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

Vitamin D can modulate the expression of several miRNAs and reduces asthma exacerbations, but its molecular interaction with ICS remains unclear.

维生素D可以调节几种miRNAs的表达并减少哮喘发作，但它与ICS的分子相互作用尚不清楚。

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

我们假设维生素D通过miRNA调控影响长期ICS反应。

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.

在儿童哮喘管理计划（CAMP）中，从462名受试者中进行了基线血清miRNAs测序，其中187名随机接受ICS治疗的受试者被纳入本研究。

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.

线性回归评估了miRNA表达与基线维生素D水平分层的4年内支气管扩张前1秒用力呼气量占预测值百分比（FEV1%）变化之间的关联，并在交互作用模型中进行了测试。

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).

对22名CAMP受试者使用地塞米松（DEX）、维生素D或安慰剂处理的淋巴母细胞B细胞（淋巴母细胞系（LCLs））进行了微阵列分析，识别了差异表达基因（DEGs）。

An miRNA target gene network was constructed, clustered and annotated by enrichment analysis.

构建了一个miRNA靶基因网络，通过聚类和富集分析进行了注释。

Top miRNAs were evaluated for ICS response prediction.

评估了顶级miRNAs对ICS反应预测的效能。

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).

在维生素D不足的受试者中，有12种微小RNA（miRNAs）与吸入性糖皮质激素（ICS）介导的第1秒用力呼气容积（FEV1%）变化显著相关，且有11种miRNAs显示出与维生素D的显著相互作用（p≤0.05）。

Three miRNAs were approximately replicated in the Genetics of Asthma in Costa Rica Study.

在哥斯达黎加哮喘遗传学研究中，有三种微小RNA（miRNAs）的发现得到了大致复制。

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).

微阵列分析分别在DEX和维生素D处理的LCLs中识别出220个和240个差异表达基因（DEGs）。miRNAs hsa-miR-125a-5p、hsa-miR-181a-5p、hsa-miR-101-3p和hsa-miR-107在造血和白细胞分化通路中富集（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.

两种miRNAs，hsa-miR-125a-5p和hsa-miR-181a-5p，在维生素D不足组中预测ICS反应，接收者操作特征曲线下面积为0.86。

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.

维生素D可能通过参与免疫细胞分化的miRNAs调节ICS反应，这些miRNAs可能作为ICS反应的生物标志物，特别是在维生素D不足的个体中。