title: Frequency of Common VKORC1 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population.
abstract: Polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene lead to interindividual variability in warfarin dose requirement. The characterization of genotype frequency distribution is required in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common VKORC1 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted and genotype analysis for VKORC1 1173C>T and VKORC1-1639G>A polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of results. Data were analyzed using SPSS version 20. Genotype frequency distributions of VKORC1 1173C>T and VKORC1-1639G>A were found to be different from other populations. Both of these polymorphisms did not demonstrate significant effect on warfarin dose requirement. Although Cytochrome P450 2C9 (CYP2C9) and VKORC1 polymorphisms together attributed only 3.8% variability in warfarin dose but it was statistically significant ( p value = .004). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome. At the same time, no effect on warfarin dose variation explained by VKORC1 polymorphisms and small variability explained by studied genotypes stresses the need for exploration of more genetic and nongenetic factors in Pakistani population.
authors.affiliation: 1 Department of Pharmacology, Fazaia Medical College, Air University, Islamabad, Pakistan.
authors.forename: Aisha
authors.initials: A
authors.lastname: Qayyum
authors.affiliation: 2 Department of Pharmacology, Foundation University Medical College, Islamabad, Pakistan.
authors.forename: Muzammil Hasan
authors.initials: MH
authors.lastname: Najmi
authors.affiliation: 3 Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan.
authors.forename: Qaisar
authors.initials: Q
authors.lastname: Mansoor
authors.affiliation: 4 Department of Zoology, Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Irfan
authors.affiliation: 5 Department of Biochemistry, Islamic International Medical College, Riphah International University, Rawalpindi, Pakistan.
authors.forename: Abdul Khaliq
authors.initials: AK
authors.lastname: Naveed
authors.affiliation: 3 Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan.
authors.forename: Andleeb
authors.initials: A
authors.lastname: Hanif
authors.affiliation: 3 Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan.
authors.forename: Ali Raza
authors.initials: AR
authors.lastname: Kazmi
authors.affiliation: 3 Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ismail
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010154:Pakistan / Q000453:epidemiology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: CYP2C9 polymorphism; PCR-RFLP; VKORC1 1173C>T; VKORC1–1639G>A; Warfarin; direct DNA sequencing