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Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study.
J Thromb Thrombolysis. 2006 Dec; 22(3):191-7.JT

Abstract

BACKGROUND

Warfarin has a narrow therapeutic range and wide inter-individual dosing requirements that may be related to functional variants of genes affecting warfarin metabolism (i.e., CYP2C9) and activity (i.e., vitamin K epoxide reductase complex subunit 1-VKORC1). We hypothesized that variants in these two genes explain a substantial proportion of variability in stable warfarin dose and could be used as a basis for improved dosing algorithms.

METHODS

Consecutive consenting outpatients (n = 213) with stable INR (2-3) for >1 month were enrolled. Buccal DNA was extracted using a Qiagen mini-column and CYP2C9*2 and VKORC1 genotyping performed by the Taqman 3' nuclease assay. Sequencing for CYP2C9*3, genotyping was done using Big Dye v3.1 terminator chemistry Dose by genotype was assessed by linear regression.

RESULTS

Weekly warfarin dose averaged 30.8 +/- 13.9 mg/week; average INR was 2.42 +/- 0.72. CYP2C9*2/*3 genotype distribution was: CC/AA (wild-type [WT]) = 71.4%, CT/AA = 18.3%, CC/AC = 9.4%, and CT/AC = 1%; VKORC1 genotypes were CC (WT) = 36.6%, CT = 50.7%, and TT = 12.7%. Warfarin doses (mg/week) varied by genotype: for CYP2C9, 33.3 mg/week for WT (CC/AA), 27.2 mg/week for CT/AA (P = 0.04 vs. WT), 23.0 mg/week for CC/AC (P = 0.003), and 6.0 mg/week for CT/AC (P < 0.001), representing dose reductions of 18-31% for single and 82% for double variant carriers; for VKORC1: 38.4 mg/week for WT (CC), 28.6 mg/week for CT (P < 0.001 vs. WT), 20.95 mg/week for TT (P < 0.001). In multiple linear regression, genotype was the dominant predictor of warfarin dose (P = 2.4 x 10(-15)); weak predictors were age, weight, and sex. Genotype-based modeling explained 33% of dose-variance, compared with 12% for clinical variables alone.

CONCLUSION

In this large prospective study of warfarin genetic dose-determinants, carriage of a single or double CYP2C9 variant, reduced warfarin dose 18-72%, and of a VKORC1 variant by 65%. Genotype-based modeling explained almost one-half of dose-variance. A quantitative dosing algorithm incorporating genotypes for 2C9 and VKORC1 could substantially improve initial warfarin dose-selection and reduce related complications.

Authors+Show Affiliations

Department of Medicine, Division of Cardiology, University of Utah School of Medicine, Cardiovascular Department, LDS Hospital, Salt Lake City, Utah, USA. john.carlquist@ihc.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17111199

Citation

Carlquist, John F., et al. "Genotypes of the Cytochrome P450 Isoform, CYP2C9, and the Vitamin K Epoxide Reductase Complex Subunit 1 Conjointly Determine Stable Warfarin Dose: a Prospective Study." Journal of Thrombosis and Thrombolysis, vol. 22, no. 3, 2006, pp. 191-7.
Carlquist JF, Horne BD, Muhlestein JB, et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis. 2006;22(3):191-7.
Carlquist, J. F., Horne, B. D., Muhlestein, J. B., Lappé, D. L., Whiting, B. M., Kolek, M. J., Clarke, J. L., James, B. C., & Anderson, J. L. (2006). Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. Journal of Thrombosis and Thrombolysis, 22(3), 191-7.
Carlquist JF, et al. Genotypes of the Cytochrome P450 Isoform, CYP2C9, and the Vitamin K Epoxide Reductase Complex Subunit 1 Conjointly Determine Stable Warfarin Dose: a Prospective Study. J Thromb Thrombolysis. 2006;22(3):191-7. PubMed PMID: 17111199.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. AU - Carlquist,John F, AU - Horne,Benjamin D, AU - Muhlestein,Joseph B, AU - Lappé,Donald L, AU - Whiting,Bryant M, AU - Kolek,Matthew J, AU - Clarke,Jessica L, AU - James,Brent C, AU - Anderson,Jeffrey L, PY - 2006/11/18/pubmed PY - 2007/2/23/medline PY - 2006/11/18/entrez SP - 191 EP - 7 JF - Journal of thrombosis and thrombolysis JO - J. Thromb. Thrombolysis VL - 22 IS - 3 N2 - BACKGROUND: Warfarin has a narrow therapeutic range and wide inter-individual dosing requirements that may be related to functional variants of genes affecting warfarin metabolism (i.e., CYP2C9) and activity (i.e., vitamin K epoxide reductase complex subunit 1-VKORC1). We hypothesized that variants in these two genes explain a substantial proportion of variability in stable warfarin dose and could be used as a basis for improved dosing algorithms. METHODS: Consecutive consenting outpatients (n = 213) with stable INR (2-3) for >1 month were enrolled. Buccal DNA was extracted using a Qiagen mini-column and CYP2C9*2 and VKORC1 genotyping performed by the Taqman 3' nuclease assay. Sequencing for CYP2C9*3, genotyping was done using Big Dye v3.1 terminator chemistry Dose by genotype was assessed by linear regression. RESULTS: Weekly warfarin dose averaged 30.8 +/- 13.9 mg/week; average INR was 2.42 +/- 0.72. CYP2C9*2/*3 genotype distribution was: CC/AA (wild-type [WT]) = 71.4%, CT/AA = 18.3%, CC/AC = 9.4%, and CT/AC = 1%; VKORC1 genotypes were CC (WT) = 36.6%, CT = 50.7%, and TT = 12.7%. Warfarin doses (mg/week) varied by genotype: for CYP2C9, 33.3 mg/week for WT (CC/AA), 27.2 mg/week for CT/AA (P = 0.04 vs. WT), 23.0 mg/week for CC/AC (P = 0.003), and 6.0 mg/week for CT/AC (P < 0.001), representing dose reductions of 18-31% for single and 82% for double variant carriers; for VKORC1: 38.4 mg/week for WT (CC), 28.6 mg/week for CT (P < 0.001 vs. WT), 20.95 mg/week for TT (P < 0.001). In multiple linear regression, genotype was the dominant predictor of warfarin dose (P = 2.4 x 10(-15)); weak predictors were age, weight, and sex. Genotype-based modeling explained 33% of dose-variance, compared with 12% for clinical variables alone. CONCLUSION: In this large prospective study of warfarin genetic dose-determinants, carriage of a single or double CYP2C9 variant, reduced warfarin dose 18-72%, and of a VKORC1 variant by 65%. Genotype-based modeling explained almost one-half of dose-variance. A quantitative dosing algorithm incorporating genotypes for 2C9 and VKORC1 could substantially improve initial warfarin dose-selection and reduce related complications. SN - 0929-5305 UR - https://www.unboundmedicine.com/medline/citation/17111199/Genotypes_of_the_cytochrome_p450_isoform_CYP2C9_and_the_vitamin_K_epoxide_reductase_complex_subunit_1_conjointly_determine_stable_warfarin_dose:_a_prospective_study_ L2 - https://doi.org/10.1007/s11239-006-9030-7 DB - PRIME DP - Unbound Medicine ER -