Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24 000 years ago

Abstract Prothrombin 20210G>A and factor V Leiden are common prothrombotic mutations in whites for which founder effects have been established. In this study, we analyzed the frequencies of 5 single nucleotide polymorphisms (SNPs) and 9 microsatellites flanking the prothrombin gene (F2) in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G>A mutation, we used the DMLE+2.0 program, which analyzed linkage disequilibria between the mutation and the multiple markers that had been assessed. This analysis yielded an age estimate of 23 720 years (95% credible set, 19 080-31 340 years). A similar analysis by the DMLE+2.0 program was performed on 5 SNPs from previously studied homozygotes for factor V Leiden and controls that yielded an age estimate of 21 340 years (95% credible set, 16 880-29 480 years). The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggest selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections).

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A Simple Genetic Thrombosis Score Of Five Single Nucleotide Polymorphisms Is Associated With Risk Of First Venous Thrombosis In Pregnant Women

Blood ◽

10.1182/blood.v122.21.3617.3617 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3617-3617

Author(s):

Lance A. Bare ◽

Hugoline G. de Haan ◽

Andre R. Arellano ◽

Carmen H. Tong ◽

James J. Devlin ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Venous Thrombosis ◽

Pregnant Women ◽

Odds Ratio ◽

Factor V Leiden ◽

Postpartum Women ◽

Factor V ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Unit Increase

Abstract Background Venous thrombosis (VT), a major cause of maternal morbidity and mortality, is increased 4- to 5- fold during pregnancy. A thrombosis score comprising 5 single nucleotide polymorphisms (SNPs) [rs6025 (Factor V Leiden), rs1799963 (Prothrombin 20210 G>A), rs8176719 (ABO 261G>deletion), rs2066865 (FGG 10034 C>T) and rs2036914 (F11 10364T>C)] was previously shown to be associated with VT events in the general population. We asked whether this thrombosis score could predict VT in pregnant and postpartum women in a case-control study on the etiology of thrombosis. Methods We studied women during pregnancy and up to three months postpartum (55 controls, 144 cases) selected from over 5000 female cases and controls of the MEGA (the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) study. The thrombosis score was calculated for each individual as a sum of risk alleles weighted by the log of the published odds ratio (de Haan et al, Blood 2012). The VT risk per unit of thrombosis score was calculated as a continuous variable in a logistic regression model that adjusted for age, smoking history and family history of VT. The thrombosis scores ranged from 0 to 1.8 in female participants in MEGA with genotypes for the 5 SNPs (n=3,464). Results In pregnant and postpartum women, the odds ratio per unit increase in thrombosis score was 10.7 (95%CI 3.2 to 36.2). When the thrombosis score was evaluated in a sub study of pregnant and postpartum women who do not carry factor V Leiden—an important contributant to the risk score— the remaining 4-SNP thrombosis score was also associated with VT: the odds ratio per unit increase in thrombosis score was 10.6 (95%CI 2.3-48.3).The American College of Obstetricians and Gynecologists recommends thromboprophylaxis during pregnancy and postpartum periods in women who are compound carriers of both factor V Leiden and prothrombin 20210 G>A; these compound carriers who do not carry other risk variants would have a thrombosis score of 1.02. Compared with women in the bottom quintile of thrombosis scores, women with thrombosis scores equal to or greater than 1.02 had an odds ratio for VT of 12.3 (95%CI 1.5 to 99.9). About 2% of female controls in MEGA had thrombosis scores equal to or greater than 1.02. Conclusions A 5-SNP thrombosis score that combines the VT risk of 5 genetic variants is associated with VT in pregnant women. Disclosures: Bare: Celera: Employment. Arellano:Celera: Employment. Tong:Celera: Employment. Devlin:Celera: Employment.

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Clinical Applications of Whole-Blood PCR with Real-Time Instrumentation

Clinical Chemistry ◽

10.1373/clinchem.2005.055327 ◽

2005 ◽

Vol 51 (11) ◽

pp. 2025-2030 ◽

Cited By ~ 11

Author(s):

Alison Castley ◽

Melinda Higgins ◽

John Ivey ◽

Cyril Mamotte ◽

David C Sayer ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Real Time ◽

Whole Blood ◽

Detection System ◽

Melting Curve ◽

Factor V Leiden ◽

Melting Curve Analysis ◽

Factor V ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

Abstract Background: As the genetic basis of many human diseases is being discovered, there is increasing need for the detection of single-nucleotide polymorphisms/mutations in medical laboratories. We describe an innovative approach that combines PCR amplification directly on whole blood and real-time detection PCR technology (WB-RTD PCR). Methods: We compared WB-RTD PCR with the method for extracted DNA-RTD PCR for the detection of mutations in the prothrombin (n = 94), factor V Leiden (n = 49), and hemochromatosis (n = 22) genes. Mutation detection on the Roche LightCycler was based on use of fluorescence resonance energy transfer (FRET) probes and melting curve analysis. We also compared the WB-RTD PCR on the LightCycler and the ABI Prism™ 7700 sequence detection system with minor groove– binding nonfluorescent quencher probes. Results: We obtained complete concordance between both methods in assigning genotypes. We also demonstrated that the WB-RTD PCR method can be performed on real-time PCR instruments from Applied Biosystems and the LightCycler. Omission of the need for DNA extraction and gel electrophoresis allowed substantial labor and cost savings with this method. Conclusion: This approach has applications for testing other medically relevant single-nucleotide polymorphisms.

