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Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction.

ABSTRACT: BACKGROUND:Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA) alone. AIMS:The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR). METHODS:Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC) before PCR amplification (LightCycler) and melting point analysis. RESULTS:The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation. CONCLUSION:CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.

SUBMITTER: Haug KBF

PROVIDER: S-EPMC2440373 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction.

Haug Kari Bente Foss KBF Sharikabad Mohammad N MN Kringen Marianne K MK Narum Sigrid S Sjaatil Stine T ST Johansen Per Wiik PW Kierulf Peter P Seljeflot Ingebjørg I Arnesen Harald H Brørs Odd O

Thrombosis journal 20080617

<h4>Background</h4>Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use ...[more]

PMID: 18559094

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Project description:What is already known about this subjectRecent studies on pharmacogenetics of warfarin have implicated apolipoprotein E (APOE) polymorphisms to influence the vitamin K dependent coagulation cascade and hence the efficacy of warfarin. Studies among Caucasian and African Americans showed a significant but conflicting role of apolipoprotein E (APOE) isoforms in warfarin pharmacogenetics. The contribution of APOE isoforms in influencing variations in warfarin requirements in Asian subjects remains to be investigated.What this study addsThis is the first report of a population study in Asians exploring the role of isoforms encoded by three APOE alleles (epsilon 2, epsilon 3, epsilon 4) in influencing warfarin dose requirements. The present study showed that the APOE epsilon 3/epsilon 3 isoform is the predominant genotype in the Asian population. The study also showed that APOE isoforms may not be important in affecting warfarin pharmacodynamics in Asian patients. It also suggested that the impact of different APOE isoforms depended on the frequency of APOE genotypes in the population, in particular the epsilon 4 allele containing genotypes.AimsTo investigate the influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients.MethodsA total of 174 Asian patients (Chinese, n = 96; Malays, n = 50; Indians, n = 28) who had stable daily warfarin doses for at least 1 month were recruited. Following genomic DNA extraction from venous blood, pharmacogenetic analysis of APOE and VKORC1 genes was done by DNA sequencing.ResultsThe majority of the Asian patients (78%) harboured the APOE epsilon 3/epsilon 3 genotype. Different APOE genotypes were found not to have any significant influence on mean daily warfarin dose requirements. Warfarin dose requirements in the pooled Asian patients homozygous for the VKORC1 H1 haplotype were significantly lower compared with patients homozygous for the H7 haplotype (H1-H1 vs. H7-H7: 2.79 +/- 1.06 mg day(-1)vs. 5.45 +/- 2.3 mg day(-1), P < 0.001).ConclusionsThe present study suggests that APOE variants have minimal impact on warfarin dose requirements in Asian patients, probably due to the low frequency of epsilon 4 allele containing genotypes.

Project description:The polymorphisms of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) are important genetic factors for warfarin dose determinations. The present study aimed to investigate the contribution of the CYP2C9 and VKORC1 genotypes to warfarin dose requirement in atrial fibrillation (AF) patients, and to evaluate the clinical application of a warfarin-dosing algorithm. A total of 122 AF patients with a target international normalized ratio of 2.0 to 3.0 were included to determine the genotypes of CYP2C9 (rs1057910) and VKORC1 (rs9923231). A warfarin-dosing algorithm was developed based on age, height, and the CYP2C9 and VKORC1 genotypes of AF patients. The results indicated that the mean warfarin daily dose requirement was lower in the CYP2C9*1/*3 genotype compared with those in the homozygous wild-type CYP2C9*1/*1 patients (P<0.05), and was higher in patients with the VKORC1 AG and GG genotypes compared with those with the AA genotype (P<0.05). The multivariate regression model showed that age, height, and the CYP2C9 and VKORC1 genotypes were the best variables for estimating warfarin dose (R2=56.4%). A new warfarin-dosing algorithm was developed and its validity was confirmed in a second cohort of AF patients. During the 50-day follow-up, 63.3% (19/30) of control group patients and 86.7% (26/30) of patients in the experimental group acquired the warfarin maintenance dose. Among all the patients who acquired the warfarin maintenance dose, the mean time elapse from initiation until warfarin maintenance dose was significantly less in the experimental group (25.8±1.7 day) compared to the control group (33.1±1.9 day) (P<0.05). There was significant linear correlation between predicted warfarin maintenance dose and actual dose (r=0.822, P<0.01). In conclusion, a new warfarin-dosing algorithm was developed based on the CYP2C9 and VKORC1 genotypes, and it can shorten the time elapse from initiation until warfarin maintenance dose in AF patients with warfarin therapy.

Dataset Information

Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction.

Publications

Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction.

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