Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population

Veenstra, David L.; You, Joyce H. S.; Rieder, Mark J.; Farin, Federico M.; Wilkerson, Hui Wen; Blough, David K.; Cheng, Gregory; Rettie, Allan E.

doi:10.1097/01.fpc.0000174789.77614.68

Cited by 160 publications

(120 citation statements)

References 17 publications

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“…Most studies focused on FGB polymorphisms. However, results are not consistent and none of these polymorphisms has been found to be associated with an increased risk of venous [6,7] or arterial thrombosis [7]. Recently, we reported that a specific haplotype (H2) of the fibrinogen gamma gene (FGG) was associated with a 2.4-fold increased risk of deep venous thrombosis [95% confidence intervals (CI): 1.5-3.9] [6].…”

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confidence: 83%

“…Population differences of VKORC1 haplotype and CYP2C9 genotype frequencies have also been suggested from initial studies [1,4,6]. We identified the frequency of genotype combinations across world populations of the four haplotype tag SNPs for VKORC1 described by Reider et al [1] (861, 5808, 6853, and 9041) and CYP2C9 (*2 and *3) using Pyrosequencing [1,4] in 556 unrelated healthy individuals from the following populations: European-American, African, African-American, Hispanic (Mexican and Peruvian) and Asian (Table 1).…”

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confidence: 99%

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Population variation in VKORC1 haplotype structure

Marsh

King

Porche-Sorbet

et al. 2006

Journal of Thrombosis and Haemostasis

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confidence: 83%

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confidence: 99%

Population variation in VKORC1 haplotype structure

Marsh

King

Porche-Sorbet

et al. 2006

Journal of Thrombosis and Haemostasis

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“…Luego se detectaron el polimorfismo -1639G>A en el gen VKORC1 y los polimorfismos 430C>T (*2) y 1075A>C (*3) en el gen CYP2C9 mediante PCR en tiempo real, utilizando el sistema fluorescente LightMix ® de Roche, como se ha descrito previamente (23,24). En resumen, durante la amplificación de fragmentos específicos de 289 pares de bases para el VKORC1 y de 374 y 180 pares de bases para el CYP2C9, se logró la hibridación de las sondas fluorogénicas.…”

Section: Genotipificaciónunclassified

Predicción de sensibilidad a la warfarina basada en VKORC1 y CYP2C9 en pacientes de diferentes lugares de Colombia

2015

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Contribución de los autores:Ricardo A. Cifuentes: concepción del proyecto, genotipificación y análisis de datos Todos los autores participaron en la captación de los pacientes, la recolección de datos, la interpretación de los resultados y la escritura del manuscrito.Predicción de la sensibilidad a la warfarina con base en polimorfismos de los genes VKORC1 y CYP2C9 en pacientes colombianos Introducción. La validación de los factores predictores de la sensibilidad a la warfarina es importante para evitar las hemorragias asociadas con la terapia anticoagulante. En los estudios previos hechos en Colombia con polimorfismos de los genes VKORC1 y CYP2C9, se reportaban algoritmos con rendimientos diferentes para explicar la variación de las dosis, pero no se evaluaba la predicción de la sensibilidad a la warfarina. Objetivo. Determinar la exactitud del análisis farmacogenético de los polimorfismos *2 y *3 en el gen CYP2C9 y 1639G>A en el gen VKORC1 para predecir la sensibilidad a la warfarina en pacientes del Hospital Militar Central, un centro de referencia que atiende pacientes de diferentes lugares de Colombia. Materiales y métodos. Se recopilaron los datos demográficos y clínicos de 130 pacientes que habían recibido una dosis estable de warfarina durante más de dos meses. Se obtuvieron sus genotipos mediante un análisis de curvas de fusión, y, después de verificar el equilibrio de Hardy-Weinberg de los polimorfismos, se hizo un análisis estadístico con enfoque multivariado y predictivo.Resultados. Se construyó un modelo farmacogenético que explicó el 52,8 % de la variación de la dosis (p<0,001), solo 4 % por encima del rendimiento obtenido con los mismos datos usando el algoritmo del International Warfarin Pharmacogenetics Consortium. El modelo predictivo de sensibilidad logró 77,8 % de exactitud e incluyó como factores la edad (p=0,003), los polimorfismos *2 y *3 (p=0,002) y el polimorfismo 1639G>A (p<0,001). Conclusiones. Estos resultados en una población mestiza colombiana respaldan la validez de la predicción de la sensibilidad a la warfarina basada en los polimorfismos de los genes VKORC1 y CYP2C9. Prediction of sensitivity to warfarin based on VKORC1 and CYP2C9 polymorphisms in patients from different places in Colombia Introduction: In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin. Objective: To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients' sensitivity to warfarin at the Hospital Militar Central, a reference center for patients born in different parts of Colombia. Materials and methods: Demographic and clinical data were obtained from 130 patients with stable doses of warfari...

