Department of Neuroendocrinology and Bone Diseases, Endocrinology Research Centre, Moscow, Russia.
Genetics Laboratory, Federal Research and Clinical Center FMBA of Russia, Moscow, Russia.
J Clin Endocrinol Metab. 2022 Jan 18;107(2):500-511. doi: 10.1210/clinem/dgab695.
Excessive production of growth hormone causes marked multiorgan changes in patients with acromegaly, which may involve epigenetic mechanisms.
To evaluate differences in circulating microRNAs (miRNAs) associated with chronic growth hormone overproduction in adults.
A cross-sectional case-control study was conducted at a tertiary medical center.
We enrolled 12 consecutive patients with acromegaly along with 12 age- and 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.
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.
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, Padjusted < 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, Padjusted < 0.001), AUC 0.829 (95% CI 0.698-0.907; P < 0.001) to differentiate patients with acromegaly from healthy controls.
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.
生长激素过度分泌会导致肢端肥大症患者多器官发生明显变化，这可能涉及表观遗传机制。
评估与成年人慢性生长激素过度产生相关的循环 microRNAs（miRNAs）的差异。
在一家三级医疗中心进行了一项横断面病例对照研究。
在研究的发现阶段，我们连续纳入了 12 例肢端肥大症患者和 12 例年龄和性别匹配的对照组，并将该队列扩展至 47 例肢端肥大症患者和 28 例健康对照组进行验证研究。
在发现阶段通过下一代测序（NGS）定量血浆 miRNAs。使用逆转录定量聚合酶链反应（RT-qPCR）在扩展队列中验证选定 miRNA 的水平，在组间进行比较，并与临床参数相关联。
基于 NGS 数据，我们选择了 3 种在肢端肥大症患者中与健康对照组相比下调的血浆 miRNA：miR-4446-3p-1.317（P = 0.001），miR-215-5p-3.040（P = 0.005）和 miR-342-5p-1.875（P = 0.013），而这 3 种 miRNA 的多重校正均未校正。在验证阶段，通过 RT-qPCR 对 3 种 miRNA 中的 2 种进行了确认：miR-4446-3p（P < 0.001，P < 0.001），曲线下面积（AUC）为 0.862（95%CI 0.723-0.936；P < 0.001）和 miR-215-5p（P < 0.001，P < 0.001），AUC 为 0.829（95%CI 0.698-0.907；P < 0.001），以区分肢端肥大症患者与健康对照组。
在使用 2 种不同技术的 2 期实验中，我们发现并验证了与健康受试者相比，肢端肥大症患者血浆 miR-4446-3p 和 miR-215-5p 的下调，这使其成为进一步研究的有前途的生物标志物。
