From the Genomics of Complex Diseases Group, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain (A.R.-R., S.L., A.M.-P., J.M.S.).
Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (J.C.S.).
Arterioscler Thromb Vasc Biol. 2020 May;40(5):1392-1399. doi: 10.1161/ATVBAHA.120.314092. Epub 2020 Mar 12.
Venous thrombosis (VT) is a complex condition with a highly heritable genetic component that predisposes one to its development. Certain microRNAs (miRNAs) might be used as biomarkers of VT, but few studies have examined miRNA expression in this respect. The aim of the present work was to identify a plasma miRNA profile associated with VT. Approach and Results: miRNAs were analyzed by quantitative polymerase chain reaction in plasma samples from members of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) population (n=935). A discovery phase involving the screening of 752 miRNAs from a subset of 104 GAIT-2 subjects was followed by an internal validation phase in which the selected miRNAs were quantified in the whole GAIT-2 population. In the discovery phase, 16 miRNAs were selected, including 9 associated with VT and 7 that correlated with an intermediate phenotype of VT. In the next phase, 4 miRNAs were validated as differentially expressed (false discovery rate, <0.1) in VT: hsa-miR-126-3p, hsa-miR-885-5p, hsa-miR-194-5p, and hsa-miR-192-5p. The 4 miRNAs each returned a significant (<0.05) odds ratio for VT (range of 1.3-1.8). A risk model including the 4 miRNAs, age, and sex returned an area under the receiver operating characteristic curve of 0.77. Moreover, all 4 miRNAs showed significant correlations with intermediate phenotypes of VT (eg, protein S and factor VII). The targets of the miRNAs in the blood coagulation pathway and their interactions are also discussed.
The present results suggest a 4-miRNA plasma profile associated with VT is of potential use in predicting the risk of this condition.
静脉血栓形成（VT）是一种具有高度遗传性遗传成分的复杂疾病，使其易于发生。某些 microRNAs（miRNAs）可能被用作 VT 的生物标志物，但很少有研究在这方面检查 miRNA 的表达。本研究的目的是确定与 VT 相关的血浆 miRNA 谱。
通过定量聚合酶链反应分析 GAIT-2（特发性血栓形成遗传分析 2）人群（n=935）成员的血浆样本中的 miRNA。首先进行了包括 104 个 GAIT-2 主题中的 104 个亚组的 752 个 miRNA 的筛选发现阶段，然后在整个 GAIT-2 人群中对选定的 miRNA 进行了内部验证阶段。在发现阶段，选择了 16 个 miRNA，包括 9 个与 VT 相关的 miRNA 和 7 个与 VT 的中间表型相关的 miRNA。在下一阶段，在 VT 中验证了 4 个 miRNA 的差异表达（错误发现率<0.1）：hsa-miR-126-3p、hsa-miR-885-5p、hsa-miR-194-5p 和 hsa-miR-192-5p。这 4 个 miRNA 各自为 VT 提供了显著的（<0.05）比值比（1.3-1.8 范围）。包括 4 个 miRNA、年龄和性别在内的风险模型返回了 0.77 的接收者操作特征曲线下面积。此外，所有 4 个 miRNA 均与 VT 的中间表型（例如蛋白 S 和因子 VII）显著相关。还讨论了血液凝固途径中 miRNA 的靶标及其相互作用。
本研究结果表明，与 VT 相关的 4-miRNA 血浆谱在预测该疾病的风险方面具有潜在的应用价值。