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“…Veenstra et al 60 reported on the combined effect of CYP2C9 and VKORC1 allelic variants. Among patients with the VKORC1AA haplotype in a Hong Kong Chinese population, 4 (5.8%) were heterozygous for CYP2C9*3 and had a lower dose requirement (1.9 mg/d) than patients who exhibited the CYP2C9*1/*1 genotype (3.0 mg/d).…”

Section: Effect Of Allelic Variants On Warfarin Activitymentioning

confidence: 99%

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Moyer

O’Kane

Baudhuin

et al. 2009

Mayo Clinic Proceedings

114

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ADE = adverse drug event; AEI = American Enterprise Institute; ASPE = allele-specific primer extension; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; PCR = polymerase chain reaction; SNP = single-nucleotide polymorphism; VitKH 2 = vitamin K hydroquinone; VKOR = vitamin K epoxide reductase; VKORC1 = VKOR complex, subunit 1 W arfarin is a well-accepted therapy used for the prevention of stroke in patients with atrial fibrillation, for prophylaxis of venous thromboembolism and pulmonary embolism in patients with prosthetic heart valves and myocardial infarction, and for prevention of pulmonary embolism or deep venous thrombosis in patients undergoing orthopedic surgery or with a history of venous or arterial thromboembolism. Many reviews and clinical practice guidelines (summarized by Ansell et al, 1 Baglin et al, 2 Flockhart et al, 3 Husted et al, 4 and Singer et al 5 ) outline the substantial benefits of warfarin therapy for the prevention of strokes in these patients. The American Enterprise Institute (AEI)-Brookings Joint Center for Regulatory Studies Report, which reviewed the use of warfarin in the United States, estimates that approximately 2 million US citizens are prescribed warfarin annually. 6 In 2003, a total of 21.2 million prescriptions were written for oral warfarin in the United States. 7 Warfarin interferes with coagulation by inhibiting regeneration of the reduced form of vitamin K, a cofactor in the γ-glutamyl-carboxylase -mediated activation of coagulation factors II, VII, IX, and X ( Figure 1). The oxidized, inactive form of vitamin K is converted to the reduced form of vitamin K by vitamin K epoxide reductase (VKOR); warfarin inhibits VKOR, resulting in less of the reduced form of vitamin K available to support the factor carboxylation required to sustain the coagulation cascade. 8 Warfarin has a narrow therapeutic index that contributes either to therapeutic failure (potentially leading to stroke or other complications) or therapeutic excess (potentially leading to bleeding and hemorrhage). Many surveys have described the incidence of warfarin-related adverse drugThe antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to ach...

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Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population

Cited by 160 publications

References 17 publications

Population variation in VKORC1 haplotype structure

Population variation in VKORC1 haplotype structure

Predicción de sensibilidad a la warfarina basada en VKORC1 y CYP2C9 en pacientes de diferentes lugares de Colombia

Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

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