5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients

Abstract

White and Japanese patients require different warfarin dosages to achieve therapeutic anticoagulation, but this can be only partly explained by genetic variability in the coding region of CYP2C9-a critical enzyme in the drug's metabolism. Accordingly, analysis of the ؊2.1-kb 5-flanking region of CYP2C9 was undertaken in 22 white and 38 Japanese patients whose unbound oral clearance of S-warfarin had been previously determined. Thirteen single nucleotide polymorphisms (SNPs) were identified, some of which were in linkage disequilibrium with functionally defective coding region variants. Those 5-flanking patterns linked with at least one CYP2C9*3 allele or CYP2C9*2/*3 were associated with reduced CYP2C9 activity and warfarin dose. Japanese patients possessing the wildtype promoter and coding sequences had significantly (P < .01) greater CYP2C9 activity than white patients with the corresponding genotype. In conclusion, either unidentified polymorphisms further upstream in the promoter region or environmental factor(s) account for the differences in the warfarin doses between whites and Japanese. IntroductionPopulation differences in the drug-metabolizing enzymes are important in bridging therapeutic doses and safety profiles of drugs from one population to another. Warfarin is a widely used oral anticoagulant and its effect is largely attributable to the pharmacologically more active S-enantiomer. 1 Recently, we observed that Japanese patients receiving warfarin therapy had a significantly greater body weight-normalized plasma unbound clearance (CLpo,u) of S-warfarin than white patients, 2 which is predominantly reflective of CYP2C9-mediated hepatic metabolism. 3 At present, 11 coding region variant alleles of the gene have been reported. 4 Because whites have greater allelic frequencies than Southeast Asians 5 of the 2 most common functionally defective variants (CYP2C9*2 and CYP2C9*3), it is possible that the population differences in S-warfarin metabolism may be attributed to this distribution difference. However, in our previous study a difference in S-warfarin metabolism was noted even when the 2 populations were matched with respect to the homozygous wildtype CYP2C9 genotype (CYP2C9*1/*1). 2 This indicates that such a coding region polymorphism cannot fully account for the population differences in the CYP2C9 activity. Recently, Shintani et al 6 reported 7 single nucleotide polymorphisms (SNPs) in the 5Ј-flanking region of CYP2C9 in Japanese subjects, some of which were associated with an altered level of gene transcription. Accordingly, we investigated SNPs within the Ϫ2.1-kb promoter region of CYP2C9 in white and Japanese patients receiving warfarin and assessed their contribution to the variability of in vivo CYP2C9 activity within and between the 2 populations. Study designThe promoter region analysis was performed in the participants of an earlier investigation, 2 22 white (9 men and 13 women) and 38 Japanese patients (25 men and 13 women), whose DNA samples were available. Details of the study have be...

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