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

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 (FEV 1 ), forced vital capacity (FVC), FEV 1 /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 FEV 1 (β=2.5, p=4.9 × 10 -3 ) and FVC (β=7.6, p=7.7 × 10 -14 ) but lower FEV 1 /FVC (β=−3.9, p=2.0 × 10 -16 ); vitamin D showed no association. In adults, both vitamins were positively associated with FEV 1 (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 FEV 1 /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.