MicroRNAs in hemostasis

Teruel‐Montoya, Raúl; Rosendaal, Frits R.; Martı́nez, Constantino

doi:10.1111/jth.12788

Cited by 44 publications

(42 citation statements)

References 99 publications

(107 reference statements)

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“…Since these two modules contain over 100 genes each, we took advantage of the putative role of miRNAs in platelet reactivity regulation (Teruel-Montoya et al 2015) to identify the most promising genes by selecting candidate miRNAs' targets within these modules. The miRNA expression levels correlated well with previous studies (Landry et al 2009;Nagalla et al 2011;Simon et al 2014) and 12 miRNAs were differentially expressed between the two groups of patients.…”

Section: Discussionmentioning

confidence: 99%

“…Two sub-networks were thus identified containing 123 and 182 genes, respectively. Since miRNAs seem to play an important role in platelet physiology (Esteller 2011;Teruel-Montoya et al 2015;Willeit et al 2013), we evaluated differentially expressed platelet miRNAs in these 2 groups of patients and identified their predicted gene targets within the subnetworks. We provide here original findings derived from an integrative networkbased approach for the understanding of the modulators of platelet reactivity in CV patients.…”

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confidence: 99%

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New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach

et al. 2016

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Platelet reactivity (PR) is variable between individuals and modulates clinical outcome in cardiovascular (CV) patients treated with antiplatelet drugs. Although several data point to a genetic control of platelet reactivity, the genes contributing to the modulation of this phenotype are not clearly identified. Integration of data derived from high-throughput technologies may yield novel insights into the molecular mechanisms that govern platelet reactivity. The aim of this study is to identify candidate genes modulating platelet reactivity in aspirin-treated CV patients using an integrative network-based approach. Patients with extreme high (n = 6) or low PR (n = 6) were selected and data derived from quantitative proteomic of platelets and platelet sub-cellular fractions, as well as from transcriptomic analysis were integrated with a network biology approach. Two modules within the network containing 123 and 182 genes were identified. We then specifically assessed the level of miRNAs in these two groups of patients. Among the 12 miRNAs differentially expressed, 2 (miR-135a-5p and miR-204-5p) correlated with PR. The predicted targets of these miRNAs were mapped onto the network, allowing the identification of seven overlapping genes (THBS1, CDC42, CORO1C, SPTBN1, TPM3, GTPBP2, and MAPRE2), suggesting a synergistic effect of these two miRNAs on these predicted targets. Integration of several omics data sets allowed the identification of 2 candidate miRNAs and 7 candidate genes regulating platelet reactivity in aspirin-treated CV patients.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach

et al. 2016

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“…This makes it likely that this phenotype is caused by the genetic defect found in these families. Despite the absence of linkage data, other potential causes for antithrombin deficiency in these patients may be found outside the direct molecular context of SERPINC1 gene regulation, such as microRNAs (Teruel‐Montoya et al , ) or the antithrombin‐modulating gene LARGE1 (de la Morena‐Barrio et al , ). Recently, de la Morena‐Barrio et al () identified hypoglycosylation, not only of antithrombin but also of other N‐glycoproteins in 8 out of 30 antithrombin‐deficient cases without alterations in SERPINC1 .…”

Section: Discussionmentioning

confidence: 99%

“…This makes it likely that this phenotype is caused by the genetic defect found in these families. Despite the absence of linkage data, other potential causes for antithrombin deficiency in these patients may be found outside the direct molecular context of SER-PINC1 gene regulation, such as microRNAs (Teruel-Montoya et al, 2015) or the antithrombin-modulating gene LARGE1 The novel mutations included 3 missense mutations, 1 splice site variant and 1 insertion. The novel missense mutation p.Phe179Cys (147) was identified in 1 family (Family A).…”

Section: Discussionmentioning

confidence: 99%

SERPINC1 gene mutations in antithrombin deficiency

Mulder

Huntington

et al. 2017

Br J Haematol

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Existing evidence suggests that in most cases antithrombin deficiency can be explained by mutations in its gene, SERPINC1. We investigated the molecular background of antithrombin deficiency in a single centre family cohort study. We included a total of 21 families comprising 15 original probands and sixty-six relatives, 6 of who were surrogate probands for the genetic analysis. Antithrombin activity and antigen levels were measured. The heparin-antithrombin binding ratio assay was used to distinguish between the different subtypes of type II antithrombin deficiency. SERPINC1 mutations were detected by direct sequencing of all 7 exons and regulatory regions, and multiplex ligation-dependent probe amplification. Eighty-six per cent of the families had a detrimental SERPINC1 gene mutation that segregated in the family. We detected 13 different SERPINC1 gene mutations of which 5 were novel. Among all these mutations, 44% was associated with type I deficiency, whereas the remainder was associated with type II heparin binding site (11%), type II pleiotropic effect (33%), type II reactive site (6%) or had the antithrombin Cambridge II mutation (6%). The current study reports several novel SERPINC1 mutations, thereby adding to our knowledge of the molecular background of antithrombin deficiency. Finally, our results point out the importance of future research outside the conventional SERPINC1 gene approach.

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“…MiRNAs are small non-coding conserved RNAs of about 22 nucleotides, which predominantly bind to the 3 0 untranslated region (UTR) of target genes (Bartel, 2009). Recent in vitro studies demonstrated that plasminogen-activator inhibitor-1 (PAI-1), fibrinogen, tissue factor and factor XI may be regulated by miRNAs, thereby supporting their role in regulating levels of haemostatic factors (Fort et al, 2010;Teruel et al, 2011;Marchand et al, 2012;Salloum-Asfar et al, 2014;Teruel-Montoya et al, 2015). Recent in vitro studies demonstrated that plasminogen-activator inhibitor-1 (PAI-1), fibrinogen, tissue factor and factor XI may be regulated by miRNAs, thereby supporting their role in regulating levels of haemostatic factors (Fort et al, 2010;Teruel et al, 2011;Marchand et al, 2012;Salloum-Asfar et al, 2014;Teruel-Montoya et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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MicroRNAs in hemostasis

Cited by 44 publications

References 99 publications

New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach

New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach

SERPINC1 gene mutations in antithrombin deficiency

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

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