Roldán Vanessa, Arroyo Ana Belen, Salloum-Asfar Sallam, Manzano-Fernández Sergio, García-Barberá Nuria, Marín Francisco, Vicente Vicente, González-Conejero Rocío, Martínez Constantino
Rocío González-Conejero, Centro Regional de Hemodonación, Ronda de Garay s/n, 30003 Murcia, Spain, Tel.: +34 968341990, Fax: +34 968261914, E-mail:
Constantino Martínez, Centro Regional de Hemodonación, Ronda de Garay s/n, 30003 Murcia, Spain, Tel.: +34 968341990, Fax: +34 968261914, E-mail:
Thromb Haemost. 2014 Oct;112(4):781-8. doi: 10.1160/TH14-01-0092. Epub 2014 Jul 10.
There are few biomarkers able to forecast new thrombotic events in patients with AF. In this framework, microRNAs have emerged as critical players in cardiovascular biology. In particular, miR-146a-5p is recognised as an important negative regulator of inflammation. This study aims to evaluate the prognostic role and biological effect of functional MIR146A polymorphisms, rs2431697 and rs2910164, in non-valvular atrial fibrillation (AF) patients under oral anticoagulation.We studied 901 patients with permanent/paroxysmal AF stabilized for at least six months. Patients were followed-up for two years and adverse cardiovascular events (ACE) were recorded. In vitro studies were performed in monocytes from healthy homozygous for the two genotypes of rs2431697. Rs2910164 had no association with ACE. However, multivariate analysis (adjusted by CHA2DS2-VASc score) revealed that rs2431697TT was associated with adverse cardiovascular events [HR: 1.64 (1.09-2.47); p=0.017]. The predictive value of usefulness of the CHA2DS2-VASc+IL6+rs2431697 for predicting ACE, was statistically better than that predicted by CHA2DS2-VASc+IL6. Functional studies showed that after 24 hours incubation, monocytes from CC individuals showed a 65 % increase in miR-146a-5p levels, while TT individuals only showed a 28 % increase. Indeed, after 24 hours of LPS activation, TT monocytes showed a higher increase in IL6 mRNA expression than CC (52 % vs 26 %). Our study established MIR146A rs2431697 as a prognostic biomarker for ACE in anticoagulated AF patients. These data suggest that TT individuals, when submitted to an inflammatory stress, may be prone to a highest pro-inflammatory state due, in part, to lower levels of miR-146a-5p.
能够预测房颤患者新血栓形成事件的生物标志物很少。在此背景下，微小RNA已成为心血管生物学中的关键因素。特别是，miR-146a-5p被认为是炎症的重要负调节因子。本研究旨在评估功能性MIR146A基因多态性rs2431697和rs2910164在接受口服抗凝治疗的非瓣膜性房颤（AF）患者中的预后作用和生物学效应。我们研究了901例永久性/阵发性房颤且病情稳定至少6个月的患者。对患者进行了两年的随访，并记录不良心血管事件（ACE）。对rs2431697两种基因型的健康纯合子单核细胞进行了体外研究。Rs2910164与ACE无关联。然而，多变量分析（根据CHA2DS2-VASc评分进行调整）显示，rs2431697TT与不良心血管事件相关[风险比：1.64（1.09-2.47）；p=0.017]。CHA2DS2-VASc+IL6+rs2431697预测ACE的有用性的预测价值在统计学上优于CHA2DS2-VASc+IL6预测的价值。功能研究表明，孵育24小时后，CC个体的单核细胞miR-146a-5p水平增加65%，而TT个体仅增加28%。事实上，LPS激活24小时后，TT单核细胞的IL6 mRNA表达增加幅度高于CC（52%对26%）。我们的研究确定MIR146A rs2431697是接受抗凝治疗的房颤患者ACE的预后生物标志物。这些数据表明，TT个体在受到炎症应激时，可能部分由于miR-146a-5p水平较低而易于处于更高的促炎状态。
