Circulating Piwi-Interacting RNAs Associate With Childhood Asthma ICS Response With Vitamin D Effect Modification

Piwi-interacting RNAs (piRNAs) have been linked to type 2-high asthma phenotypes. Although vitamin D modulates inhaled corticosteroid (ICS) response via microRNAs, its potential role through piRNAs remains unknown.

Baseline plasma piRNA expression was profiled by small RNA sequencing in 492 participants from the Childhood Asthma Management Program (CAMP), with 187 children randomised to the ICS arm. Serum vitamin D levels were classified as insufficient (≤ 30 ng/mL) or sufficient (> 30 ng/mL). Linear regression was used to assess associations between piRNA expression and changes in prebronchodilator percent predicted forced expiratory volume in 1 s (FEV₁%) over 4 years, including interaction analyses with vitamin D status. Replication was performed in 375 ICS-treated participants from the Genetics of Asthma in Costa Rica Study (GACRS).

Fourteen piRNAs were significantly associated with FEV₁% changes among vitamin D-insufficient children, six showing significant interactions with vitamin D status (p < 0.05). Four piRNAs were replicated in GACRS, with piR-36241 also confirmed in interaction analyses. Predicted targets of piR-36241 were enriched in immune- and respiratory-related pathways. piR-36241 demonstrated strong predictive performance for ICS response in vitamin D-insufficient children (AUROC = 0.84) and was detected in bronchial epithelial cells, where it was differentially expressed in asthma.

Circulating piRNAs are associated with ICS response in childhood asthma, with vitamin D acting as an effect modifier, which may serve as non-invasive biomarkers for ICS responsiveness, particularly in vitamin D-insufficient patients.

ClinicalTrials.gov Identifier: NCT00000575 and NCT00021840.