Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement

Wang, Daqing; Chen, Huizi; Momary, Kathryn M.; Cavallari, Larisa H.; Johnson, Julie A.; Sadée, Wolfgang

doi:10.1182/blood-2008-03-144899

Cited by 186 publications

(161 citation statements)

References 46 publications

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“…The fact that in vitro transient transfection assays failed to recapitulate validated expression differences in the reporter gene system could either reflect that the true functional SNP was not included in our genotyped sites but is in strong LD with them or that the requirement of additional regulatory elements (i.e., proper sequence and chromatin context) or transcription factors were not present in the reporter gene system used. The latter possibility is highlighted by recent studies observing disconnection between in vitro transfection assay results and in vivo determined genetically controlled expression (Cirulli and Goldstein 2007;Wang et al 2008). …”

Section: Discussionmentioning

confidence: 96%

Population genomics in a disease targeted primary cell model

Grundberg

Kwan²,

Ge³

et al. 2009

Genome Res.

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The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < ;10 À3 ) were tested for cisassociation of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 3 10 À10 À 7 3 10 À16 ) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P combined = 5.6 3 10 À5 ). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r 2 = 0.5, P = 2.6 3 10 À15 ). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

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Section: Discussionmentioning

confidence: 96%

Population genomics in a disease targeted primary cell model

Grundberg

Kwan²,

Ge³

et al. 2009

Genome Res.

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“…34 This may result from decreased production of VKORC1 mRNA by the -1639A allele and reduced expression of the enzyme VKOR. 35 As a result of the reduced expression of VKOR, less warfarin is needed in patients carrying the -1639A promoter variant to maintain the target INR. Population studies have shown that the VKORCI -1639A allele predominates in people of Asian descent but is less common in white people and those of African descent.…”

Section: Incidence Of Warfarin-related Adesmentioning

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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“…Su polimorfismo -1639G>A (rs9923231) se asocia con la sensibilidad a la warfarina y la disminución de la cantidad requerida (2). Se ha observado una asociación preferencial con la cromatina activa del alelo G en la posición -1639 del VKORC1, mientras que el alelo menor A en esta misma posición genera un sitio de unión E-box de tipo supresor, lo que resulta en una menor síntesis de ARN (12).…”

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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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Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement

Cited by 186 publications

References 46 publications

Population genomics in a disease targeted primary cell model

Population genomics in a disease targeted primary cell model

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

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

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