Allele frequency distribution of 1691G&gt;A F5 (which confers Factor V Leiden) across Europe, including Slavic populations

Jw, Clark; Adler, Grażyna; Salkić, Nermin N.; Ciechanowicz, Andrzej

doi:10.1007/s13353-013-0166-9

Cited by 18 publications

(22 citation statements)

References 56 publications

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“…Given its frequency in the Caucasian population (3.8%), 21 we can extrapolate that almost one hundred donors with that mutation received G-CSF in our cohort alone, without any adverse effects, supporting our approach to this entity. Donors engaging in sexual behaviors considered exclusion criteria for whole blood donation were not automatically excluded as donors; with specific testing for blood transmissible STDs and consent from the TC, such donors could be cleared for stem cell donation.…”

Section: Stem Cell Donors and Donor Evaluationsupporting

confidence: 55%

Deferrals of volunteer stem cell donors referred for evaluation for matched-unrelated stem cell donation

Bräuninger

Thorausch

Luxembourg

et al. 2014

Bone Marrow Transplant

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Section: Stem Cell Donors and Donor Evaluationsupporting

confidence: 55%

Deferrals of volunteer stem cell donors referred for evaluation for matched-unrelated stem cell donation

Bräuninger

Thorausch

Luxembourg

et al. 2014

Bone Marrow Transplant

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“…The Factor V Leiden variant (F5 L ) is a common inherited risk factor for VTE with an average allele frequency of 3.5% in the European population (6)(7)(8). F5 L is estimated to account for up to 25% of the genetically-attributable thrombosis risk in these populations (6).…”

Section: Introductionmentioning

confidence: 99%

A sensitized mutagenesis screen in Factor V Leiden mice identifies novel thrombosis suppressor loci

Westrick

Tomberg²,

Siebert³

et al. 2016

Preprint

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Factor V Leiden (F5 L ) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized ENU mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for F5 L (F5 L/L ) and haploinsufficient for tissue factor pathway inhibitor (Tfpi +/-). F8 deficiency enhanced survival of F5 L/L Tfpi +/mice, demonstrating that F5 L/L Tfpi +/lethality is genetically suppressible. ENU-mutagenized F5 L/L males and F5 L/+ Tfpi +/females were crossed to generate 6,729 progeny, with 98 F5 L/L Tfpi +/offspring surviving until weaning. Sixteen lines exhibited transmission of a putative thrombosuppressor to subsequent generations, with these lines referred to as MF5L (Modifier of Factor 5 Leiden) 1-16. Linkage analysis in MF5L6 identified a chromosome 3 locus containing the tissue factor gene (F3). Though no ENU-induced F3 mutation was identified, haploinsufficiency for F3 (F3 +/-) suppressed F5 L/L Tfpi +/lethality. Whole exome sequencing in MF5L12 identified an Actr2 gene point mutation (p.R258G) as the sole candidate. Inheritance of this variant is associated with suppression of F5 L/L Tfpi +/lethality (p=1.7x10 -6 ), suggesting that Actr2 p.R258G is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent Actr2 knockin/knockout demonstrated that Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain of function mechanism of action for Actr2 p.R258G . Our findings identify F8 and the Tfpi/F3 axis as key regulators in determining thrombosis balance in the setting of F5 L and also suggest a novel role for Actr2 in this process.Significance Statement (120 words max):Venous thromboembolism (VTE) is a common disease characterized by the formation of inappropriate blood clots. Inheritance of specific genetic variants, such as the Factor V Leiden polymorphism, increases VTE susceptibility. However, only ~10% of people inheriting Factor V Leiden develop VTE, suggesting the involvement of other genes that are currently unknown. By inducing random genetic mutations into mice with a genetic predisposition to VTE, we identified two genomic regions that reduce VTE susceptibility. The first includes the gene for blood coagulation Factor 3 and its role was confirmed by analyzing mice with an independent mutation in this gene. The second contains a mutation in the Actr2 gene. These findings identify critical genes for the regulation of blood clotting risk.

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“…Inconsistent results obtained from various authors highlight the genetic role among different ethnic groups [49, 50]. In Macedonia [51], FV Leiden is more prevalent in Macedonians (6.9%) than in Albanians (2.9%), whereas the prevalence of FV Leiden was higher in Kosovo (3.4%) [52] than in Albania (1.8%) [53].…”

Section: Discussionmentioning

confidence: 99%

Vascular Genetic Variants and Ischemic Stroke Susceptibility in Albanians from the Republic of Macedonia

Kamberi

Спироски³

2016

Open Access Maced J Med Sci

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BACKGROUND:Acute first-ever ischemic stroke (FIS) is a heterogeneous, polygenic disorder. The contribution of vascular genetic variants as inherited causes of ischemic stroke has remained controversial.AIM:To examine the association of genetic variants in vascular factors with the occurrence of FIS.MATERIAL AND METHODS:The current research was performed in a group of 39 patients with FIS (study group) and 102 healthy volunteers (control group). We analyzed the prevalence of vascular genetic variants in following genes: factor V, prothrombin, methylenetetrahydrofolate reductase (MTHFR), factor XIII, plasminogen activator 1, endothelial protein C receptor (EPCR), apolipoprotein B, apolipoprotein E, β-fibrinogen, human platelet antigen 1, angiotensin-converting enzyme (ACE), endothelial nitric oxide synthase (eNOS) and lymphotoxin alpha.RESULTS:It was found that heterozygous LTA 804C>A and FXIII V34L Leu/Leu were significantly more frequent in patients with FIS than in control group (p = 0.036 and p = 0.017, respectively). The frequency of FXIII V34L Val/Val was significantly lower in patients with FIS than in control group (p = 0.020). Other frequencies of vascular gene variants in patients with FIS and in control group were not significantly different.CONCLUSIONS:This is the first comprehensive study to present data indicating that polymorphism of vascular genes in the prevalence of acute FIS exists in the Albanian population from the Republic of Macedonia. Variations in these genes have been detected in patients with acute FIS, suggesting that their combination might act in a susceptible or protective manner in this Albanian population.

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Allele frequency distribution of 1691G>A F5 (which confers Factor V Leiden) across Europe, including Slavic populations

Abstract: The allele 1691A F5,

Cited by 18 publications

References 56 publications

Deferrals of volunteer stem cell donors referred for evaluation for matched-unrelated stem cell donation

Deferrals of volunteer stem cell donors referred for evaluation for matched-unrelated stem cell donation

A sensitized mutagenesis screen in Factor V Leiden mice identifies novel thrombosis suppressor loci

Vascular Genetic Variants and Ischemic Stroke Susceptibility in Albanians from the Republic of Macedonia

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