Cited by 376Pharmacogenetics and Drug MetabolismBlood Coagulation and Thrombosis MechanismsNutrition, Genetics, and Disease

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Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra-and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans

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Takahashi, Harumi, Wilkinson, Grant R., Nutescu, Edith A., Morita, Takashi, Ritchie, Marylyn D., Scordo, Maria G., Pengo, Vittorio, Barban, Martina, Padrini, Roberto, Ieiri, Ichiro, Otsubo, Kenji, Kashima, Toshitaka, Kimura, Sosuke, Kijima, Shinichi, Echizen, Hirotoshi·2006·Pharmacogenetics and Genomics

DOI 10.1097/01.fpc.0000184955.08453.a8

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Abstract

OBJECTIVE: To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase (VKOR) and CYP2C9. METHODS: Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset (n = 166), fully carboxylated plasma normal prothrombin levels (NPT) were also measured. Genotyping for seven CYP2C9 (CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement. RESULTS: The relationship between NPT and Cu(S) indicated Japanese are more susceptible to inhibition of NPT production by S-warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese (89.1%) than Caucasians (42.2%) and African-Americans (8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients (5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype-matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (*2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage. CONCLUSIONS: Both VKORC1 and CYP2C9 polymorphisms contribute to inter-population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.

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Authors: Takahashi, H., Wilkinson, G. R., Nutescu, E. A., Morita, T., Ritchie, M. D., Scordo, M. G., Pengo, V., Barban, M., Padrini, R., Ieiri, I., Otsubo, K., Kashima, T., Kimura, S., Kijima, S., & Echizen, H.
Affiliations: Meiji Pharmaceutical University (JP)
University of Illinois Chicago (US)
Vanderbilt University (US)
University of Messina (IT)
University of Padua (IT)
Tottori University (JP)
Eisai (Japan) (JP)
Corresponding author: Takahashi, Harumi
ORCID: Takahashi, Harumi
Wilkinson, Grant R.
Nutescu, Edith A.
Morita, Takashi
Ritchie, Marylyn D.
Pengo, Vittorio
Padrini, Roberto
Ieiri, Ichiro
Kimura, Sosuke
Kijima, Shinichi
Venue: Pharmacogenetics and Genomics
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-02
Volume: 16
Issue: 2
Pages: 101-110
ISSN: 1744-6872 (ISSN-L)
DOI: 10.1097/01.fpc.0000184955.08453.a8
OpenAlex: W2042292509
Cited by: 376
References: 31
Citations by year: 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 10 · 2019: 17 · 2018: 9 · 2017: 14 · 2016: 16 · 2015: 16 · 2014: 28 · 2013: 25 · 2012: 25
FWCI: 38.09
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: other-oa
Locations: Pharmacogenetics and Genomics (publishedVersion)
PubMed (publishedVersion)
Padua Research Archive (University of Padova) (submittedVersion, other-oa)
Funders: Eisai
National Institutes of Health (GM31304)
U.S. Public Health Service
National Institute of General Medical Sciences (GM31304, P01GM031304)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
Keywords: warfarin, VKORC1, CYP2C9, genetic polymorphism, vitamin K epoxide reductase, interpopulation variability, Japanese, Caucasians, African Americans, S-warfarin, anticoagulation, pharmacogenetics
MeSH terms: Aryl Hydrocarbon Hydroxylases, Black or African American, Female, Genotype, Humans, Mixed Function Oxygenases, Infant, Japan, Male, Pharmacogenetics, United States, Genetic Variation, Warfarin, Black People, White People, Asian People, Vitamin K Epoxide Reductases, Cytochrome P-450 CYP2C9

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Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra-and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans

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