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Investigation of the relationship between inherited thrombophilia and novel coronavirus pneumonia

Future Virology ◽

10.2217/fvl-2020-0395 ◽

2021 ◽

Author(s):

Aslihan Kiraz ◽

Seda Guzeldag ◽

Esma Eren ◽

Musa Goksu ◽

Arslan Bayram

Keyword(s):

Factor V Leiden ◽

Control Group ◽

Healthy Population ◽

Factor V ◽

Nucleotide Polymorphisms ◽

Healthy Control ◽

Prothrombin Gene ◽

Novel Coronavirus ◽

Relationship Of ◽

The Relationship

Aim: This study aimed to investigate the relationship between severe novel coronavirus pneumonia (NCP) and hypercoagulable conditions that predispose patients to thrombosis such as the prothrombin gene ( F2) rs1799963 (G20210A), factor V Leiden ( F5) rs6025 (G1691A) and PAI-1 (rs1799768). Patients: NCP-diagnosed 62 previously healthy patients were enrolled for the investigation of the thrombophilia-related polymorphisms. Materials & methods: The frequency of genotypes were compared with healthy control group frequencies from other studies. Results: There were no statistically significant differences between the severe patient group and the healthy population regarding the investigated single nucleotide polymorphisms (SNPs). Conclusion: This study is the first to rule out the relationship of rs1799963, rs6025 and rs1799768 with severe NCP.

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Risk of thromboembolic events (TEE) in metastatic colorectal cancer (mCRC) patients with single nucleotide polymorphisms (SNPs) in Factor V Leiden (FVL), Prothrombin, Plasminogen Activator Inhibitor-1 (PAI-1) and Methylenetetrahydrofolate Reductase (MTHFR)

Annals of Oncology ◽

10.1093/annonc/mdv340.16 ◽

2015 ◽

Vol 26 ◽

pp. vi41

Author(s):

S. Falvella ◽

C. Cremolini ◽

R. Miceli ◽

M. Niger ◽

R. Berenato ◽

...

Keyword(s):

Methylenetetrahydrofolate Reductase ◽

Factor V Leiden ◽

Plasminogen Activator Inhibitor ◽

Factor V ◽

Thromboembolic Events ◽

Nucleotide Polymorphisms ◽

Plasminogen Activator Inhibitor 1 ◽

Single Nucleotide ◽

Activator Inhibitor ◽

Pai 1

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Single Nucleotide Polymorphisms Other than Factor V Leiden Are Associated with Coagulopathy and Osteonecrosis of the Femoral Head in Chinese Patients

PLoS ONE ◽

10.1371/journal.pone.0104461 ◽

2014 ◽

Vol 9 (8) ◽

pp. e104461 ◽

Cited By ~ 6

Author(s):

Kou-Ti Peng ◽

Kuo-Chin Huang ◽

Tsan-Wen Huang ◽

Yun-Shien Lee ◽

Wei-Hsiu Hsu ◽

...

Keyword(s):

Femoral Head ◽

Single Nucleotide Polymorphisms ◽

Factor V Leiden ◽

Chinese Patients ◽

Factor V ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

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Influence of single nucleotide polymorphisms on thrombin generation in factor V Leiden heterozygotes

Thrombosis and Haemostasis ◽

10.1160/th13-05-0360 ◽

2014 ◽

Vol 111 (03) ◽

pp. 438-446 ◽

Cited By ~ 8

Author(s):

Olivier Segers ◽

Paolo Simioni ◽

Daniela Tormene ◽

Elisabetta Castoldi

Keyword(s):

Thrombin Generation ◽

Factor V Leiden ◽

Individual Variability ◽

Intermediate Phenotype ◽

Individual Risk ◽

Factor V ◽

Nucleotide Polymorphisms ◽

Factor X ◽

Large Variability ◽

Fv Leiden

SummaryCarriership of the factor V (FV) Leiden mutation increases the risk of venous thromboembolism (VTE) ~4-fold, but the individual risk of each FV Leiden carrier depends on several co-inherited risk and protective factors. Under the hypothesis that thrombin generation might serve as an intermediate phenotype to identify genetic modulators of VTE risk, we enrolled 188 FV Leiden heterozygotes (11 with VTE) and determined the following parameters: thrombin generation in the absence and presence of activated protein C (APC); plasma levels of prothrombin, factor X, antithrombin, protein S and tissue factor pathway inhibitor; and the genotypes of 24 SNPs located in the genes encoding these coagulation factors and inhibitors. Multiple regression analysis was subsequently applied to identify the (genetic) determinants of thrombin generation. The endogenous thrombin potential (ETP) showed a striking inter-individual variability among different FV Leiden carriers and, especially when measured in the presence of APC, correlated with VTE risk. Several SNPs in the F2 (rs1799963, rs3136516), F10 (rs693335), SERPINC1 (rs2227589), PROS1 (Heerlen polymorphism) and TFPI (rs5940) genes significantly affected the ETPAPC and/or the ETP+APC in FV Leiden carriers. Most of these SNPs have shown an association with VTE risk in conventional epidemiological studies, suggesting that the genetic dissection of thrombin generation leads to the detection of clinically relevant SNPs. In conclusion, we have identified several SNPs that modulate thrombin generation in FV Leiden heterozygotes. These SNPs may help explain the large variability in VTE risk observed among different FV Leiden carriers.

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