Novel genetic variants in Asian subjects and their influence on maintenance warfarin dose

Zhao, Feng; Loke, C. H.; Rankin, Sheila Clare; Guo, Jiayi; Lee, How Sung; Wu, Tuck Seng; Tan, Thiam Soon; Liu, Te-Chih; Lü, Wan-Liang; Lim, Yi Wan; Qiang, Zhang; Goh, Boon Cher; Lee, Soo‐Chin

doi:10.1016/j.clpt.2004.05.005

Cited by 118 publications

(117 citation statements)

References 35 publications

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“…In the present study, we assess the functional consequences of six new alleles recently reported by one of our laboratories (Zhao et al, 2004). These new alleles are as follows: CYP2C9*14 (R125H), CYP2C9*15 (S162X), CYP2C9*16 (T299A), CYP2C9*17 (P382S), CYP2C9*18 (D397A/I359L), and CYP2C9*19 (Q454H).…”

Section: Resultsmentioning

confidence: 99%

“…In our recent studies in a Southeast Asian population (59 Chinese, 37 Malay, and 26 Indians), CYP2C9 was sequenced for new mutations (Zhao et al, 2004) including the promoter, 300 base pairs downstream in the 3Ј-untranslated region, the splice-site junctions, and each of the nine CYP2C9 exons. The CYP2C9*2 and CYP2C9*3 alleles were found with varying frequencies in these groups (Indians Ͼ Chinese or Malay).…”

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confidence: 99%

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Functional Characterization of Novel Allelic Variants of CYP2C9 Recently Discovered in Southeast Asians

DeLozier

Lee²,

Coulter³

et al. 2005

J Pharmacol Exp Ther

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Functional Characterization of Novel Allelic Variants of CYP2C9 Recently Discovered in Southeast Asians

DeLozier

Lee²,

Coulter³

et al. 2005

J Pharmacol Exp Ther

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“…It has been reported that Chinese, Malay and Japanese patients required a 30-40% lower warfarinmaintenance dose than Caucasian patients (Takahashi et al 2003;Zhao et al 2004). These interethnic differences may be attributed to genetic differences.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it is well known that there are significant differences in warfarin dose requirement in different ethnic groups; for example, Chinese patients were re- ported to require a warfarin dose nearly 40% lower than that required by Caucasian patients (Zhao et al 2004). In addition, the therapeutic maintenance dose of warfarin for Japanese was also 31% lower than that for Caucasians (Takahashi et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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.

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“…With regard to the ethnic differences among patients, it has been shown that Asian populations require a markedly lower warfarin maintenance dose than Caucasians and African-Americans; however, the mechanisms underlying these differences still remain elusive [20,21].…”

Section: Introductionmentioning

confidence: 99%

Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application

Kwon

Kim

et al. 2009

Ann Lab Med

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, 건양대학교 의과대학 진단검사의학교실 5 515 515Background : Warfarin is a widely used oral anticoagulant with broad within-and between-individual dose requirements. Warfarin concentrations can be monitored by assessing its pharmacologic effects on International Normalized Ratio (INR). However, this approach has not been applied in the routine clinical management of patients receiving warfarin therapy. We performed a plasma warfarin assay using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) to determine if such an assay can be utilized in routine clinical practice.Methods : We included a total of 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr. The plasma concentrations of total warfarin and 7-hydroxywarfarin were determined by HPLC-MS/MS (Waters, UK). We assessed the association between warfarin dose, concentration, and INR as well as the effects of these factors on warfarin concentrations.Results : The mean maintenance dose of warfarin in 105 patients was 4.1±1.3 mg/day (range, 1.7-8.0 mg/day) and their mean plasma warfarin concentration was 1.3±0.5 mg/L. We defined a concentration range of 0.6-2.6 mg/L (corresponding to the 2.5th to 97.5th percentile range of the Plasma warfarin levels in the 74 patients showing INR within target range) as the therapeutic range for warfarin. The correlation of warfarin dose with warfarin concentration (r 2 =0.259, P<0.001) was higher than that with INR (r 2 =0.029, P=0.072). Conclusions : There was a significant correlation between warfarin dose and plasma warfarin concentrations in Korean patients with atrial fibrillation. Hence, plasma warfarin monitoring can help determine dose adjustments and improve our understanding of individual patient response to warfarin treatment. (Korean J Lab Med 2009;29:515-23)

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Novel genetic variants in Asian subjects and their influence on maintenance warfarin dose

Abstract: Interethnic differences in warfarin dosing in Asian subjects may result from other genetic, dietary, or environmental influences; however, these novel variants in the gene warrant further characterization through functional studies.

Cited by 118 publications

References 35 publications

Functional Characterization of Novel Allelic Variants of CYP2C9 Recently Discovered in Southeast Asians

Functional Characterization of Novel Allelic Variants of CYP2C9 Recently Discovered in Southeast Asians

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

Determination of Plasma Warfarin Concentrations in Korean Patients and Its Potential for Clinical Application

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