Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans

Kimmel, Stephen E.; Christie, Jason D.; Kealey, Carmel; Chen, Zhen; Price, Maureen; Thorn, Caroline F.; Brensinger, C. M.; Newcomb, Craig; Whitehead, Alexander S.

doi:10.1038/sj.tpj.6500445

Cited by 75 publications

(72 citation statements)

References 20 publications

(44 reference statements)

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“…Although the focus of the current study was to define the association of CYP2C9 genotype on warfarin dose and risk of complications we recognize that drug response is influenced by multiple genes. [44] [45,46] At least one other gene; Vitamin K Epoxide Reductase (VKORC1) has been consistently shown to significantly influence warfarin dose in European Americans [14,15,47,48] and recently among African Americans. [49] Expansion of genotyping efforts, within this prospective cohort, to include other genes along the warfarin pharmacodynamic and pharmacokinetic pathways will facilitate gene-gene interaction studies and help tailor warfarin therapy based on genetic, clinical and demographic characteristics.…”

Section: Discussionmentioning

confidence: 99%

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Limdi

Goldstein

Blaisdell

et al. 2007

Personalized Medicine

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Background-Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene.

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Section: Discussionmentioning

confidence: 99%

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Limdi

Goldstein

Blaisdell

et al. 2007

Personalized Medicine

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“…Several studies have cast doubt that the -1639G allele is responsible for warfarin dosing variability in people of African origin. [36][37][38] Other alleles in VKORC1 may affect warfarin dosing, such as the mild to moderate increase in warfarin dose associated with the Asp36Tyr amino acid substitution. 39 The combined interaction of the cytochrome P450 2C9 isoenzyme (CYP2C9) and VKORC1 on warfarin's anticoagulant activity is shown in Figure 2.…”

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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“…Both groups fit HWE by various tests. Given that APOE is known to be strongly associated with certain disease states (see Song et al, 2004;Kimmel et al, 2008, the source of these data), is this agreement surprising or not?…”

Section: Hwe Todaymentioning

confidence: 99%

A Century of Hardy–Weinberg Equilibrium

Mayo

2008

Twin Res Hum Genet

129

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Hardy–Weinberg equilibrium (HWE) is the state of the genotypic frequency of two alleles of one autosomal gene locus after one discrete generation of random mating in an indefinitely large population: if the alleles areAandawith frequenciespandq(=1-p), then the equilibrium gene frequencies are simplypandqand the equilibrium genotypic frequencies forAA,Aaandaaarep2, 2pqandq2. It was independently identified in 1908 by G. H. Hardy and W. Weinberg after earlier attempts by W. E. Castle and K. Pearson. Weinberg, well known for pioneering studies of twins, made many important contributions to genetics, especially human genetics. Existence of this equilibrium provides a reference point against which the effects of selection, linkage, mutation, inbreeding and chance can be detected and estimated. Its discovery marked the initiation of population genetics.

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Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans

Cited by 75 publications

References 20 publications

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

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

A Century of Hardy–Weinberg Equilibrium

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