Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Partner Site Rhine-Main, German Centre for Cardiovascular Research (DZHK), Mainz, Germany. Electronic address: https://twitter.com/cesm_mainz.
Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
J Thromb Haemost. 2023 Oct;21(10):2797-2810. doi: 10.1016/j.jtha.2023.07.010. Epub 2023 Jul 20.
Recurrent events frequently occur after venous thromboembolism (VTE) and remain difficult to predict based on established genetic, clinical, and proteomic contributors. The role of circulating microRNAs (miRNAs) has yet to be explored in detail.
To identify circulating miRNAs predictive of recurrent VTE or death, and to interpret their mechanistic involvement.
Data from 181 participants of a cohort study of acute VTE and 302 individuals with a history of VTE from a population-based cohort were investigated. Next-generation sequencing was performed on EDTA plasma samples to detect circulating miRNAs. The endpoint of interest was recurrent VTE or death. Penalized regression was applied to identify an outcome-relevant miRNA signature, and results were validated in the population-based cohort. The involvement of miRNAs in coregulatory networks was assessed using principal component analysis, and the associated clinical and molecular phenotypes were investigated. Mechanistic insights were obtained from target gene and pathway enrichment analyses.
A total of 1950 miRNAs were detected across cohorts after postprocessing. In the discovery cohort, 50 miRNAs were associated with recurrent VTE or death (cross-validated C-index, 0.65). A weighted miRNA score predicted outcome over an 8-year follow-up period (HR, 2.39; 95% CI, 1.98-2.88; P < .0001). The independent validation cohort validated 20 miRNAs (OR for score, 3.47; 95% CI, 2.37-5.07; P < .0001; cross-validated-area under the curve, 0.61). Principal component analysis revealed 5 miRNA networks with distinct relationships to clinical phenotype and outcome. Mapping of target genes indicated regulation via transcription factors and kinases involved in signaling pathways associated with fibrinolysis.
Circulating miRNAs predicted the risk of recurrence or death after VTE over several years, both in the acute and chronic phases.
静脉血栓栓塞症（VTE）后经常发生复发性事件，但基于已确定的遗传、临床和蛋白质组学因素，仍难以预测。循环 microRNAs（miRNAs）的作用尚未详细探讨。
确定可预测复发性 VTE 或死亡的循环 miRNAs，并解释其潜在的作用机制。
对急性 VTE 队列研究中的 181 名参与者和基于人群的 VTE 队列中的 302 名个体的 EDTA 血浆样本进行下一代测序，以检测循环 miRNAs。感兴趣的终点为复发性 VTE 或死亡。应用惩罚回归识别与结局相关的 miRNA 特征，并在基于人群的队列中进行验证。使用主成分分析评估 miRNA 在核心调控网络中的作用，并研究相关的临床和分子表型。通过靶基因和途径富集分析获得机制见解。
经后处理，两个队列中共检测到 1950 种 miRNAs。在发现队列中，有 50 种 miRNA 与复发性 VTE 或死亡相关（交叉验证 C 指数，0.65）。加权 miRNA 评分可预测 8 年随访期间的结局（HR，2.39；95%CI，1.98-2.88；P<0.0001）。独立验证队列验证了 20 种 miRNA（评分的 OR，3.47；95%CI，2.37-5.07；P<0.0001；交叉验证曲线下面积，0.61）。主成分分析显示，有 5 个 miRNA 网络与临床表型和结局有不同的关系。靶基因的映射表明，通过参与纤溶相关信号通路的转录因子和激酶进行调控。
在急性和慢性阶段，循环 miRNAs 均可在数年时间内预测 VTE 后的复发或死亡风险。
