{
  "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 (FEV 1%) 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 FEV 1% 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.",
  "authors": [
    {
      "affiliations": [
        "Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China"
      ],
      "name": "Mingye Jiang"
    },
    {
      "affiliations": [
        "Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China",
        "Department of Andrology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China"
      ],
      "name": "Yunxiao Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Respiratory Disease, Joint International Research Laboratory of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Tao Liu"
    },
    {
      "affiliations": [
        "Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China"
      ],
      "name": "Xiaoning Hong"
    },
    {
      "affiliations": [
        "Computational Health Informatics Program, Boston Children’s Hospital, Boston, Massachusetts, USA",
        "Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Alvin T Kho"
    },
    {
      "affiliations": [
        "Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China"
      ],
      "name": "Jiang Li"
    },
    {
      "affiliations": [
        "Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China"
      ],
      "name": "Yunfei Gao"
    },
    {
      "affiliations": [
        "Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Rinku Sharma"
    },
    {
      "affiliations": [
        "Division of Pulmonary Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"
      ],
      "name": "Juan Carlos Celedon"
    },
    {
      "affiliations": [
        "Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Michael McGeachie"
    },
    {
      "affiliations": [
        "Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA",
        "Partners Personalized Medicine, Partners Healthcare, Boston, Massachusetts, USA"
      ],
      "name": "Scott Weiss"
    },
    {
      "affiliations": [
        "Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA",
        "Division of Respiratory Medicine, Department of Pediatrics, University of California San Diego, La Jolla, California, USA"
      ],
      "name": "Kelan G Tantisira"
    },
    {
      "affiliations": [
        "Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China",
        "Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA",
        "Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China"
      ],
      "name": "Jiang Li"
    }
  ],
  "title": "Circulating miRNAs and childhood asthma ICS response: a stratified analysis in the intervention arm of an RCT with vitamin D effect modification",
  "uid": "e96c336b-d87e-53c7-a2fa-b79a915b02d6"
}