Ethnic Differences in the
            <i>VKORC1</i>
            Gene Polymorphism and an Association with Warfarin Dosage Requirements in Cardiovascular Surgery Patients

Nakai, Kenta; Tsuboi, Jyunichi; Okabayashi, Hitoshi; Fukuhiro, Y; Oka, Toshihiko; Habano, Wataru; Fukushima, Noriko; Nakai, Keiko; Obara, Wataru; Fujioka, Tomoaki; Suwabe, Akira; Genevieve, David

doi:10.2217/14622416.8.7.713

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…Furthermore, the TT variant homozygote type of VKORC1 occurs in approximately 80% of Japanese, with very few Japanese having the wild type (CC type), whereas 27% of Israeli bear the TT type. 15) In the present study, the frequencies of the CYP2C9 *2 , CYP2C9 *3 and VKORC1 SNPs were similar.…”

Section: Discussionsupporting

confidence: 69%

“…15) Fluorescent dye terminator cycle sequencing was performed with the same primers used for the PCR amplifications; the data were analyzed using an auto-sequencer (model 377KL, Applied Biosystems, Foster City, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…[6][7][8][9][10][11][12] In recent years, Mushiroda, et al reported that the CYP2C9 and VKORC1 haplotype may affect the warfarin maintenance dose. 13) Our group has also shown that there are ethnic differences in terms of the genetic polymorphism of CYP2C9 and VKORC1, 14,15) which suggests that the optimal warfarin dose could vary between ethnicities.…”

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confidence: 95%

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Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

2011

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SummaryThe individual management of anticoagulation therapy is important for safe medical outcomes, including those of oral surgery. Here, Japanese patients who received warfarin (n = 35) and normal controls (n = 125) were analyzed by real-time PCR to determine the frequencies of single nucleotide polymorphisms in VKORC1 (vitamin K epoxide reductase complex, subunit 1) and CYP2C9 and how these frequencies related to warfarin dose and PT-INR. The genetic polymorphisms CYP2C9 *2 (416 C > T), CYP2C9 *3 (1061 A > C), and intron 1-136 C > T in VKORC1 (1173 C > T) were measured. All patients had the wild-type CYP2C9 gene (*1/*1). All 160 cases had the wild-type (CC) type CYP2C9 *2 , 93.8% had AA type CYP2C9 *3 , 6.2% had AC type CYP2C9 *3 , 1.2% had CC type VKORC1, 13.8% had CT type VKO-RC1, and 85% had TT type VKORC1. The CC type VKORC1 genetic polymorphism was associated with a significantly higher mean warfarin maintenance dose (4.5 ± 0.5 mg) than other VKORC1 genotypes (TT type 2.9 ± 0.1 mg: CT type 3.4 ± 0.3 mg). Categorization of the patients in terms of the combined CYP2C9 and VKORC1 haplotype (the warfarinresponsive index; WRI) revealed the mean daily warfarin maintenance dose was 3.0 ± 0.1 mg for WRI 1 and 3.7 ± 0.3 mg for WRI 2 (P < 0.012). The event survey revealed 2 patients with nonfatal cerebral hemorrhage had a WRI score of 2 (VKORC1 C/T heterozygosity genotype). Thus, CYP2C9 and VKORC1 haplotype analysis allows prediction of warfarin maintenance dosage. The findings may provide a personalized use of warfarin in the field of oral surgery. (Int Heart J 2011; 52: 44-49)

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Section: Discussionsupporting

confidence: 69%

Section: Methodsmentioning

confidence: 99%

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Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

2011

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“…Specifically, the AJ CYP2C9 extensive, intermediate, and poor metabolizer frequencies were 62%, 33%, and 5%, and the VKORC1 c.−1639 G/G, G/A, and A/A frequencies were 29%, 48%, and 23%, respectively [38]. Related studies have identified distinct CYP2C9 ( *2 and *3 ) and VKORC1 c.174-136C>T (1173C>T) frequencies between Israeli Jewish (AJ, Yemenite, Moroccan, and Libyan) and Japanese individuals [68, 69]. Given the paucity of CYP2C9 full gene sequencing studies among Jewish individuals, it is currently unknown if unique CYP2C9 variant alleles exist in this population, suggesting further studies are warranted.…”

