Vossen Carla Y, van Hylckama Vlieg Astrid, Teruel-Montoya Raúl, Salloum-Asfar Salam, de Haan Hugoline, Corral Javier, Reitsma Pieter, Koeleman Bobby P C, Martínez Constantino
Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands.
Br J Haematol. 2017 Jun;177(5):782-790. doi: 10.1111/bjh.14629. Epub 2017 Apr 26.
MicroRNAs have been recognized as critical regulators of gene expression and might affect the risk of venous thrombosis. We aimed to identify 3' untranslated region (UTR) variants in coagulation genes that influence coagulation factor levels and venous thrombosis risk. The 3'UTR of coagulation genes were sequenced in subjects with extremely high or low plasma levels of these factors in two case-control studies. In total, 28 variants were identified. Five single nucleotide polymorphisms (SNPs) were predominantly present in one extreme level group (F2 rs1799963, F8 rs1050705 and F11 rs4253429, rs4253430 and rs1062547). Additional to F2 rs1799963, F8 rs1050705 (in men) and F11 rs4253430 were associated with an increased risk of venous thrombosis albeit confidence intervals were wide. The three F11 SNPs were in high linkage disequilibrium with functional variants rs2289252 and rs2036914. Rs1062547 and rs4253430 were associated with a significant increase of plasma FXI activity in heterozygotes and homozygotes in wild-type controls. In silico prediction revealed that these SNPs might disturb the binding sites of miR-544 and miR-513a-3p. Only miR-544 provoked a significant decrease of the luciferase activity that was not observed with a rs4253430 mutated vector. In conclusion, these results reinforce that microRNAs are candidates to play a role in haemostasis and complex disorders, such as thrombosis.
微小RNA已被公认为基因表达的关键调节因子，可能影响静脉血栓形成的风险。我们旨在鉴定凝血基因的3'非翻译区（UTR）变异，这些变异会影响凝血因子水平和静脉血栓形成风险。在两项病例对照研究中，对这些因子血浆水平极高或极低的受试者的凝血基因3'UTR进行了测序。总共鉴定出28个变异。五个单核苷酸多态性（SNP）主要存在于一个极端水平组中（F2 rs1799963、F8 rs1050705和F11 rs4253429、rs4253430和rs1062547）。除F2 rs1799963外，F8 rs1050705（在男性中）和F11 rs4253430与静脉血栓形成风险增加相关，尽管置信区间较宽。F11的三个SNP与功能变异rs2289252和rs2036914处于高度连锁不平衡状态。在野生型对照中，rs1062547和rs4253430与杂合子和纯合子血浆FXI活性的显著增加相关。计算机模拟预测表明，这些SNP可能会干扰miR-544和miR-513a-3p的结合位点。只有miR-544导致荧光素酶活性显著降低，而rs4253430突变载体未观察到这种情况。总之，这些结果进一步证明微小RNA可能在止血和血栓形成等复杂疾病中发挥作用。
