Exploring plasma microRNA profiling and signaling pathways in comorbidity-free sickle cell anemia: a pilot case-control study

Objective: Sickle cell anemia (SCA) is associated with substantial end‑organ morbidity, yet the circulating microRNA (miRNA) landscape in clinically stable, comorbidity‑free adults with SCA is poorly defined. This pilot case-control study with a limited sample size aimed to characterize a baseline plasma miRNA signature of SCA by comparing comorbidity‑free adults with SCA and strictly matched controls, with findings intended to be hypothesis‑generating. Results: Using the Mass General Brigham Biobank, we identified 4 adults with HbSS SCA and 12 HbAA controls, matched 1:3 by age, sex, and estimated glomerular filtration rate. All participants were free of diabetes, hypertension, cardiovascular disease, chronic kidney disease, and proteinuria. Plasma small RNA sequencing identified 41 differentially expressed miRNAs in SCA versus controls (2 upregulated, 39 downregulated; p < 0.05). These miRNAs mapped to 99 enriched KEGG pathways, including PI3K/Akt, MAPK, and Hippo signaling, which are implicated in endothelial dysfunction, vasculopathy, and organ complications relevant to SCA. These preliminary, hypothesis‑generating findings from a small pilot cohort support the presence of subclinical vascular and inflammatory pathway dysregulation in comorbidity‑free SCA and provide candidate miRNAs and pathways for future validation in larger, independent cohorts. These results represent unvalidated discovery signals and should not be interpreted as a definitive miRNA profile.