Identification of cytochrome P450 oxidoreductase gene variants that are significantly associated with the interindividual variations in warfarin maintenance dose

Xiuling Zhang, Lei Li, Xinxin Ding, Laurence S. Kaminsky

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Cytochrome P450 oxidoreductase (POR) is required for drug metabolism by all microsomal cytochrome P450 enzymes. The aim of this study was to investigate whether any of the common single nucleotide polymorphisms (SNPs) in the POR gene and its flanking intergenic sequences correlate with interindividual variations in the warfarin maintenance dose (which is determined partly by rates of warfarin metabolism) in patients undergoing anticoagulation therapy. Warfarin dose and patients' demographic and clinical information were collected from 124 patients, who had attained a stable warfarin dose while receiving treatment at the Stratton VA Medical Center. Genomic DNAs were isolated from blood samples and were genotyped for 15 SNPs (including 10 SNPs on the POR gene). Association analysis was performed on 122 male patients by linear regression. Simple regression analysis revealed that vitamin K epoxide reductase complex subunit 1 (VKORC1) -1639A>G, CYP2C9*2, CYP2C9*3, age, and chronic aspirin therapy were significantly associated with warfarin dose. In contrast, multiple regression analysis revealed that, in addition to several known factors contributing to the variations in warfarin maintenance dose (VKORC1 -1639A>G, CYP2C9*2, CYP2C9*3, CYP4F2 rs2108622, and chronic aspirin therapy), three common POR SNPs (-173C>A, -208C>T, and rs2868177) were also significantly associated with variations in warfarin maintenance dose. These results indicate, for the first time, that three common SNPs in the POR gene may contribute to the interindividual variability in warfarin maintenance dose. Further studies on functional characterization of the POR SNPs identified, including their impact on the in vivo metabolism of additional drugs, are needed.

Original languageEnglish (US)
Pages (from-to)1433-1439
Number of pages7
JournalDrug Metabolism and Disposition
Volume39
Issue number8
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

Fingerprint

Warfarin
Cytochrome P-450 Enzyme System
Oxidoreductases
Single Nucleotide Polymorphism
Genes
Vitamin K Epoxide Reductases
Aspirin
Regression Analysis
Intergenic DNA
Therapeutics
Pharmaceutical Preparations
Linear Models
Demography
Cytochrome P-450 CYP2C9
DNA

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Identification of cytochrome P450 oxidoreductase gene variants that are significantly associated with the interindividual variations in warfarin maintenance dose. / Zhang, Xiuling; Li, Lei; Ding, Xinxin; Kaminsky, Laurence S.

In: Drug Metabolism and Disposition, Vol. 39, No. 8, 01.08.2011, p. 1433-1439.

Research output: Contribution to journalArticle

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