title: Factor VII R353Q genetic polymorphism is associated with altered warfarin sensitivity among CYP2C9 *1/*1 carriers.
abstract: OBJECTIVE
  Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction.
  
  
  METHODS
  Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation.
  
  
  RESULTS
  Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14 ± 0.11 vs. 0.08 ± 0.50 mg⁻¹ Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism.
  
  
  CONCLUSIONS
  The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore unlikely that its use would be of clinical importance.
authors.affiliation: Clinical Pharmacology Unit, Division of Medicine, Hadassah University Hospital, Jerusalem 91120, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Mlynarsky
authors.forename: Idit
authors.initials: I
authors.lastname: Bejarano-Achache
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Caraco
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D016903:Drug Monitoring; D004351:Drug Resistance; D005167:Factor VII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011655:Pulmonary Embolism / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D020246:Venous Thrombosis / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D005167:Factor VII; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases
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