Circulating miRNAs and childhood asthma ICS response: a stratified analysis in the intervention arm of an RCT with vitamin D effect modification

Abstract

Background: miRNAs play a crucial role in the anti-inflammatory effects of inhaled corticosteroids (ICS) in asthma. Vitamin D can modulate the expression of several miRNAs and reduces asthma exacerbations, but its molecular interaction with ICS remains unclear.

Objective: We hypothesised that vitamin D influences long-term ICS response through miRNA regulation.

Methods: Baseline serum miRNAs were sequenced from 462 subjects in the Childhood Asthma Management Program (CAMP), with 187 randomised to ICS treatment included in this study. Linear regression assessed associations between miRNA expression and prebronchodilator forced expiratory volume in 1 s per cent predicted (FEV₁%) change over 4 years, stratified by baseline vitamin D levels and tested in interaction models. Microarray analysis of lymphoblastoid B cells (lymphoblastoid cell lines (LCLs)) from 22 CAMP subjects treated with dexamethasone (DEX), vitamin D or sham identified differentially expressed genes (DEGs). An miRNA target gene network was constructed, clustered and annotated by enrichment analysis. Top miRNAs were evaluated for ICS response prediction.

Results: 12 miRNAs were significantly associated with ICS-mediated FEV₁% change in vitamin D insufficient subjects, and 11 miRNAs showed significant interaction with vitamin D (p≤0.05). Three miRNAs were approximately replicated in the Genetics of Asthma in Costa Rica Study. Microarray analysis identified 220 and 240 DEGs in DEX and vitamin D-treated LCLs, respectively. miRNAs hsa-miR-125a-5p, hsa-miR-181a-5p, hsa-miR-101-3p and hsa-miR-107 were enriched in haemopoiesis and leucocyte differentiation pathways (p≤0.05). Two miRNAs, hsa-miR-125a-5p and hsa-miR-181a-5p, predicted ICS response with an area under the receiver operating characteristic curve of 0.86 in the vitamin D insufficient group.

Conclusions: Vitamin D may modulate ICS response through miRNAs involved in immune cell differentiation, which could serve as biomarkers for ICS response, particularly in vitamin D insufficient individuals.

Keywords: Asthma; Asthma Mechanisms; Child; Paediatric asthma.