Section: Jewish Pharmacogeneticsmentioning

confidence: 99%

Pharmacogenetics in Jewish populations

Yao

Peter

Scott

2014

Drug Metabolism and Drug Interactions

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Spanning over 2000 years, the Jewish population has a long history of migration, population bottlenecks, expansions, and geographical isolation, which has resulted in a unique genetic architecture among the Jewish people. As such, many Mendelian disease genes and founder mutations for autosomal recessive diseases have been discovered in several Jewish groups, which have prompted recent genomic studies in the Jewish population on common disease susceptibility and other complex traits. Although few studies on the genetic determinants of drug response variability have been reported in the Jewish population, a number of unique pharmacogenetic variants have been discovered that are more common in Jewish populations than in other major racial groups. Notable examples identified in the Ashkenazi Jewish (AJ) population include the vitamin K epoxide reductase complex subunit 1 (VKORC1) c.106G>T (p.D36Y) variant associated with high warfarin dosing requirements and the recently reported cytochrome P450 2C19 (CYP2C19) allele, CYP2C19*4B, that harbors both loss-of-function [*4 (c.1A>G)] and increased-function [*17 (c.−806C>T)] variants on the same haplotype. These data are encouraging in that like other ethnicities and subpopulations, the Jewish population likely harbors numerous pharmacogenetic variants that are uncommon or absent in other larger racial groups and ethnicities. In addition to unique variants, common multi-ethnic variants in key drug metabolism genes (e.g., ABCB1, CYP2C8, CYP2C9, CYP2C19, CYP2D6, NAT2) have also been detected in the AJ and other Jewish groups. This review aims to summarize the currently available pharmacogenetics literature and discuss future directions for related research with this unique population.

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“…The incorporation of the CYP2C9 * 8 allele into a pharmacogenetic dosing algorithm increases accuracy in African–Americans [61]. The population frequencies of the −1639 A allele indicating haplotype A are remarkably different across populations and reported as 75–92% in East Asians [19,55,63,64], 35–47% in Europeans [56,60,65,66], 9–12% in African–Americans [19,29,48,61] and 29–48% in mixed populations [19,39]. The pronounced disparity in haplotype A frequency explains, in part, why mean effective warfarin dose is often lower in East Asian [67,68] and higher in African compared with Caucasian populations [48].…”

Section: Prediction Of Warfarin Responsivenessmentioning

confidence: 99%

Implementing genotype-guided Antithrombotic Therapy

Seip

Duconge²,

Ruaño³

2010

Future Cardiol.

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Genotyping has the potential to improve the efficacy and safety of major antithrombotic drugs. For warfarin, the stable maintenance dose varies from 1-10 mg/day. The VKORC1 −1639G>A allele and the CYP2C9*2 and *3 alleles (cumulative frequency: 90% in Asians, 65% in Europeans and 20% in Africans), explain 45% of response variability in European and 30% in African populations. The large clinical trials COAG and EU-PACT will define the extent to which pharmacogenetic dosing affects the safety and efficacy of warfarin and coumarin derivatives. The platelet inhibitor clopidogrel requires activation by the CYP2C19 enzyme. CYP2C19*2 and *3 alleles (cumulative frequency: 20-50%) produce null enzyme activity, and their presence attenuates platelet inhibition and increases cardiovascular events. The US FDA-mandated drug labeling recognizes the relevance of genotyping in the selection and dosing of both warfarin and clopidogrel. Keywordsclopidogrel; CYP2C19; CYP2C9; pharmacogenetics; platelet; VKORC1; warfarin One of the promises of the human genome project is individualization of patient care based on highly heterogeneous innate metabolic factors determined by DNA typing of gene polymorphisms. The practice of DNA-guided medicine requires the translation of such gene polymorphisms into clinical decision support for personalized healthcare. Pharmacogenetics serves as the foundation for the most clinically advanced application of DNA-guided medicine.Knowledge of the patient's genetic status for common variants in the VKORC1 and CYP2C9 genes can already guide antithrombotic intervention with warfarin. Common variants in the CYP2C19 gene influence antiplatelet therapy with clopidogrel, exemplifying a phase of investigation that is rapidly approaching clinical utility.Genomic research interest is high in the area of prediction of drug responsiveness based on genetic variation. It is a useful goal to predict variability in drug responsiveness. Such The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript. NIH Public Access Prediction of warfarin responsivenessOne of the leading examples of the translation of genetic understanding into the prediction of a drug response is the case of warfarin. Warfarin is prescribed for prophylaxis and therapy of patients with a wide variety of venous and arterial thromboembolic disorders, including those with atrial fibrillation and other cardiac arrhythmias, surgical cardiac valve replacement, deep vein thrombosis, thrombophlebitis with or without pulmonary embolism, and those at risk of stroke [1]. Over 20 million warfarin prescriptions are written per year in the USA, making it the 11th most prescribed drug in the USA [2]. Approximately two million new prescriptions are written annually, many for anticoagulant-naive patients ...

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Ethnic Differences in the VKORC1 Gene Polymorphism and an Association with Warfarin Dosage Requirements in Cardiovascular Surgery Patients

Cited by 19 publications

References 29 publications

Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

Pharmacogenetics in Jewish populations

Implementing genotype-guided Antithrombotic Therapy

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