Circulating Plasma MicroRNA in Patients With Active Acromegaly

Context: Excessive production of growth hormone causes marked multiorgan changes in patients with acromegaly, which may involve epigenetic mechanisms. Objective: To evaluate differences in circulating microRNAs (miRNAs) associated with chronic growth hormone overproduction in adults. Design and Setting: A cross-sectional case-control study was conducted at a tertiary medical center. Participants: We enrolled 12 consecutive patients with acromegaly along with 12 ageand sex-matched controls in the discovery phase of the study and then extended this cohort to 47 patients with acromegaly and 28 healthy controls for the validation study. Main Outcome Measures: Plasma miRNAs were quantified by next-generation sequencing (NGS) in the discovery phase. Levels of selected miRNAs were validated on extended cohorts using reverse transcription quantitative polymerase chain reaction (RT-qPCR), compared between groups, and correlated with clinical parameters. Results: Based on NGS data, we selected 3 plasma miRNAs downregulated in patients with acromegaly compared to healthy controls: miR-4446-3p -1.317 (P = 0.001), miR-215-5p -3.040 (P = 0.005), and miR-342-5p -1.875 (P = 0.013) without multiplicity correction for all 3 miRNAs. These results were confirmed by RT-qPCR in the validation phase for 2 miRNAs out of 3: miR-4446-3p (P < 0.001, P-adjusted < 0.001), area under the receiver-operator curve (AUC) 0.862 (95% CI 0.723-0.936; P < 0.001) and miR-215-5p (P < 0.001, P-adjusted < 0.001), AUC 0.829 (95% CI 0.698-0.907; P < 0.001) to differentiate patients with acromegaly from healthy controls. Conclusions: In a 2-phase experiment using 2 different techniques we found and validated the downregulation of plasma miR-4446-3p and miR-215-5p in patients with acromegaly compared to healthy subjects, which makes them promising biomarkers for further research.