Warfarin dose adjustments based on CYP2C9 genetic polymorphisms

Mark W. Linder, Stephen Warwick Looney, Jesse E. Adams, Nancy Johnson, Deborah Antonino-Green, Nichole Lacefield, Bonny L. Bukaveckas, Roland Valdes

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.

Original languageEnglish (US)
Pages (from-to)227-232
Number of pages6
JournalJournal of Thrombosis and Thrombolysis
Volume14
Issue number3
DOIs
StatePublished - Dec 1 2002
Externally publishedYes

Fingerprint

Genetic Polymorphisms
Warfarin
Genotype
Alleles
International Normalized Ratio
Cytochrome P-450 CYP2C9
Phenotype
DNA Restriction Enzymes
Cytochromes
Half-Life
Digestion
Hypersensitivity

Keywords

  • CYP2C9
  • Pharmacogenetics
  • Warfarin

ASJC Scopus subject areas

  • Hematology
  • Cardiology and Cardiovascular Medicine

Cite this

Linder, M. W., Looney, S. W., Adams, J. E., Johnson, N., Antonino-Green, D., Lacefield, N., ... Valdes, R. (2002). Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. Journal of Thrombosis and Thrombolysis, 14(3), 227-232. https://doi.org/10.1023/A:1025052827305

Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. / Linder, Mark W.; Looney, Stephen Warwick; Adams, Jesse E.; Johnson, Nancy; Antonino-Green, Deborah; Lacefield, Nichole; Bukaveckas, Bonny L.; Valdes, Roland.

In: Journal of Thrombosis and Thrombolysis, Vol. 14, No. 3, 01.12.2002, p. 227-232.

Research output: Contribution to journalArticle

Linder, MW, Looney, SW, Adams, JE, Johnson, N, Antonino-Green, D, Lacefield, N, Bukaveckas, BL & Valdes, R 2002, 'Warfarin dose adjustments based on CYP2C9 genetic polymorphisms', Journal of Thrombosis and Thrombolysis, vol. 14, no. 3, pp. 227-232. https://doi.org/10.1023/A:1025052827305
Linder, Mark W. ; Looney, Stephen Warwick ; Adams, Jesse E. ; Johnson, Nancy ; Antonino-Green, Deborah ; Lacefield, Nichole ; Bukaveckas, Bonny L. ; Valdes, Roland. / Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. In: Journal of Thrombosis and Thrombolysis. 2002 ; Vol. 14, No. 3. pp. 227-232.
@article{864b53f0062b40878923b0d9f7aca7ae,
title = "Warfarin dose adjustments based on CYP2C9 genetic polymorphisms",
abstract = "Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.",
keywords = "CYP2C9, Pharmacogenetics, Warfarin",
author = "Linder, {Mark W.} and Looney, {Stephen Warwick} and Adams, {Jesse E.} and Nancy Johnson and Deborah Antonino-Green and Nichole Lacefield and Bukaveckas, {Bonny L.} and Roland Valdes",
year = "2002",
month = "12",
day = "1",
doi = "10.1023/A:1025052827305",
language = "English (US)",
volume = "14",
pages = "227--232",
journal = "Journal of Thrombosis and Thrombolysis",
issn = "0929-5305",
publisher = "Springer Netherlands",
number = "3",

}

TY - JOUR

T1 - Warfarin dose adjustments based on CYP2C9 genetic polymorphisms

AU - Linder, Mark W.

AU - Looney, Stephen Warwick

AU - Adams, Jesse E.

AU - Johnson, Nancy

AU - Antonino-Green, Deborah

AU - Lacefield, Nichole

AU - Bukaveckas, Bonny L.

AU - Valdes, Roland

PY - 2002/12/1

Y1 - 2002/12/1

N2 - Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.

AB - Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.

KW - CYP2C9

KW - Pharmacogenetics

KW - Warfarin

UR - http://www.scopus.com/inward/record.url?scp=0042915883&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0042915883&partnerID=8YFLogxK

U2 - 10.1023/A:1025052827305

DO - 10.1023/A:1025052827305

M3 - Article

C2 - 12913403

AN - SCOPUS:0042915883

VL - 14

SP - 227

EP - 232

JO - Journal of Thrombosis and Thrombolysis

JF - Journal of Thrombosis and Thrombolysis

SN - 0929-5305

IS - 3

ER -