Warfarin Dosing in Patients With CYP2C9*5 Variant Alleles

Kathryn J. Lindley, Nita A. Limdi, Larisa H. Cavallari, Minoli A. Perera, Petra Lenzini, Julie A. Johnson, Alan H.B. Wu, Paul M. Ridker, Cristi R. King, Charles S. Eby, Shitalben Patel, Shimoli V. Shah, T. Mark Beasley, Juan Li, Brian F. Gage

Research output: Contribution to journalArticlepeer-review

Abstract

Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in vitro studies suggest CYP2C9*5 is associated with reduced clearance of warfarin. The clinical relevance of this single-nucleotide variation (SNV) (formerly SNP) is uncertain. In this multicentered study of 2,298 patients (49% female, 35% Black) taking warfarin, we quantified the association between the CYP2C9*5 allele and warfarin requirements. The CYP2C9*5 SNV was present in 2.3% of Black and 0.07% of White patients. Without taking CYP2C9*5 into account, pharmacogenetic algorithms that include other SNVs overestimated the warfarin dose by 30% (95% confidence interval (19–40%), P < 0.001), an average of 1.87 mg/day (SD 1.64) in heterozygotes (P < 0.001). Noncarriers required a slightly (0.23 mg/day, SD 2.09) higher than predicted dose. Genotyping for CYP2C9*5 corrected the potential overdose and halved overall dosing error in heterozygotes. Patients carrying CYP2C9*5 require a clinically relevant reduction in warfarin dose. Given the potential to improve the accuracy and safety of warfarin dosing in populations of African ancestry, we have incorporated this SNV into a nonprofit website to assist warfarin initiation (www.WarfarinDosing.org).

Original languageEnglish
Pages (from-to)950-955
Number of pages6
JournalClinical pharmacology and therapeutics
Volume111
Issue number4
DOIs
StatePublished - Apr 2022

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