素D充足与较低的表观遗传衰老程度相对应。较高的维生素水平与干扰素调节因子5（IRF5）调控区胞嘧啶-鸟嘌呤二核苷酸（CpG）位点的胞嘧啶低甲基化相关，并对应于更好的肺功能和较低的衰老程度。研究还鉴定出不同的维生素相关miRNA，其共同靶基因富集于免疫和细胞周期通路。中介分析提示，甲基化和miRNA具有统计学上的部分中介效应。
结论：在哮喘儿童中，维生素A而非维生素D与更好的肺功能和较低的表观遗传衰老程度相关，其效应由DNA甲基化和miRNA调控介导。
The impact of vitamins A and D on lung function and regulatory epigenetics in adult and childhood asthma
Rinku Sharma, Priyadarshini Kachroo, Kevin M Mendez, Qingwen Chen, Julian Hecker, Sofina Begum, Rachel S Kelly, Ryan Smith, Varun Dwaraka, Juan Carlos Celedon, Kelan G Tantisira, Dawn L DeMeo, Scott Weiss, Jessica Lasky-Su, Michael McGeachie
Abstract
BACKGROUND:Vitamins A and D regulate numerous genes through intersecting metabolic pathways, influencing lung development and asthma. This article aimed to examine the impact of vitamins A and D on lung function, epigenetic ageing and regulatory epigenetics in children and adults with asthma.
METHODS:Two asthma cohorts, GACRS (Genetic Epidemiology of Asthma in Costa Rica Study; 1165 children) and ODOLLFA (Omic Determinants of Longitudinal Lung Function in Asthma; 1041 adults) were included. Serum miRNA profiles, blood DNA methylation and plasma/serum vitamin A and D levels were measured. Associations between vitamin levels and lung function (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC), miRNA expression and DNA methylation were evaluated. In adults, mediation analysis assessed whether methylation status and miRNAs mediated the relationship between vitamins and lung function or epigenetic ageing.
RESULTS:In children, higher vitamin A was associated with higher FEV1 (β=2.5, p=4.9 × 10⁻³) and FVC (β=7.6, p=7.7 × 10⁻¹⁴) but lower FEV1/FVC (β=-3.9, p=2.0 × 10⁻¹⁶); vitamin D showed no association. In adults, both vitamins were positively associated with FEV1 (vitamin A: β=4.7, p=9.3 × 10⁻³, vitamin D: β=0.16, p=8.6 × 10⁻³) and FVC (vitamin A: β=3.4, p=3.0 × 10⁻², vitamin D: β=0.18, p=4.6 × 10⁻⁴); only vitamin A was associated with FEV1/FVC (vitamin A: β=2.5, p=3.9 × 10⁻²). Vitamin D sufficiency corresponded to lower epigenetic ageing in adults. Higher vitamin levels were associated with IRF5 regulatory cytosine hypomethylation at cytosine-guanine dinucleotides (CpG), corresponding to better lung function and lower ageing. Distinct vitamin-associated miRNAs were identified, with shared targets enriched in immune and cell-cycle pathways. Mediation analyses indicated statistical partial effects through methylation and miRNAs.
CONCLUSION:Vitamin A, but not vitamin D, in children was associated with better lung function and lower epigenetic ageing in asthma, with effects mediated by DNA methylation and miRNA regulation.
