title: Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 genes and the therapeutic warfarin dose in Brazilian patients with thrombosis: a prospective cohort study.
abstract: BACKGROUND
  There are several pharmacogenetic algorithms to determine the warfarin doses required in patients treated for thromboembolism, but they only explain 60% of dose variation, suggesting that other genes may influence the dose required.
  
  
  OBJECTIVE
  This study aimed to evaluate the impact of clinical factors and CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, MDR1 3435C>T, APOE* ε4, and UGT1A1(TA)n polymorphisms on the warfarin dose required, especially in those individuals requiring a high warfarin dose.
  
  
  METHODS
  We studied 116 Brazilian patients who received warfarin therapy for thromboembolism. Associations between dose variability and age, body mass index (BMI), gender, use of warfarin antagonists, and genetic polymorphisms were examined.
  
  
  RESULTS
  CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *ε4 were associated with lower warfarin doses. Of these subjects, 21% required a warfarin dose higher than 70 mg/week, which was associated with a BMI greater than 25 kg/m(2), use of warfarin antagonists, and the presence of the MDR1 3435T allele and UGT1A1(TA) 7 polymorphism. These individuals were considered to exhibit warfarin resistance. The individuals with the MDR1 3435TT genotype required a dose 21% higher than that required by 3435CT and 3435CC individuals. The UGT1A1(TA) 7 allele was positively correlated with the warfarin dose.
  
  
  CONCLUSIONS
  CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *ε4 were associated with lower warfarin doses, while MDR1 3435C>T and UGT1A1(TA) n polymorphisms were associated with a requirement for higher doses. This is the first study to evaluate warfarin resistance, APOE *ε4 and UGT1A1(TA) n genotypes in the Brazilian population, and the association of these two genotypes with warfarin dose required.
authors.affiliation: Department of General Biology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Cx. Postal 486, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil, vanessa@rumotecnologia.com.br.
authors.forename: Vanessa Cristina
authors.initials: VC
authors.lastname: de Oliveira Almeida
authors.forename: Daniel Dias
authors.initials: DD
authors.lastname: Ribeiro
authors.forename: Karina Braga
authors.initials: KB
authors.lastname: Gomes
authors.forename: Ana Lúcia Brunialti
authors.initials: AL
authors.lastname: Godard
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000925:Anticoagulants / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000032:analysis*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D013927:Thrombosis / Q000188:drug therapy* / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000627:therapeutic use*; D000099148:UGT1A1 Enzyme
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000925:Anticoagulants; D001057:Apolipoproteins E; D015415:Biomarkers; D065729:Cytochrome P-450 CYP2C9; D014453:Glucuronosyltransferase; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin; D000099148:UGT1A1 Enzyme; C513055:ABCB1 protein, human; C450260:CYP2C9 protein, human; C578523:VKORC1 protein, human