Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients

Abstract

Warfarin is the most commonly used oral anticoagulant for treatment of thromboembolism, but adjustment of the dose appropriate to each patient is not so easy because of the large inter-individual variation in dose requirement. We analyzed single nucleotide polymorphism (SNP) genotypes of the VKORC1 and CYP2C9 genes using DNA from 828 Japanese patients treated with warfarin, and investigated association between SNP genotype and warfarin-maintenance dose. Five SNPs in VKORC1, 5¢ flankingÀ1413A>G, intron 1À136T>C, intron 2+124C>G, intron 2+837T>C and exon 3 343G>A, were in absolute linkage disequilibrium, and showed a significant association with daily warfarin dose of these patients. The median warfarin dose of patients with homozygosity for the minor allele was 4.0 mg/day, which is significantly higher than those heterozygous for the minor allele (3.5 mg/day) or those homozygous for the major allele (2.5 mg/day; P=5.1·10 À11 in the case of intron 1À136T>C SNP). We then genotyped the CYP2C9 gene for the Japanese common genetic variant, CYP2C9*3 and, based on the genotype of these two genes, classified patients into three categories, which we call ''warfarin-responsive index.'' The median warfarin daily dose varied significantly in this classification according to the warfarin-responsive index (2.0 mg/day for index 0 group, 2.5 mg/day for index 1 group, and 3.5 mg/day for index 2 group; P=4.4·10 À13 ). Thus, analysis of the combination of VKORC1 and CYP2C9 genotypes should identify warfarin-sensitive patients who require a lower dose of drug, allowing personalized warfarin treatment.

Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

“…[6][7][8][9][10][11][12] In recent years, Mushiroda, et al reported that the CYP2C9 and VKORC1 haplotype may affect the warfarin maintenance dose. 13) Our group has also shown that there are ethnic differences in terms of the genetic polymorphism of CYP2C9 and VKORC1, 14,15) which suggests that the optimal warfarin dose could vary between ethnicities.…”

High-resolution SNP and haplotype maps of the human gamma-glutamyl carboxylase gene (GGCX) and association study between polymorphisms in GGCX and the warfarin maintenance dose requirement of the Japanese population

“…Although most of the variability observed in patients' response to warfarin may be attributed to genetic varations in VKORC1 (Mushiroda et al 2006;Schwartz and Stein 2006) that functions to regenerate reduced vitamin K (Rost et al 2004;Li et al 2004), polymorphisms in GGCX have also been indicated to have some association with inter-individual variation in warfarin maintenance-dose requirement (Shikata et al 2004;Chen et al 2005;Loebstein et al 2005;Wadelius et al 2005;Herman et al 2006;Kimura et al 2007;Vecsler et al 2006).…”

Accuracy assessment of pharmacogenetic algorithms for warfarin dose prediction in Chinese patients

“…Xiaoying Lei, 1 Yanhai Guo, 1 Jianbin Sun, 1 Heping Zhou, 2 Yonglan Liu, 1 Ping Liang, 1 and Zhen Yan 1 * A few warfarin pharmacogenetic dosing algorithms have been proposed, based on multiethnic or homogeneous populations, to estimate warfarin therapeutic doses. However, it remains to be proven that which algorithm is accurate in predicting warfarin dose in Chinese people.…”

“…Recent pharmacogenetic studies showed that variations in genes, especially vitamin-K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 family 2 subfamily C polypeptide 9 (CYP2C9), contributed significantly to differences in warfarin dose requirements among patients, along with clinical and demographic factors [2][3][4][5]. Subsequent to these investigations, in 2007 the US Food and Drug Administration added pharmacogenetic information to the warfarin product label, highlighting the benefits of genotyping individual patients to improve the initial estimate of a reasonable warfarin dose [6].…”

“…A major breakthrough in the field of SCD-related brain injury has been the success of TCD ultrasonography to identify asymptomatic children with SCD who are at an increased risk of stroke and the administration of chronic transfusion to prevent its occurrence [1,2]. SCD is the most common inherited genetic disorder affecting Nigerians and its incidence in the country is amongst the highest in the world [3].…”