Ethnic differences in the VKORC1 gene polymorphism and an association with warfarin dosage requirements in cardiovascular surgery patients.
OBJECTIVE
Vitamin K epoxide reductase (VKORC1) is the drug target for inhibition by coumarin-based anticoagulant drugs such as warfarin. Warfarin therapy has been reported as a leading cause of drug-related hospitalization and there is therefore an urgent need to develop tests for better warfarin prescription. We report here the distribution of the intron 1 -136 T>C (1173 T>C intron) polymorphism of VKORC1, previously reported to be associated with warfarin maintenance dose in Caucasians and Japanese, in several ethnic populations from Japan and Israel, and describe its significance for warfarin dosage in Japanese cardiovascular surgery patients.


METHODS
Subjects consisted of 132 Japanese individuals and 341 Israeli individuals from four Jewish ethnic groups (86 Ashkenazi Jews, 95 Yemenite Jews, 73 Moroccan Jews and 87 Libyan Jews). In addition, 31 Japanese patients receiving warfarin therapy after cardiovascular surgery, maintained with a target International Normalized Ratio, were studied. The genotyping for the 1173 T>C intron polymorphism of VKORC1 was determined using rapid real-time PCR.


RESULTS
The allele frequency of the combined VKORC1 1173 CT and CC genotypes varied among the four Israeli ethnic groups and was, on average, much higher in the Israeli (0.728) than in the Japanese population (0.152). For the Japanese cardiovascular surgery patients, the maintenance dose of warfarin was significantly larger in the combined VKORC1 1173 TC and CC genotype group than in the 1173 TT genotype group (3.6 +/- 0.5 mg vs 2.8 +/- 0.7 mg, respectively; p = 0.02).


CONCLUSIONS
The frequencies of the intron 1 VKORC1 1173 T>C SNP show significant differences between ethnic groups and are associated with warfarin dose requirements for achieving a recommended International Normalized Ratio range in Japanese cardiovascular surgery patients. This study supports the example of warfarin as an appropriate model for applying personalized medicine for anticoagulant drugs, and highlights the importance of ethnicity in pharmacogenetics.
Nakai
Kenji
K
Iwate Medical University, Department of Laboratory Medicine, Morioka 020-8505, Japan. knakai@iwate-med.ac.jp
Tsuboi
Jyunichi
J
Okabayashi
Hitoshi
H
Fukuhiro
Yoshiaki
Y
Oka
Takanori
T
Habano
Wataru
W
Fukushima
Noriko
N
Nakai
Keiko
K
Obara
Wataru
W
Fujioka
Tomoaki
T
Suwabe
Akira
A
Gurwitz
David
D
D000925:Anticoagulants / Q000627:therapeutic use*; D044466:Asian People; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000601:surgery*; D013504:Cardiovascular Surgical Procedures; D004305:Dose-Response Relationship, Drug; D005006:Ethnicity / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007438:Introns; D007564:Japan; D007585:Jews; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases