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Comparative Study
. 2008 May;9(5):511-26.
doi: 10.2217/14622416.9.5.511.

Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans

Nita A Limdi  1 , Donna K Arnett, Joyce A Goldstein, T Mark Beasley, Gerald McGwin, Brian K Adler, Ronald T Acton
Affiliations
Comparative Study

Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans

Nita A Limdi et al. Pharmacogenomics. 2008 May.

Abstract

Aims: The influence of CYP2C9 and VKORC1 on warfarin dose, time to target International Normalized Ratio (INR), time to stabilization, and risk of over-anticoagulation (INR: > 4) was assessed after adjustment for clinical factors, intraindividual variation in environmental factors and unobserved heterogeneity.

Materials & methods: Common CYP2C9 and VKORC1 polymorphisms were assessed in 302 European-Americans and 273 African-Americans receiving warfarin. Race-stratified multivariable analyses evaluated the influence of CYP2C9 and VKORC1 on warfarin response.

Results & conclusion: CYP2C9 and VKORC1 accounted for up to 30% of the variability in warfarin dose among European-Americans and 10% among African-Americans. Neither CYP2C9 nor VKORC1 influenced the time to target INR or stabilization among patients of either race, and neither influenced the risk of over-anticoagulation among African-Americans. The risk of over-anticoagulation was higher among European-Americans with variant VKORC1 1173C/T (p < 0.01) and marginally significant among those with variant CYP2C9 (p = 0.08) genotype. Although CYP2C9 and VKORC1 genotyping can facilitate individualized initiation of warfarin dose in African and European-Americans, the ability to predict the risk of over-anticoagulation is inconsistent across race. Identification of other factors that can predict such risk consistently in a racially diverse group will facilitate individualized maintenance of warfarin therapy.

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Figures

Figure 1
Figure 1
Mean warfarin dose (mg/day) by CYP2C9 and VKORC1, stratified by race.
Figure 2
Figure 2
Average warfarin dose (mg/day) by CYP2C9 and VKORC1, stratified by race after adjusting for clinical variables. The referent patient is a 61 year old man with BMI =30, current non-smoker, non-drinker, with no comorbidities (e.g. CHF, cancer, renal failure) and no inhibitors of CYP2C9 (e.g. amiodarone). 2C9 wt indicates CYP2C9 *1/*1 genotype; 2C9 v indicates one or more variant CYP2C9 allele (2, *3, *5, *6, *11). VKOR wt indicates VKORC11173’CC’ genotype; VKOR v indicates VKORC11173’CT’ or ‘TT’ genotype.
Figure 3
Figure 3
Estimated survival curves from Cox PH model for European Americans (A and B) and African Americans (C and D). Dotted line indicates variant genotype; Full line indicates wild-type genotype. A. Adjusted for CYP2C9 genotype, age, sex, BMI, smoking, vitamin K intake, number of comorbid conditions, drug interactions, Vscore and socio-demographic factors B. Adjusted for VKORC1 1173C/T genotype, age, sex, BMI, smoking, vitamin K intake, number of comorbid conditions, drug interactions, Vscore and socio-demographic factors. C. Adjusted for CYP2C9 genotype, age, sex, BMI, smoking, vitamin K intake, number of comorbid conditions, drug interactions, Vscore and socio-demographic factors. D. Adjusted for VKORC1 1173C/T genotype, age, sex, BMI, smoking, vitamin K intake, number of comorbid conditions, drug interactions, Vscore and socio-demographic factors.
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