Abstract
To explore the pharmacogenomics of warfarin using the extreme-discordant-phenotype (EDP) methodology. The target phenotype was the stable warfarin dose prescribed to 353 patients. Pharmacogenetic polymorphisms assessed were coagulation factor VII (FVII) -401G>T and FVII -402G>A, VKORC1 3673G>A, and CYP2C9*2, *3, *5, and *11 alleles. The EDP analyses contrasted the frequencies of these polymorphisms at different cutoff points (5th through 30th percentiles of the warfarin dose distribution) at opposite ends of the warfarin dose distribution. Significant differences existed in FVII -402G>A genotype frequency at the 5th percentile with an over-representation of the wildtype GG genotype at low warfarin doses and in VKORC1 3673G>A and CYP2C9 polymorphisms at all cutoff points where the variant alleles were overrepresented at low warfarin doses. The EDP methodology provides increased statistical power for detection of small contributions of genetic polymorphisms to multiple drug-response phenotypes, such as warfarin dose requirement for adequate anticoagulation.
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