title: Association of Genetic Polymorphisms in the VKORC1 and CYP2C9 Genes with Warfarin Dosage in a Group of Kuwaiti Individuals.
abstract: OBJECTIVE
  Warfarin is the most widely prescribed oral anticoagulant worldwide. The narrow therapeutic index and the large variation in the inter-individual dose of warfarin are problematic, since the side effects can be lethal. Single nucleotide polymorphisms (SNP) in CYP2C9 and VKORC1 have been shown to significantly affect warfarin dosage toleration and this effect varies among different populations. We aimed to investigate the effect of these SNPs on warfarin dosage in a sample of Kuwaiti patients.
  
  
  METHODS
  Kuwaiti patients who were taking a maintenance dose of warfarin were genotyped for CYP2C9*1, *2 and *3 and VKORC1 rs9923231, rs9934438, rs7294 and rs2884737. The association of these SNPs with the warfarin dose was evaluated.
  
  
  RESULTS
  For CYP2C9, the CYP2C9 *1/*1 genotype required a higher dose (5.5 ± 3.3 mg/day) compared to non-*1/*1 (3.3 ± 1.7 mg/day) (p = 0.003). For VKORC1, the daily warfarin dose was significantly different (p = 0.001) among the three genotypes of rs9923231, rs9934438 and rs2884737, with carriers of the wild-type genotype requiring the highest dose compared to variant allele carriers (p ≤ 0.001-0.002). There was no association found between the daily warfarin dose and the rs7294 polymorphism.
  
  
  CONCLUSIONS
  Our data showed that individuals carrying the wild-type allele of CYP2C9 or VKORC1 rs9923231, rs9934438 or rs2884737 are less sensitive than individuals with the variant alleles of these SNPs and therefore required a higher daily maintenance dose of warfarin. Our study confirms the association between SNPs in CYP2C9 and VKORC1 and warfarin dose tolerance in Kuwaiti patients.
authors.affiliation: Department of Biological Sciences, Faculty of Science, Kuwait University, PO Box 5969, Safat, 13060, Kuwait, Kuwait. maryam.alrashid@ku.edu.kw.
authors.forename: Maryam H
authors.initials: MH
authors.lastname: Alrashid
authors.affiliation: Department of Pathology, Faculty of Medicine, Kuwait University, Safat, Kuwait.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Serri
authors.affiliation: Department of Medicine, Faculty of Medicine, Kuwait University, Safat, Kuwait.
authors.forename: Salem H
authors.initials: SH
authors.lastname: Alshemmari
authors.affiliation: Department of Biological Sciences, Faculty of Science, Kuwait University, PO Box 5969, Safat, 13060, Kuwait, Kuwait.
authors.forename: Philip
authors.initials: P
authors.lastname: Koshi
authors.affiliation: Department of Biological Sciences, Faculty of Science, Kuwait University, PO Box 5969, Safat, 13060, Kuwait, Kuwait.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Al-Bustan
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D007730:Kuwait; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases