title: Linkage disequilibrium between the CYP2C19*2,*17 and CYP2C9*1 alleles and impact of VKORC1, CYP2C9, CYP2C19 gene polymorphisms and gene-gene interactions on warfarin therapy.
abstract: Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped. CYP2C9*1 allele is in complete linkage disequilibrium with CYP2C19*2 and CYP2C19*17 (D' = 1) in our study population. Patient with VKORC1-1639 G > A, CYP2C9*2 and CYP2C9*3 genetic variants need significant lower warfarin dose than patient with wild type allele of VKORC1 1639 G or CYP2C9*1. There is no significant differences between CYP2C19 allele variants for warfarin stable dose and INR > 5 event. Because of the complete linkage disequilibrium between CYP2C19*2,*17 and CYP2C9*1, patient with CYP2C19 *2/*2, *2/*17 and *17/*17 genotypes tend to have higher warfarin dose than patient with CYP2C19*1/*1 genotype. Stepwise regression analysis showed that VKORC1, CYP2C9, body mass index (BMI), age and gender were included as a factor significantly contributing to warfarin dose, whereas CYP2C19 did not contribute to warfarin dose. No statistically significant interaction between CYP2C9 and VKORC1 on warfarin dose and INR > 5 event was detected in univariate general linear model analysis. Our study suggests that polymorphic variants of VKORC1 and CYP2C9 affect warfarin dose independently, whereas CYP2C19 did not contribute to warfarin therapy.
authors.affiliation: Easton Cardiovascular Associates, Division of Cardiology, Department of Medicine, Easton Hospital, Easton, PA, USA. koroushkhalighi@gmail.com.|School of Medicine, Drexel University, Philadelphia, PA, USA. koroushkhalighi@gmail.com.
authors.forename: Koroush
authors.initials: K
authors.lastname: Khalighi
authors.affiliation: Easton Cardiovascular Associates, Division of Cardiology, Department of Medicine, Easton Hospital, Easton, PA, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Easton Cardiovascular Associates, Division of Cardiology, Department of Medicine, Easton Hospital, Easton, PA, USA.
authors.forename: Seyedabbas
authors.initials: S
authors.lastname: Mirabbasi
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA, USA.
authors.forename: Bahar
authors.initials: B
authors.lastname: Khalighi
authors.affiliation: Easton Cardiovascular Associates, Division of Cardiology, Department of Medicine, Easton Hospital, Easton, PA, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Easton Cardiovascular Associates, Division of Cardiology, Department of Medicine, Easton Hospital, Easton, PA, USA.
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Fan
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: CYP2C19; CYP2C9; Interaction; VKORC1; Warfarin