title: [Association of polymorphisms of cytochrome P450 2C9 exon 4 and -65G>C with warfarin sensitivity].
abstract: OBJECTIVE
  To investigate the association of the polymorphisms of cytochrome P450 2C9 (CYP2C9) exon 4 608T/G, 561A/C, 537A/C and 527A/C, and -65G/C with warfarin sensitivity.
  
  
  METHODS
  A total of 102 patients under warfarin anticoagulant therapy were selected. During follow-up, warfarin dosage and associated Prothrombin Time-International Normalized Ratio (P-INR) values were recorded. Simultaneous monitoring of incidence of bleeding and thrombosis adverse effect was recommended. Genetic polymorphisms of the above mentioned loci were identified by polymerase chain reaction and DNA sequencing.
  
  
  RESULTS
  The average age of the 102 patients was (62.1+/-10.5) years. The body mass index (BMI) was (24.7+/-3.8) kg/m2. Mean daily warfarin requirement was from 1.250 to 5.077 mg/day when therapeutic PT-INR (1.5-2.5) was maintained. DNA sequencing showed no polymorphisms of 608T/G, 561A/C, 537A/C, 527A/C in CYP2C9 exon 4. Warfarin daily dosage in CYP2C9 exon 4 -65C carriers was 3.106+/-0.619 mg/d, while it was (2.555+/-0.708) mg/d in individuals with wild-type -65G (P=0.020). Receiver operating characteristic (ROC) analysis showed that warfarin daily dosage of more than 2.5 mg/d can be used to predict the CYP2C9 exon 4 -65GC genotype (AUC: 0.770, P=0.005, 95%CI:0.626-0.915). Logistic regression indicated that BMI was an independent factor of bleeding during anti-coagulation therapy (OR=0.794, 95%CI: 0.651-0.970, P=0.024).
  
  
  CONCLUSIONS
  The Chinese population are, generally, warfarin-sensitive. Exon 4 of the CYP2C9 gene is highly conserved in this population. The warfarin maintenance dosage in CYP2C9 exon 4 -65CG carriers was significantly higher than those with wild-type -65GG. The clinical significance needs further investigation with more large-scale, multi-center trials.
authors.affiliation: Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjing, 300052 PR China.
authors.forename: Zan-xin
authors.initials: ZX
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Heng
authors.initials: H
authors.lastname: Cai
authors.forename: Jian-long
authors.initials: JL
authors.lastname: Men
authors.forename: Min-xin
authors.initials: MX
authors.lastname: Wei
mesh_terms: D000328:Adult; D000483:Alleles; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011110:Polymorphism, Genetic; D013927:Thrombosis / Q000188:drug therapy; D014859:Warfarin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases