title: Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese.
abstract: Warfarin is a commonly used anticoagulant, whose dose needs to be determined for each individual patient owing to large inter-individual variability in its therapeutic dose. Although several clinical and genetic variables influencing warfarin dose have been identified, uncovering additional factors are critically important for safer use of warfarin. Through a genome-wide association study, we identified single-nucleotide polymorphism (SNP) rs2108622 [cytochrome P450, family 4, subfamily F, polypeptide 2 (CYP4F2)] as a genetic determinant of warfarin responsiveness for Japanese. Stratifying subjects who have been pre-classified according to the genotypes of SNP rs10509680 [cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9)] and SNP rs9923231 [vitamin K epoxide reductase complex subunit 1 (VKORC1)], based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin. Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age, body surface area, status of amiodarone co-administration and genotypes of SNPs in the CYP2C9 and VKORC1 genes improved the model's predictability to 43.4%. In this study, the association of CYP4F2 with warfarin dose of the Japanese has been established for the first time. Besides, a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co-administration status was suggested for the Japanese. Our study also implied that common SNPs other than those in the CYP2C9, VKORC1 and CYP4F2 genes that show strong effect on the therapeutic warfarin dose might not exist.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo,Tokyo, Japan.
authors.forename: Pei-Chieng
authors.initials: PC
authors.lastname: Cha
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Shiro
authors.initials: S
authors.lastname: Minami
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000368:Aged; D000465:Algorithms; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases