VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation

Geisen, Christof; Watzka, Matthias; Sittinger, Katja; Steffens, Michael; Daugela, Laurynas; Seifried, Erhard; Müller, C. R.; Wienker, Thomas F.; Oldenburg, Johannes

doi:10.1160/th05-04-0290

Cited by 226 publications

(203 citation statements)

References 38 publications

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“…Con este panorama, a pesar de que el VKORC1 se considera el principal modulador genético de las diferencias étnicas en la reacción a la warfarina, y se conoce su utilidad para explicar la reacción a este medicamento en pacientes con diferentes ancestros (34,35), no debe descartarse la posibilidad de mejorar la predicción teniendo en cuenta aspectos específicos de cada población. Reportes recientes indican que la utilidad de los algoritmos farmacogenéticos podría ser mayor si se logra un mejor control de las variables clínicas.…”

Section: Discussionunclassified

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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Section: Discussionunclassified

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

2015

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“…The VKORC1 2255CϾT SNP is seen in group A haplotypes, which are associated with increased warfarin sensitivity, as well as in haplotype H4, a less common haplotype for which there is little information on warfarin dose correlation. The 3730 GϾA SNP is associated with group B haplotypes, which have been correlated with higher warfarin doses, 1,5 but it is not included in any of the dosing algorithms. In addition, DNA sequencing demonstrated a novel single nucleotide change in the promoter, VKORC1 Ϫ477 (4835) G/A, which to our knowledge has not been published previously.…”

Section: Dosing Algorithm Comparisonmentioning

confidence: 99%

“…A single common VKORC1 SNP Ϫ1639/3673 AϾG defines VKORC1 haplotypes with increased sensitivity to warfarin (group A haplotypes, H1 and H2). [1][2][3][4][5][6][7][8][9] CYP2C9 is responsible for metabolism of Ͼ90% of S-warfarin, the more active enantiomer of warfarin. Two common allelic variants of CYP2C9 with reduced enzymatic activity (CYP2C9*2 and CYP2C9*3) have been associated with reduced metabolism of warfarin, lower required doses of warfarin to achieve adequate anticoagulation, and increased risk of adverse events when beginning warfarin therapy.…”

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confidence: 99%

Validation of Clinical Testing for Warfarin Sensitivity

Langley

Booker

Evans

et al. 2009

The Journal of Molecular Diagnostics

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Responses to warfarin (Coumadin) anticoagulation therapy are affected by genetic variability in both theIn 2007, the US Food and Drug Administration modified the package insert for warfarin (Coumadin) to include information on the relationship of safe and effective dosage to specific single nucleotide polymorphisms (SNPs) in two genes, cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1). Warfarin binds to and inhibits vitamin K epoxide reductase (VKOR), encoded by VKORC1, thereby inhibiting activation of vitamin K-dependent clotting factors. A single common VKORC1 SNP Ϫ1639/3673 AϾG defines VKORC1 haplotypes with increased sensitivity to warfarin (group A haplotypes, H1 and H2).1-9 CYP2C9 is responsible for metabolism of Ͼ90% of S-warfarin, the more active enantiomer of warfarin. Two common allelic variants of CYP2C9 with reduced enzymatic activity (CYP2C9*2 and CYP2C9*3) have been associated with reduced metabolism of warfarin, lower required doses of warfarin to achieve adequate anticoagulation, and increased risk of adverse events when beginning warfarin therapy. -12As a result of increased awareness of the impact of these SNPs on warfarin dosage, it is likely that clinical laboratories will increasingly be asked to provide genotype information for the above genes. Thus, there is a need to evaluate both the analytic and clinical validity of genotyping to make dosing recommendations for warfarin. Several assays for genotyping are now commercially available. We evaluated four platforms for determining relevant SNPs in CYP2C9 and VKORC1: the Third Wave Invader Plus CYP2C9 and VKORC1 reagents, the Cepheid SmartCycler Rapid Genotyping Assay for CYP2C9 and VKORC1 (developed by ParagonDx), the Idaho Technology Warfarin Genotyping Reagents on the Roche LightCycler and the AutoGenomics Infiniti 2C9-VKORC1 assay (now marketed as Warfarin XP).Several different dosing algorithms have been devised that incorporate VKORC1 and CYP2C9 genotype, in addition to demographic and clinical information, to predict optimal warfarin dose. We compared the accuracy of four published algorithms for determining warfarin dosage,

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“…The DNA segments containing the following SNPs of the VKORC1 locus 3673G4A (rs9923231), 5808T4G (rs 2884737), 6009C4T (rs 17708472), 6484C4T (rs 9934438) and 9041G4A (rs 7294) (GeneBank accession number AY587020) 7,8 were PCR-amplified and analyzed by DNA sequencing of the PCR product.…”

Section: Genotypingmentioning

confidence: 99%

Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

et al. 2012

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The objective of our present study was to develop a warfarin dosing algorithm for the Omani patients, as performances of warfarin dosing algorithms vary across populations with impact on the daily maintenance dose. We studied the functional polymorphisms of CYP2C9, CYP4F2 and VKORC1 genes to evaluate their impact on the warfarin maintenance dose in an admixed Omani patient cohort with Caucasian, African and Asian ancestries. We observed a 64-fold inter-patient variability for warfarin to achieve stable international normalized ratio in these patients. Univariate analysis revealed that age, gender, weight, atrial fibrillation, deep vein thrombosis/pulmonary embolism and variant genotypes of CYP2C9 and VKORC1 loci were significantly associated with warfarin dose in the studied patient population. However, multiple regression model showed that only the atrial fibrillation, and homozygous CYP2C9 variant genotypes (*2/*3 and *3/*3) and VKORC1 GA and AA genotypes remained significant. A multivariate model, which included demographic, clinical and pharmacogenetic variables together explained 63% of the overall inter-patient variability in warfarin dose requirement in this microgeographically defined, ethnically admixed Omani patient cohort on warfarin. This locally developed model performed much better than the International Warfarin Pharmacogenetics Consortium (IWPC) model as the latter could only explain 34% of the inter-patient variability in Omani patients. VKORC1 3673G4A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R 2 ¼ 0.45).

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VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation

Cited by 226 publications

References 38 publications

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

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

Validation of Clinical Testing for Warfarin Sensitivity

Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

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