What is the clinical evidence from this study?

Study design: Observational. Population: Patients requiring stable anticoagulation therapy (n=365). Intervention: Warfarin vs. Inter-population and inter-genotype comparison (Caucasians vs Japanese vs African-Americans; VKORC1 and CYP2C9 variants). Primary outcome: Median daily warfarin maintenance dose (Caucasians vs Japanese) (p=<0.01).

February 1, 2006Open Access

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

Q: What are the key findings of this study?

Genetic polymorphisms in VKORC1 and CYP2C9, along with age and body weight, independently accounted for 57% of the interindividual and inter-population variability in warfarin maintenance doses.

Key Result

Genetic polymorphisms in VKORC1 and CYP2C9, along with age and body weight, independently accounted for 57% of the interindividual and inter-population variability in warfarin maintenance doses.

Study Design

Type

Observational (n=365)

Multicenter

Yes

Structured PICO

Do VKORC1 and CYP2C9 polymorphisms explain intra- and inter-population differences in warfarin maintenance dose requirements among Japanese, Caucasians, and African-Americans?

Population

157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients, along with 66 healthy African-Americans for genotyping (total n=431)

Intervention

Genotyping for seven CYP2C9 variants (*1 through 6 and *11) and seven VKORC1 variants

Comparator

Comparisons across different racial/ethnic populations (Japanese, Caucasians, African-Americans) and different genotype groups

Outcome

Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)], and INRsurrogate

VKORC1 and CYP2C9 polymorphisms significantly contribute to both intra- and inter-population differences in warfarin maintenance dose requirements among Japanese, Caucasian, and African-American populations.

Main Result

Absolute Event Rate: 5.5% vs 3.5%

p-value: p=<0.01

Limitations

Small number of African-American patients (n=36) participating in the study.
DNA samples for African-Americans were obtained from healthy subjects rather than the patients on warfarin.
Identified demographic and genetic covariates only account for 57% of interindividual variability, leaving other determinants unknown.
Rarity of some novel variants made it impossible to assess their functional consequences.

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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