title: Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients.
abstract: OBJECTIVE
  Warfarin is a commonly used oral anticoagulant with a narrow therapeutic index and various genetic and clinical factors that influence interpatient variability in dose requirements. This study investigated the impact of genetic and nongenetic factors on warfarin dose requirements in Egyptians.
  
  
  METHODS
  DNA was extracted from 207 patients taking warfarin for more than 2 months and genotyped for VKORC1 (3673 G>A), CYP2C9 *2*3*4*5*8, CYP4F2 (V33M; rs2108622), APOE (rs429358, rs7412), and CALU(rs339097) gene polymorphisms. Linear regression modeling was conducted to identify the genetic and nongenetic factors that independently influence warfarin dose requirements.
  
  
  RESULTS
  VKORC1 3673 AA or GA genotype (P<0.0001), one or two variant alleles of CYP2C9 gene (P=0.0004), APOE ε2 haplotype (P=0.01), and increasing age (P<0.0001) were all associated with lower warfarin dose, whereas smoking (P=0.025) and pulmonary embolism (P=0.0059) showed association with higher warfarin doses. These factors explained 31% of the warfarin dose variability. This is the first independent confirmation of the association of the CALU rs339097 variant with higher warfarin dose requirement, although inclusion of this single nucleotide polymorphism in the multiple regression model failed to achieve significance (P=0.066). CYP4F2 (V33M) polymorphism was not significant (P=0.314), despite its high frequency in the studied population (42%).
  
  
  CONCLUSIONS
  The study shows that VKORC1, CYP2C9 polymorphisms, APOE ε2 variant, and several clinical/demographic variables are important determinants of warfarin dose requirements in Egyptian patients. The percentage of variability explained by these factors is lower than in those of European ancestry, but similar to the variability explained in Asians and African ancestry.
authors.affiliation: Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
authors.forename: Mohamed Hossam A
authors.initials: MH
authors.lastname: Shahin
authors.forename: Sherief I
authors.initials: SI
authors.lastname: Khalifa
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Lamiaa N
authors.initials: LN
authors.lastname: Hammad
authors.forename: Mohamed T H
authors.initials: MT
authors.lastname: Sallam
authors.forename: Mostafa
authors.initials: M
authors.lastname: El Shafey
authors.forename: Shawky S
authors.initials: SS
authors.lastname: Ali
authors.forename: Mohamed-Eslam F
authors.initials: ME
authors.lastname: Mohamed
authors.forename: Taimour
authors.initials: T
authors.lastname: Langaee
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage*; D001057:Apolipoproteins E / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D004534:Egypt; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011655:Pulmonary Embolism / Q000378:metabolism; D012907:Smoking / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases