Dataset Information

Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation.

ABSTRACT: Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92?±?1.61 vs 2.81?±?1.57, p?=?0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

SUBMITTER: Ibrahim-Kosta M

PROVIDER: S-EPMC6403374 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation.

Ibrahim-Kosta M M Suchon P P Couturaud F F Smadja D D Olaso R R Germain M M Saut N N Goumidi L L Derbois C C Thibord F F Debette S S Amouyel P P Deleuze J F JF van Doorn P P Castoldi E E Patin E E Alessi M C MC Trégouët D A DA Morange P E PE

Scientific reports 20190306 1

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the associatio ...[more]

PMID: 30842582

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Project description:Abstract Introduction Venous thromboembolic events (VTE) are common complications in patients with glioblastoma (GBM). Factor V Leiden (FVL) polymorphism (rs6025, c.1601 G>A) is a known risk factor for VTE, evaluated in cancer associated thrombosis (CAT) in different tumor types. Little is known about the role of this variant in development of CAT in patients with GBM. Material and Methods A cohort of 116 GBM patients (73 males and 43 females) all treated with concomitant temozolomide and radiotherapy, were genotyped for FVL using PCR- pyrosequencing. Of the cohort, 40 patients were diagnosed with and 76 without VTE. Allele frequencies of respective variant were also compared with data from the SweGen Variant Frequency Browser (https://swegen-exac.nbis.se/). Statistical analyses in regard to VTE and its association with FVL and prognostic factors were performed. Results The variant A/G of FVL was carried by 17 (15%) of the patients and 99 (85%) were wild type, G/G. Chi2 test including the prognostic factors age, type of surgery, gender and blood group showed that these were evenly distributed between those with G/G and A/G, except for blood group in relation to FVL variant, which showed a borderline significance (p=0.07). Among the patients having blood group 0, 32% (n= 32) were G/G and 59% (n= 10) were A/G. Statistical tests did not reveal any correlation between blood group and FVL variant. In the logistic regression analysis apart from FVL, age, gender and blood group were included. This showed a significant difference for blood group 0 versus non-0 (A, B or AB) for decreased risk of VTE (P=0.014). There was no significant difference between heterozygous FVL (A/G) versus the G/G genotype in VTE risk (p=0.09). There were no differences in survival in relation to VTE or not or variant of FVL. The FVL AG variant is slightly overrepresented among GBM compared to the normal Swedish population, but does not reach statistical significance, OR 1.63 (0.93–2.84). Conclusions We examined the influence of FVL variants together with clinical factors in a homogenously treated cohort of GBM patients for the risk to develop a VTE. We confirmed blood group 0 versus non-0 as reducing the VTE risk. For FVL c.1601 G>A variant, the differences between AG vs GG did not reach statistical significance. In our cohort we found a trend towards increased risk of developing GBM for the A/G variant. We plan to further study other factors involved in coagulation for their potential role in GBM patients.

Project description:BackgroundRecurrent venous thromboembolism (VTE) is common. Current guidelines suggest that patients with unprovoked VTE should continue anticoagulants unless they have a high bleeding risk, whereas all others can stop. Prediction models may refine this dichotomous distinction, but existing models apply only to patients with unprovoked first thrombosis. We aimed to develop a prediction model for all patients with first VTE, either provoked or unprovoked.Methods and findingsData were used from two population-based cohorts of patients with first VTE from the Netherlands (Multiple Environment and Genetic Assessment of Risk Factors for Venous Thrombosis [MEGA] follow-up study, performed from 1994 to 2009; model derivation; n = 3,750) and from Norway (Tromsø study, performed from 1999 to 2016; model validation; n = 663). Four versions of a VTE prediction model were developed: model A (clinical, laboratory, and genetic variables), model B (clinical variables and fewer laboratory markers), model C (clinical and genetic factors), and model D (clinical variables only). The outcome measure was recurrent VTE. To determine the discriminatory power, Harrell's C-statistic was calculated. A prognostic score was assessed for each patient. Kaplan-Meier plots for the observed recurrence risks were created in quintiles of the prognostic scores. For each patient, the 2-year predicted recurrence risk was calculated. Models C and D were validated in the Tromsø study. During 19,201 person-years of follow-up (median duration 5.7 years) in the MEGA study, 507 recurrences occurred. Model A had the highest predictive capability, with a C-statistic of 0.73 (95% CI 0.71-0.76). The discriminative performance was somewhat lower in the other models, with C-statistics of 0.72 for model B, 0.70 for model C, and 0.69 for model D. Internal validation showed a minimal degree of optimism bias. Models C and D were externally validated, with C-statistics of 0.64 (95% CI 0.62-0.66) and 0.65 (95% CI 0.63-0.66), respectively. According to model C, in 2,592 patients with provoked first events, 367 (15%) patients had a predicted 2-year risk of >10%, whereas in 1,082 patients whose first event was unprovoked, 484 (45%) had a predicted 2-year risk of <10%. A limitation of both cohorts is that laboratory measurements were missing in a substantial proportion of patients, which therefore were imputed.ConclusionsThe prediction model we propose applies to patients with provoked or unprovoked first VTE-except for patients with (a history of) cancer-allows refined risk stratification, and is easily usable. For optimal individualized treatment, a management study in which bleeding risks are also taken into account is necessary.

Dataset Information

Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation.

Publications

Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation.

Similar Datasets

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