Exploring warfarin pharmacogenomics with the extreme-discordant-phenotype methodology: impact of FVII polymorphisms on stable anticoagulation with warfarin.
OBJECTIVE
To explore the pharmacogenomics of warfarin using the extreme-discordant-phenotype (EDP) methodology.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Fuchshuber-Moraes
Mateus
M
Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rua André Cavalcanti 37, Rio de Janeiro, 21230-050, Brazil.
Perini
Jamila A
JA
Rosskopf
Dieter
D
Suarez-Kurtz
Guilherme
G
D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044383:Black People / Q000235:genetics; D001938:Brazil; D065729:Cytochrome P-450 CYP2C9; D005167:Factor VII / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044465:White People / Q000235:genetics
D000925:Anticoagulants; D014859:Warfarin; D005167:Factor VII; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases