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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)101-110
Number of pages10
JournalPharmacogenetics and Genomics
Volume16
Issue number2
DOIs
Publication statusPublished - Jan 1 2006
Externally publishedYes

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Warfarin
African Americans
Population
Prothrombin
Vitamin K Epoxide Reductases
Genotype
International Normalized Ratio
Cytochrome P-450 CYP2C9
Research Design
Multivariate Analysis
Pharmacokinetics
Weights and Measures

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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. / 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.

In: Pharmacogenetics and Genomics, Vol. 16, No. 2, 01.01.2006, p. 101-110.

Research output: Contribution to journalArticle

Takahashi, H, Wilkinson, GR, Nutescu, EA, Morita, T, Ritchie, MD, Scordo, MG, Pengo, V, Barban, M, Padrini, R, Ieiri, I, Otsubo, K, Kashima, T, Kimura, S, Kijima, S & Echizen, H 2006, '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', Pharmacogenetics and Genomics, vol. 16, no. 2, pp. 101-110. https://doi.org/10.1097/01.fpc.0000184955.08453.a8
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. / 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. In: Pharmacogenetics and Genomics. 2006 ; Vol. 16, No. 2. pp. 101-110.
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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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T1 - 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

AU - Takahashi, Harumi

AU - Wilkinson, Grant R.

AU - Nutescu, Edith A.

AU - Morita, Takashi

AU - Ritchie, Marylyn D.

AU - Scordo, Maria G.

AU - Pengo, Vittorio

AU - Barban, Martina

AU - Padrini, Roberto

AU - Ieiri, Ichiro

AU - Otsubo, Kenji

AU - Kashima, Toshitaka

AU - Kimura, Sosuke

AU - Kijima, Shinichi

AU - Echizen, Hirotoshi

PY - 2006/1/1

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N2 - 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.

AB - 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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