Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population

LEE, S; Ng, Siew Bee; Oldenburg, J.; Chong, Poh Kuan; Rost, S.; Guo, Jia; Yap, Hui-Kim; Rankin, Sheila Clare; Khor, Hong Tar; Yeo, Tiong‐Cheng

doi:10.1016/j.clpt.2005.11.006

Cited by 136 publications

(118 citation statements)

References 36 publications

(62 reference statements)

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“…69,71 Furthermore, a number of studies have shown that common SNPs in VKORC1 are strongly associated with warfarin maintenance dose in several populations (Table 3). [72][73][74][75][76][77][78][79][80][81][82][83] Additionally, a similar relationship has been demonstrated with the other vitamin K antagonists acenocoumarol and phenprocoumon, 84,85 with one study suggesting an association with coumarin-related bleeding. 85 The associated VKORC1 SNPs are within a region of strong linkage disequilibrium, and a combination of several SNPs does not contribute greater information than one individual SNP.…”

Section: The Vitamin K Cyclementioning

confidence: 70%

“…Polymorphisms in the VKORC1 and CYP2C9 genes and a limited subset of environmental determinants account for around 50-60% of the variance in warfarin dose requirement. 73,76,77,79,[81][82][83] In six studies, the relative contribution of VKORC1 is greater than that of CYP2C9, 73,74,78,[81][82][83] in two, CYP2C9 has a greater quantitative contribution, 72,76 whereas VKORC1 and CYP2C9 contribute equally in one study. 79 Sconce et al 76 have gone on to develop a dosing table based on a regression equation combining age, height and CYP2C9*2 and CYP2C9*3, and the VKORC1 SNP À1639G4A.…”

Section: Future Challenges For Clinical Practicementioning

confidence: 99%

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Pharmacogenetics of warfarin: current status and future challenges

2006

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Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P 450 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.

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Section: The Vitamin K Cyclementioning

confidence: 70%

Section: Future Challenges For Clinical Practicementioning

confidence: 99%

Pharmacogenetics of warfarin: current status and future challenges

2006

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“…The dose requirements of oral anticoagulants were also found to be in accordance with the trend shown by the genotypes [13]. In a study involving Chinese, Malay and Indians living in Singapore [14], the mean weight-normalized COA dose was lower for Chinese and Malays than for Indians. In our study, we genotyped 180 patients of northern Indian origin, who were on COA therapy with stabilized INR range values between 2.0 and 3.5, for VKORC1 -1639 G [ A polymorphism and observed that the VKORC1 -1639G [ A minor allele frequency in the northern Indian patient group was 22% [10].…”

Section: Genetic Variants In Components Of the Coagulation Cascadementioning

confidence: 60%

Pharmacogenetic Aspects of Coumarinic Oral Anticoagulant Therapies

et al. 2011

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Coumarinic oral-anticoagulants (COAs) are commonly used for treatment of thromboembolic events. However, these medications have a narrow therapeutic range and there are large inter-individual variations in drug response. This is especially important in the initial phases of oral-anticoagulant therapy. Recent advancements in pharmacogenetics have established that clinical outcomes in oral-anticoagulant therapy are affected by genetic factors. The allelic variants of genes like cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are closely associated with maintenance dose of oral anti-coagulants. In addition, GGCX (Gammaglutamyl carboxylase) polymorphism at position 12970 (rs11676382), CYP4F2 (rs2108622; V433M; 1347 C [ T) and Apolipoprotein E (APOE) variants have been shown to explain a small but significant influence on dose requirements. There are large differences in the frequencies of these polymorphisms between different world populations which are also related to the requirements of oral anticoagulants. However, the final drug dosage in an individual is determined by complex sets of genetic and environmental factors and several dosing algorithms which combine clinical and genetic parameters to predict therapeutic COA doses have also been developed. The algorithm based dose prediction shows the importance of pharmacogenetic testing in patients undergoing oral anticoagulant therapies.

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“…[24][25][26] In the Singapore populations, the Indians were observed to display warfarin resistance, thus requiring a higher dose as compared with the Chinese and Malays. [26][27][28][29] There is no significant difference in ROH frequencies among the populations (ROH frequencies of 21, 13 and 20% for the Chinese, Malays and Indians, respectively). However, if we examine the haplotypes in this region, there is significant difference.…”

Section: Frequency Of Rohs and Frequency Of Haplotypes Within Rohsmentioning

confidence: 99%

Regions of homozygosity in three Southeast Asian populations

Teo

Salim

et al. 2011

J Hum Genet

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The genomes of outbred populations were first shown in 2006 to contain regions of homozygosity (ROHs) of several megabases. Further studies have also investigated the characteristics of ROHs in healthy individuals in various populations but there are no studies on Singapore populations to date. This study aims to identify and investigate the characteristics of ROHs in three Singapore populations. A total of 268 samples (96 Chinese, 89 Malays and 83 Indians) are genotyped on Illumina Human 1 M Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We use the PennCNV algorithm to detect ROHs. We report an abundance of ROHs (X500 kb), with an average of more than one hundred regions per individual. On average, the Indian population has the lowest number of ROHs and smallest total length of ROHs per individual compared with the Chinese and Malay populations. We further investigate the relationship between the occurrence of ROHs and haplotype frequency, regional linkage disequilibrium (LD) and positive selection. Based on the results of this data set, we find that the frequency of occurrence of ROHs is positively associated with haplotype frequency and regional LD. The majority of regions detected for recent positive selection and regions with differential LD between populations overlap with the ROH loci. When we consider both the location of the ROHs and the allelic form of the ROHs, we are able to separate the populations by principal component analysis, demonstrating that ROHs contain information on population structure and the demographic history of a population.

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Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population

Abstract: Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

Cited by 136 publications

References 36 publications

Pharmacogenetics of warfarin: current status and future challenges

Pharmacogenetics of warfarin: current status and future challenges

Pharmacogenetic Aspects of Coumarinic Oral Anticoagulant Therapies

Regions of homozygosity in three Southeast Asian populations

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