背景：维生素A和D通过相互交叉的代谢通路调控众多基因，从而影响肺发育和哮喘。本研究旨在考察维生素A和D对哮喘儿童及成人肺功能、表观遗传衰老和表观遗传调控的影响。
方法：纳入两项哮喘队列：哥斯达黎加哮喘遗传流行病学研究（GACRS；1,165名儿童）和哮喘纵向肺功能组学决定因素研究（ODOLLFA；1,041名成人）。检测血清miRNA谱、血液DNA甲基化，以及血浆/血清维生素A和D水平；评估维生素水平与肺功能〔1秒用力呼气容积（FEV1）、用力肺活量（FVC）及FEV1/FVC〕、miRNA表达和DNA甲基化之间的关联。在成人中，采用中介分析评估甲基化状态和miRNA是否介导维生素与肺功能或表观遗传衰老之间的关系。
结果：在儿童中，较高的维生素A水平与较高的FEV1（β=2.5，p=4.9 × 10⁻³）和FVC（β=7.6，p=7.7 × 10⁻¹⁴）相关，但与较低的FEV1/FVC（β=-3.9，p=2.0 × 10⁻¹⁶）相关；维生素D未见相关性。在成人中，两种维生素均与FEV1呈正相关〔维生素A：β=4.7，p=9.3 × 10⁻³；维生素D：β=0.16，p=8.6 × 10⁻³〕，并与FVC呈正相关〔维生素A：β=3.4，p=3.0 × 10⁻²；维生素D：β=0.18，p=4.6 × 10⁻⁴〕；仅维生素A与FEV1/FVC相关（β=2.5，p=3.9 × 10⁻²）。成人维生素D充足与较低的表观遗传衰老程度相对应。较高的维生素水平与干扰素调节因子5（IRF5）调控区胞嘧啶-鸟嘌呤二核苷酸（CpG）位点的胞嘧啶低甲基化相关，并对应于更好的肺功能和较低的衰老程度。研究还鉴定出不同的维生素相关miRNA，其共同靶基因富集于免疫和细胞周期通路。中介分析提示，甲基化和miRNA具有统计学上的部分中介效应。
结论：在哮喘儿童中，维生素A而非维生素D与更好的肺功能和较低的表观遗传衰老程度相关，其效应由DNA甲基化和miRNA调控介导。
（中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校）
（Thorax. 2026 Jun; DOI: https://doi.org/10.1136/thorax-2025-223756）
（Thorax. 2026 Jun; DOI: https://doi.org/10.1136/thorax-2025-223756）
The impact of vitamins A and D on lung function and regulatory epigenetics in adult and childhood asthma
Rinku Sharma, Priyadarshini Kachroo, Kevin M Mendez, Qingwen Chen, Julian Hecker, Sofina Begum, Rachel S Kelly, Ryan Smith, Varun Dwaraka, Juan Carlos Celedon, Kelan G Tantisira, Dawn L DeMeo, Scott Weiss, Jessica Lasky-Su, Michael McGeachie
Abstract
BACKGROUND:Vitamins A and D regulate numerous genes through intersecting metabolic pathways, influencing lung development and asthma. This article aimed to examine the impact of vitamins A and D on lung function, epigenetic ageing and regulatory epigenetics in children and adults with asthma.
METHODS:Two asthma cohorts, GACRS (Genetic Epidemiology of Asthma in Costa Rica Study; 1165 children) and ODOLLFA (Omic Determinants of Longitudinal Lung Function in Asthma; 1041 adults) were included. Serum miRNA profiles, blood DNA methylation and plasma/serum vitamin A and D levels were measured. Associations between vitamin levels and lung function (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC), miRNA expression and DNA methylation were evaluated. In adults, mediation analysis assessed whether methylation status and miRNAs mediated the relationship between vitamins and lung function or epigenetic ageing.
RESULTS:In children, higher vitamin A was associated with higher FEV1 (β=2.5, p=4.9 × 10⁻³) and FVC (β=7.6, p=7.7 × 10⁻¹⁴) but lower FEV1/FVC (β=-3.9, p=2.0 × 10⁻¹⁶); vitamin D showed no association. In adults, both vitamins were positively associated with FEV1 (vitamin A: β=4.7, p=9.3 × 10⁻³, vitamin D: β=0.16, p=8.6 × 10⁻³) and FVC (vitamin A: β=3.4, p=3.0 × 10⁻², vitamin D: β=0.18, p=4.6 × 10⁻⁴); only vitamin A was associated with FEV1/FVC (vitamin A: β=2.5, p=3.9 × 10⁻²). Vitamin D sufficiency corresponded to lower epigenetic ageing in adults. Higher vitamin levels were associated with IRF5 regulatory cytosine hypomethylation at cytosine-guanine dinucleotides (CpG), corresponding to better lung function and lower ageing. Distinct vitamin-associated miRNAs were identified, with shared targets enriched in immune and cell-cycle pathways. Mediation analyses indicated statistical partial effects through methylation and miRNAs.
CONCLUSION:Vitamin A, but not vitamin D, in children was associated with better lung function and lower epigenetic ageing in asthma, with effects mediated by DNA methylation and miRNA regulation.
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