Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin

L. K. Teh, I. M. Langmia, M. H. Fazleen Haslinda, H. A. Ngow, M. J. Roziah, R. Harun, Z. A. Zakaria, Mohd Zaki Salleh

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    What is known and Objectives: Testing for cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia. Methods: Patients who were attending clinics at our hospital and prescribed warfarin with stabilized INR levels of 2-4 were selected. DNA was extracted from blood samples and subsequently genotyped for CYP2C9*1,*2,*3, VKORC1 (G-1639A) and VKORC1 C1173T. Linear regression modelling using age, CYP2C9 and VKORC1 genotypes, sex, weight and height was undertaken to define a warfarin dosing algorithm. An initial model was developed using data from one cohort of patients and validated using data from a second cohort. Results and Discussion: A model which included age and variants of CYP2C9 and VKORC1 account for about 37% of the variability in warfarin dose required to achieve INR of 2-4. Among the parameters evaluated, only VKORC1 (G-1639A) and (C1173T) alleles, and age correlated with warfarin dose at 6 month. The mean dose predicted using the algorithm derived from cohort 1 was lower than the actual dose for cohort 2 (3·30 mg, SD 0·84 vs. 3·45 mg, SD 1·42). There was no relationship between INR values and the dose taken by the patients. Race, sex, weight and height did not correlate with dose. What is new and Conclusion: This study identifies factors which affect warfarin dosing in the Malaysia population. However, our best model does not account sufficiently for the variability in dose requirements for it to be used in dose prediction for the individual patient. Other important influential factors affecting warfarin dose requirement remain to be identified.

    Original languageEnglish
    Pages (from-to)232-236
    Number of pages5
    JournalJournal of Clinical Pharmacy and Therapeutics
    Volume37
    Issue number2
    DOIs
    Publication statusPublished - Apr 2012

    Fingerprint

    Vitamin K Epoxide Reductases
    Warfarin
    Cytochrome P-450 Enzyme System
    International Normalized Ratio
    Malaysia
    Alleles
    Weights and Measures
    Genetic Polymorphisms
    Population
    Linear Models
    Genotype

    Keywords

    • CYP2C9
    • Personalized medicine
    • Pharmacogenotyping
    • VKORC1
    • Warfarin

    ASJC Scopus subject areas

    • Pharmacology (medical)
    • Pharmacology

    Cite this

    Teh, L. K., Langmia, I. M., Fazleen Haslinda, M. H., Ngow, H. A., Roziah, M. J., Harun, R., ... Salleh, M. Z. (2012). Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin. Journal of Clinical Pharmacy and Therapeutics, 37(2), 232-236. https://doi.org/10.1111/j.1365-2710.2011.01262.x

    Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin. / Teh, L. K.; Langmia, I. M.; Fazleen Haslinda, M. H.; Ngow, H. A.; Roziah, M. J.; Harun, R.; Zakaria, Z. A.; Salleh, Mohd Zaki.

    In: Journal of Clinical Pharmacy and Therapeutics, Vol. 37, No. 2, 04.2012, p. 232-236.

    Research output: Contribution to journalArticle

    Teh, LK, Langmia, IM, Fazleen Haslinda, MH, Ngow, HA, Roziah, MJ, Harun, R, Zakaria, ZA & Salleh, MZ 2012, 'Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin', Journal of Clinical Pharmacy and Therapeutics, vol. 37, no. 2, pp. 232-236. https://doi.org/10.1111/j.1365-2710.2011.01262.x
    Teh, L. K. ; Langmia, I. M. ; Fazleen Haslinda, M. H. ; Ngow, H. A. ; Roziah, M. J. ; Harun, R. ; Zakaria, Z. A. ; Salleh, Mohd Zaki. / Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin. In: Journal of Clinical Pharmacy and Therapeutics. 2012 ; Vol. 37, No. 2. pp. 232-236.
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    abstract = "What is known and Objectives: Testing for cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia. Methods: Patients who were attending clinics at our hospital and prescribed warfarin with stabilized INR levels of 2-4 were selected. DNA was extracted from blood samples and subsequently genotyped for CYP2C9*1,*2,*3, VKORC1 (G-1639A) and VKORC1 C1173T. Linear regression modelling using age, CYP2C9 and VKORC1 genotypes, sex, weight and height was undertaken to define a warfarin dosing algorithm. An initial model was developed using data from one cohort of patients and validated using data from a second cohort. Results and Discussion: A model which included age and variants of CYP2C9 and VKORC1 account for about 37{\%} of the variability in warfarin dose required to achieve INR of 2-4. Among the parameters evaluated, only VKORC1 (G-1639A) and (C1173T) alleles, and age correlated with warfarin dose at 6 month. The mean dose predicted using the algorithm derived from cohort 1 was lower than the actual dose for cohort 2 (3·30 mg, SD 0·84 vs. 3·45 mg, SD 1·42). There was no relationship between INR values and the dose taken by the patients. Race, sex, weight and height did not correlate with dose. What is new and Conclusion: This study identifies factors which affect warfarin dosing in the Malaysia population. However, our best model does not account sufficiently for the variability in dose requirements for it to be used in dose prediction for the individual patient. Other important influential factors affecting warfarin dose requirement remain to be identified.",
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    AU - Langmia, I. M.

    AU - Fazleen Haslinda, M. H.

    AU - Ngow, H. A.

    AU - Roziah, M. J.

    AU - Harun, R.

    AU - Zakaria, Z. A.

    AU - Salleh, Mohd Zaki

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    N2 - What is known and Objectives: Testing for cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia. Methods: Patients who were attending clinics at our hospital and prescribed warfarin with stabilized INR levels of 2-4 were selected. DNA was extracted from blood samples and subsequently genotyped for CYP2C9*1,*2,*3, VKORC1 (G-1639A) and VKORC1 C1173T. Linear regression modelling using age, CYP2C9 and VKORC1 genotypes, sex, weight and height was undertaken to define a warfarin dosing algorithm. An initial model was developed using data from one cohort of patients and validated using data from a second cohort. Results and Discussion: A model which included age and variants of CYP2C9 and VKORC1 account for about 37% of the variability in warfarin dose required to achieve INR of 2-4. Among the parameters evaluated, only VKORC1 (G-1639A) and (C1173T) alleles, and age correlated with warfarin dose at 6 month. The mean dose predicted using the algorithm derived from cohort 1 was lower than the actual dose for cohort 2 (3·30 mg, SD 0·84 vs. 3·45 mg, SD 1·42). There was no relationship between INR values and the dose taken by the patients. Race, sex, weight and height did not correlate with dose. What is new and Conclusion: This study identifies factors which affect warfarin dosing in the Malaysia population. However, our best model does not account sufficiently for the variability in dose requirements for it to be used in dose prediction for the individual patient. Other important influential factors affecting warfarin dose requirement remain to be identified.

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