Changes in circular RNA expression in acute chest syndrome and vaso-occlusive crisis in sickle cell disease: analysis of a public RNA-seq cohort

Background: Sickle cell disease (SCD) is a monogenic hemoglobinopathy characterized by recurrent vaso-occlusive crises (VOCs) that affect any organ and progress to multi-organ failure. Acute chest syndrome (ACS) is a major complication and leading cause of death. This study explored whole-blood circRNA signatures as candidate molecular markers for VOC and ACS and examined their functional relevance through miRNA mapping and pathway enrichment. Research design and methods: A publicly available total RNA-seq dataset (GSE139912) was analyzed for circRNA expression at baseline (n = 12), VOC (n = 10), and ACS (n = 11). Results: Significant circRNA dysregulation was identified in ACS vs. baseline and VOC vs. baseline. An exploratory panel of the top 20 upregulated and 16 downregulated circRNAs in ACS was summarized as a composite circRNA score. The unchanged score increased stepwise across clinical states, with mean differences of 1.60 for VOC vs. baseline and 1.08 for ACS vs. VOC. Standardized effect sizes were Cohen’s d = 2.89 and 1.61, respectively. VOC showed intermediate scores between baseline and ACS. Enrichment analyses suggested immune and inflammatory involvement, including interleukin signaling and PI3K/AKT/MAPK-related cascades. Conclusions: These findings support circRNA expression as a source of candidate biomarkers for ACS and VOC, although validation in independent multicenter cohorts is required.