Identification of coagulation gene 3′UTR variants that are potentially regulated by microRNAs

Abstract

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.

What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies

“…All these observations strongly suggest that properly designed studies investigating DNA methylation marks associated with VTE deserve to be conducted. In a similar way, the expression of several VTE‐associated genes are predicted to be regulated by microRNAs (Marchand et al , ; Wang et al , ; Sennblad et al , ; Vossen et al , ). Several candidate microRNAs have been proposed as novel biomarkers for VTE as part of a case‐control study on plasma samples (Starikova et al , ).…”

A Bioinformatics Toolkit: In Silico Tools and Online Resources for Investigating Genetic Variation

“…Micro-RNAs (miRNAs) play a role in regulating gene expression and studies have highlighted interactions with coagulation factors. 51,52 A useful (regularly updated) online resource for investigating whether genetic variants influence reported/potential miRNA binding targets or generate a potential miRNA binding target is miRBase (►Table 2).…”

A novel rationale for targeting FXI: Insights from the hemostatic miRNA targetome for emerging anticoagulant strategies

“…Chen, et al, 2010). SNPs in the 3′UTR of the F2, F8 and F11 genes are associated with increased plasma activity of the gene-products (Rosset, Vieira, Salzano, & Bandinelli, 2016;Sabater-Lleal, et al, 2012;Sennblad, et al, 2017;Voetsch & Loscalzo, 2004;Vossen, et al, 2017).…”

“…Dysregulated miRNA-mediated control of factor XI expression can increase thrombotic risk. The F11 3'UTR SNP rs4253430 is associated with plasma factor XI levels and clotting time in idiopathic thrombophilia patients (Sabater-Lleal, et al, 2012;Sennblad, et al, 2017), and with increased factor XI activity and risk of VTE (Vossen, et al, 2017). This SNP disrupts a binding site for miR-544a preventing the miRNA from silencing factor XI expression and resulting in increased plasma factor XI activity (Vossen, et al, 2017).…”

“…Zhou Zhang, 2014;X. F. Zhu, et al, 2015) miR-30a-3p Targets FXI (Nourse, et al, 2018) miR-30a-3p Biomarker for AMI and ischemic stroke (Long, et al, 2012;Long, et al, 2013) miR-30d-3p Targets FXI (Nourse, et al, 2018) miR-544a Targets FXI (Vossen, et al, 2017) miR-96-5p Targets FXI (Nourse, et al, 2018) miR-96-5p Biomarker for DVT and DIC (Xie, et al, 2016;…”