Identification of Cytochrome P450 Oxidoreductase Gene Variants That Are Significantly Associated with the Interindividual Variations in Warfarin Maintenance Dose

Abstract

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.

Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3

“…However, these changes in activity are relatively modest; even in the case of drugs metabolized solely by CYP2D6 or CYP2C9, only a 50% change in metabolism would be expected and thus, less than a two-fold change in area under a curve would be expected when evaluated in vivo. Hence, it may not be surprising that POR A503V was not identified as a significant variable affecting the dose of warfarin, whereas the POR polymorphisms -173C > A, -208C > T, and rs2868177 were identified [36], although these polymorphisms do not affect POR promoter activity in vitro [37]. However, that study did not evaluate sufficient number of participants to identify a combined effect of CYP2C9 polymorphism and any of the POR polymorphisms.…”

Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis

“…Of these, 26 studies 5,6,15–38 evaluated this association for warfarin (7,313 patients), two for acenocoumarol (1,838 patients), 39,40 and two for phenprocoumon (319 patients). 41,42 The characteristics of the individual studies are summarized in Table 1.…”

Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency

“…Twentysix missense mutations/polymorphisms of the POR gene, encoding CYPOR, have been described by Miller's laboratory in patients with Antley-Bixler syndrome (ABS) and/or disordered steroidogenesis (3,4). Others have also described such mutations (5)(6)(7). ABS (8) is a disorder characterized by severe midface hypoplasia, humeroradial synostoses, bowing and fracture of femora, and other malformations.…”