VKORC1-1639G&gt;A, CYP2C9, EPHX1691A&gt;G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China

Gu, Qiang; Kong, Yan; Schneede, Jörn; Ye, Xiao; Chen, Lin; Zhong, Qin; Wang, Xuefeng; Hao, Jia; Chen, Baicheng; Chen, Jing-Jin

doi:10.1007/s00228-010-0863-9

Cited by 34 publications

(32 citation statements)

References 41 publications

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“…Our findings are in concordance with previous studies carried on a Japanese [14], Chinese [41] and Indonesian population [23]. This is in contrast to other reports [7][8][9].…”

Section: Discussionsupporting

confidence: 50%

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Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients

et al. 2013

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VKORC1 (1173C>T) contributes to the warfarin dose variability. Patients' age and genetic variants of VKORC1 account for nearly 20.5% of the variability in warfarin dose required to achieve an INR of 2-3. The success of a prediction equation based on these variables was proved in a different cohort: the predicted dose correlated significantly with the maintenance dose and the equation was more successful among patients with a dose≥35 mg/week. The results of the warfarin algorithm we developed were comparable with those of the IWPC and Gage algorithms with the advantage of using one SNP (VKORC1 1173C>T) only. This represents an economic advantage in our community. Replication of this study in a larger cohort of patients is necessary before translation of this knowledge into clinical guidelines for warfarin prescription.

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“…Our findings are in concordance with previous studies carried on a Japanese [14], Chinese [41] and Indonesian population [23]. This is in contrast to other reports [7][8][9].…”

Section: Discussionsupporting

confidence: 50%

“…The median (25th-75th percentiles) age of the 84 patients was 39 (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48) years. Forty-one were men and 43 were women.…”

Section: Demographic Data Of the 84 Studied Subjectsmentioning

confidence: 99%

Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients

et al. 2013

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“…The lower warfarin dose in Asians suggests that future studies on additional defective CYP2C9 alleles in Asians or on other factors affecting the activity of CYP2C9 are needed. Recently Gu et al [42] reported that Chinese patients with the CYP2C9 IVS3-65 GC or CC genotype received lower doses of warfarin (0.9 Ϯ 0.2 mg day -1 ) than those with the CYP2C9*1/*1 genotype (2.6 Ϯ 1.4 mg day -1 ). Still, the plasma total and unbound warfarin concentrations were significantly lower in the patients with the CYP2C9*1/*1 genotype.…”

Section: Discussionmentioning

confidence: 99%

Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

Yang

Niu

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The mean catalytic activities of CYP1A2, CYP2A6, CYP2D6, CYP2E1 and CYP3A4 in human liver microsomes (HLM) of Japanese origin were found to be lower than the corresponding mean values of Caucasian HLM, but the distribution patterns of data in these studies were not well addressed.• Interindividual variations in metabolic activities of Chinese HLM samples were reported for CYP1A2, CYP2C9, CYP2D6 and CYP3A4, but little is known about the difference in CYP activities between Chinese and Caucasian HLM samples.• The vast majority of the preceding studies were based on the measurement of metabolite formation rates at a certain fixed substrate concentration, rather than enzyme kinetic analyses.WHAT THIS STUDY ADDS• Significant differences in metabolic capability were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1 with the median values lower for the Chinese HLM samples vs. the Caucasian samples, which were associated with differences in Michaelis constant or maximum velocity.• Despite negligible differences in metabolic capability for CYP2A6, CYP2B6, CYP2C8, CYP2D6 and CYP3A, Michaelis constant of CYP2B6 appeared to have a significant ethnic difference.AIM The most common causes of variability in drug response include differences in drug metabolism, especially when the hepatic cytochrome P450 (CYP) enzymes are involved. The current study was conducted to assess the differences in CYP activities in human liver microsomes (HLM) of Chinese or Caucasian origin.METHODS The metabolic capabilities of CYP enzymes in 30 Chinese liver microsomal samples were compared with those of 30 Caucasian samples utilizing enzyme kinetics. Phenacetin O‐deethylation, coumarin 7‐hydroxylation, bupropion hydroxylation, amodiaquine N‐desethylation, diclofenac 4′‐hydroxylation (S)‐mephenytoin 4′‐hydroxylation, dextromethorphan O‐demethylation, chlorzoxazone 6‐hydroxylation and midazolam 1′‐hydroxylation/testosterone 6β‐hydroxylation were used as probes for activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Mann‐Whitney U test was used to assess the differences.RESULTS The samples of the two ethnic groups were not significantly different in cytochrome‐b5 concentrations but were significantly different in total CYP concentrations and NADPH‐P450 reductase activity (P < 0.05). Significant ethnic differences in intrinsic clearance were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1; the median values of the Chinese group were 54, 58, 26, and 35% of the corresponding values of the Caucasian group, respectively. These differences were associated with differences in Michaelis constant or maximum velocity. Despite negligible difference in intrinsic clearance, the Michaelis constant of CYP2B6 appeared to have a significant ethnic difference. No ethnic difference was observed for CYP2A6, CYP2C8, CYP2D6 and CYP3A.CONCLUSIONS These data extend our knowledge on the ethnic differences in CYP enzymes and will have implications for drug discovery and drug therapy for patients from different ethnic origins.

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“…A recent association study with a Chinese population also confirmed this observation [16]. Candidate gene studies have also detected associations between other SNPs and warfarin dose, such as SNPs in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) [17], GGCX (gamma-glutamyl carboxylase) [18], [19], [20], [21], EPHX1 (epoxide hydrolase 1) [21], [22], [23], [24], CALU (calumenin) [25], and MPZ (myelin protein zero) [12]. However, the associations of these SNPs with warfarin dose were inconsistent.…”

Section: Introductionmentioning

confidence: 66%

“…Three variants, rs1057910 (*3), rs4917639, and rs9332127 in the CYP2C9 gene have been reported to be associated with warfarin dose [12], [22], [24]. Among these variants, rs9332127 was not detected in Caucasian individuals but was reported to affect warfarin dose in Chinese people [22], [24], [35]; however, no significant association was observed in Indonesian populations [36]. In our study and previous studies [12], [37], univariate analyses showed that rs4917639 was significantly associated with warfarin dose.…”

Section: Discussionmentioning

confidence: 99%

A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

et al. 2014

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Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001). Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients.

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VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China

Cited by 34 publications

References 41 publications

Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients

Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients

Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

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