The impact of vitamins A and D on lung function and regulatory epigenetics in adult and childhood asthma

Abstract

Objective: 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. Conclusions: 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.