Racial background is a determinant factor in the maintenance dosage of Warfarin

Gan, Gin Gin; A, Teh; Goh, Kim Yen; Chong, Heng Thay; Pang, Kang Wah

doi:10.1007/bf02983247

Cited by 49 publications

(33 citation statements)

References 8 publications

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“…5, 9 Moreover, it has been reported that compared with Europeans, the incidence of thromboembolism is low in Japan, despite the less intensive regimen; 10,11 which indicates that adjusted low-dose warfarin (eg, PT-INR 1.6-2.6) is optimal for prevention of thromboembolism in Japanese patients. 12, 13 Considering these racial differences in the anticoagulation therapy, we attempted to validate the IWPC pharmacogenetic dose algorithm for warfarin in Japanese patients under low-TAKEUCHI F et al…”

Section: Editorial P 850mentioning

confidence: 99%

Evaluation of Pharmacogenetic Algorithm for Warfarin Dose Requirements in Japanese Patients

Takeuchi

Kashida

Okazaki

et al. 2010

Circ J

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Background: Warfarin dosing is difficult to establish because of considerable interindividual variation. Thus, warfarin pharmacogenetics have attracted particular interest in relation to appropriate control of anticoagulation. Methods and Results:The 200 eligible subjects were chosen from participants in a hospital cohort. Performance of a pharmacogenetic algorithm recently developed by the International Warfarin Pharmacogenetics Consortium (IWPC) was tested and compared with a clinical algorithm (without genotype data) by calculating the percentage of patients for whom the predicted dose deviated by less than 7 mg/week (1 mg/day) from the actual dose. The pharmacogenetic algorithm accurately identified a significantly (P<0.05) larger proportion of patients to achieve the target international normalized ratio than did the clinical algorithm (68% vs 36% for a low-dose group; and 21% vs 0% for a high-dose group). Also, an increase in warfarin dosage was found to be appropriate for the current status of alcohol drinking (4 mg/week, as against non-drinking) and smoking (3.3 mg/week, as against non-smoking). Conclusions:The IWPC pharmacogenetic algorithm has clinical application, particularly in identifying Japanese patients who require a low dosage of warfarin and are at greater risk of excessive anticoagulation. (Circ J 2010; 74: 977 - 982)

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Section: Editorial P 850mentioning

confidence: 99%

Evaluation of Pharmacogenetic Algorithm for Warfarin Dose Requirements in Japanese Patients

Takeuchi

Kashida

Okazaki

et al. 2010

Circ J

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“…We hypothesize that Asp36Tyr may be relevant to other population groups of whom warfarin resistance is characteristic, such as Indians. 7 The issue of incompatibility of present knowledge with prediction of warfarin dose response in patients of African origin has been raised in several recent studies. [8][9][10] It has been suggested that African ethnic groups For personal use only.…”

Section: Vkorc1 Asp36tyr Warfarin Resistance Marker Is Common In Ethimentioning

confidence: 99%

VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals

Aklillu¹,

Leong²,

Loebstein³

et al. 2008

Blood

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“…[14][15][16] Ethnic stratification of the known CYP2C9 and VKORC1 genetic variants provides only partial explanation of these differences. 10,[17][18][19][20][21][22] The major limitation of this study is the small number of patients and its cross-sectional nature.…”

Section: Asp36tyr and Vkorc1 Haplotypesmentioning

confidence: 99%

A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance

Loebstein

Dvoskin²,

Halkin

et al. 2006

Blood

151

113

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CYP2C9 and VKORC1 genetic variants are associated with low and intermediate warfarin dose requirements, but markers of high doses are less well characterized. We analyzed the VKORC1 coding sequence and known CYP2C9 and VKORC1 polymorphisms in 15 selected warfarin-resistant (dose, 80 to 185 mg/wk) and 8 warfarinsensitive patients (7 to 13 mg/wk) and 99 unselected controls (8 to 105 mg/wk). We identified a coding VKORC1 Asp36Tyr polymorphism in 7 of 15 resistant compared with 0 of 8 sensitive patients (P ‫؍‬ .026) Carriers of Asp36Tyr in the control group (8 of 99) required significantly higher warfarin doses of 80.9 ؎ 10.1 mg/wk compared with 42.7 ؎ 7.5 mg/wk in noncarriers (F ‫؍‬ 9.79, P ‫؍‬ .002). Asp36Tyr was significantly associated with doses of more than 70 mg/wk (odds ratio, 13.0; 95% confidence limit, 1.3 to 124.2), while doses of 20 to 70 mg/wk were associated with Asp36Tyr (partial r 2 ‫؍‬ .11; P ‫؍‬ .004), CYP2C9*2 and *3 (r 2 ‫؍‬ .08; P ‫؍‬ .01), and VKORC1*2 and *3 markers (r 2 ‫؍‬ .05; P ‫؍‬ .05). All Asp36Tyr carriers also had VKORC1*1 tag-single nucleotide polymorphisms (tag-SNPs) indicating a new haplotype. Asp36Tyr was common in Jewish ethnic groups of Ethiopian (15%) and Ashkenazi (4%) origin. We suggest that Asp36Tyr is a new marker of the high end of the warfarin dosing range. IntroductionReduced warfarin dose requirements are dictated by the CYP2C9*2 and *3 genetic variants due to decreased S-warfarin metabolic clearance and by the VKORC1*2 haplotype (or H1 and H2) with decreased VKORC1 activity and lower ambient reduced vitamin K levels. [1][2][3][4][5][6][7] Variants affecting the intermediate range of warfarin doses include the VKORC1*3 and *4 (or H7, H8, and H9) haplotypes. [4][5] At the other end of the dose spectrum, several rare VKORC1 mutations have been described, including the original report on 4 distinct mutations in warfarin-resistant individuals, 8 a rare Val66Met mutation associated with high warfarin doses, 9-10 and an Asp36Tyr mutation described in 2 patients with doses of 40 to 50 mg/wk 11 However, genetic effects on the highest warfarin doses (more than 80 mg/wk), which are met in clinical practice, have been less well characterized. In an attempt to identify novel markers of warfarin resistance, we performed sequence analysis of all the coding exons in the VKORC1 gene in a selected group of warfarin-resistant and warfarin-sensitive patients, including an analysis of known polymorphisms in CYP2C9 and VKORC1. We validated our findings in a series of unselected warfarin-treated patients described in our previous studies. [12][13] Patients, materials, and methods Patients were at stable anticoagulation (therapeutic international normalized ratio [INR] in 4 clinic visits). Resistant patients were defined by warfarin dose requirements of at least 80 mg/wk in the absence of known dose-increasing factors and sensitive patients by doses of 13 mg/wk or less.The controls were 99 previously described patients recruited as an unselected consecutive series. We recorded patient sex, a...

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Racial background is a determinant factor in the maintenance dosage of Warfarin

Cited by 49 publications

References 8 publications

Evaluation of Pharmacogenetic Algorithm for Warfarin Dose Requirements in Japanese Patients

Evaluation of Pharmacogenetic Algorithm for Warfarin Dose Requirements in Japanese Patients

VKORC1 Asp36Tyr warfarin resistance marker is common in Ethiopian individuals

A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance

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