Genetic Variation of VKORC1 and CYP4F2 Genes Related to Warfarin Maintenance Dose in Patients with Myocardial Infarction

Kringen, Marianne Kristiansen; Haug, Kari Bente Foss; Grimholt, Runa M; Stormo, Camilla; Narum, Sigrid; Opdal, Mimi Stokke; Fosen, Jan Toralf; Piehler, Armin; Johansen, Per Wiik; Seljeflot, Ingebjørg; Berg, Jens Petter; Brørs, Odd

doi:10.1155/2011/739751

Cited by 21 publications

(19 citation statements)

References 18 publications

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“…This observation is in line with a previous finding that CYP4F2*3 has only a small effect on warfarin dose variability [23]. However, the effect of CYP4F2*3 on warfarin dose-response variability is debatable; in fact, it ranges from 1%–7% [23], [33], [34] to not significant [26], [27].…”

Section: Discussionsupporting

confidence: 92%

“…Subjects bearing polymorphisms in one or both of these genes require lower or higher warfarin doses than subjects bearing the wild-type genes to obtain an adequate anticoagulant effect [1], [8], [16], [19]–[22]. More recently, patients bearing a SNP (rs2108622) in the CYP4F2 gene (Gene Bank Accession Number AF22194; chr.19p13.12), which is the vitamin K 1 oxidase involved in vitamin K 1 metabolism, were found to require a warfarin dose slightly higher than normal [23]–[25] or similar to normal [26], [27]. Moreover, a meta-analysis revealed a statistically significant association between rs2108622 and the interindividual warfarin dose variation [28], [29].…”

Section: Introductionmentioning

confidence: 99%

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Warfarin Anticoagulant Therapy: A Southern Italy Pharmacogenetics-Based Dosing Model

et al. 2013

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Background and AimWarfarin is the most frequently prescribed anticoagulant worldwide. However, warfarin therapy is associated with a high risk of bleeding and thromboembolic events because of a large interindividual dose-response variability. We investigated the effect of genetic and non genetic factors on warfarin dosage in a South Italian population in the attempt to setup an algorithm easily applicable in the clinical practice.Materials and MethodsA total of 266 patients from Southern Italy affected by cardiovascular diseases were enrolled and their clinical and anamnestic data recorded. All patients were genotyped for CYP2C9*2,*3, CYP4F2*3, VKORC1 -1639 G>A by the TaqMan assay and for variants VKORC1 1173 C>T and VKORC1 3730 G>A by denaturing high performance liquid chromatography and direct sequencing. The effect of genetic and not genetic factors on warfarin dose variability was tested by multiple linear regression analysis, and an algorithm based on our data was established and then validated by the Jackknife procedure.ResultsWarfarin dose variability was influenced, in decreasing order, by VKORC1-1639 G>A (29.7%), CYP2C9*3 (11.8%), age (8.5%), CYP2C9*2 (3.5%), gender (2.0%) and lastly CYP4F2*3 (1.7%); VKORC1 1173 C>T and VKORC1 3730 G>A exerted a slight effect (<1% each). Taken together, these factors accounted for 58.4% of the warfarin dose variability in our population. Data obtained with our algorithm significantly correlated with those predicted by the two online algorithms: Warfarin dosing and Pharmgkb (p<0.001; R2 = 0.805 and p<0.001; R2 = 0.773, respectively).ConclusionsOur algorithm, which is based on six polymorphisms, age and gender, is user-friendly and its application in clinical practice could improve the personalized management of patients undergoing warfarin therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Warfarin Anticoagulant Therapy: A Southern Italy Pharmacogenetics-Based Dosing Model

et al. 2013

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“…5,6,15–20,25–33,35–40,42 for these studies, we performed a separate meta-analysis stratified by gender and exploratory meta-analyses to evaluate the association between polymorphisms of VKORC1 and CYP2C9 and coumarin maintenance dose in the same populations that had been genotyped for the CYP4F2 variant, as well as the impact of the CYP4F2 p.V433M variant, after stratification for different genotypes. Data extraction from published primary studies was possible for 24 articles.…”

Section: Resultsmentioning

confidence: 99%

“…Data extraction from published primary studies was possible for 24 articles. 5,6,15,17–25,27–32,35–37,39,41,42 Data from one article34 were obtained from a published meta-analysis. 43 …”

Section: Resultsmentioning

confidence: 99%

Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis

Danese

Montagnana

Johnson

et al. 2012

Clin Pharmacol Ther

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A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6–11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

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“…Kringen et al [14] found that 32% of the variability in warfarin dose requirements among myocardial infarction patients could be explained by the VKORC1 and CYP2C9 polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Impact of CYP2C9 and VKORC1 genetic polymorphisms upon warfarin dose requirements in Egyptian patients with acute coronary syndrome

Ghozlan

Foad²,

Darwish³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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Warfarin is the most widely prescribed anticoagulant drugs. Cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase-oxidaxe complex subunit 1 (VKORC1) contribute significantly to the variability of warfarin dose requirements among patients. We investigated the impact of CYP2C9 and VKORC1 polymorphisms on the variability of warfarin dosage requirements in Egyptian patients with acute coronary syndrome and their association with other nongenetic factors. Eighty participants with acute coronary syndrome were enrolled in this cross-sectional study. Associations between CYP2C9 and VKORC1 gene variants together with daily warfarin dose, demographic data, clinical status of patients and time to target international normalized ratio were assessed. Mean warfarin dose among patients with wild-type CYP2C91/1 genotype was significantly higher than heterozygous CYP2C91/2 and CYP2C91/3 variants (P ≤ 0.001). Patients with wild VKORC1 (G/G) genotype were treated with significantly higher daily warfarin dosages than homozygous (A/A) and heterozygous (G/A) genotypes. Patients carrying VKORC1 (G/G) genotype in combination with the CYP2C91/1 type alleles had the highest daily warfarin dosage, whereas the lowest daily warfarin dosage to achieve the required clinical effect was found among patients having CYP2C91/2 and CYP2C91/3 genotypes combined with VKORC1 (A/A) genotype (P ≤ 0.001). Regression analysis revealed that age, height, CYP2C9 and VKORC1 genotypes were significantly associated with warfarin dose. Genetic polymorphisms in VKORC1, CYP2C9 along with age and height are determinants of warfarin dose requirements in Egyptian population acute coronary syndrome. Higher warfarin loading dose is required for both wild CYP2C9 and VKORC1 gene variants which may contribute to warfarin-resistant cases.

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Genetic Variation of VKORC1 and CYP4F2 Genes Related to Warfarin Maintenance Dose in Patients with Myocardial Infarction

Cited by 21 publications

References 18 publications

Warfarin Anticoagulant Therapy: A Southern Italy Pharmacogenetics-Based Dosing Model

Warfarin Anticoagulant Therapy: A Southern Italy Pharmacogenetics-Based Dosing Model

Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis

Impact of CYP2C9 and VKORC1 genetic polymorphisms upon warfarin dose requirements in Egyptian patients with acute coronary syndrome

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