title: Evaluation of the warfarin-resistance polymorphism, VKORC1 Asp36Tyr, and its effect on dosage algorithms in a genetically heterogeneous anticoagulant clinic.
abstract: OBJECTIVE
  To assess allele frequency and potential predictive value of recurrent polymorphisms affecting warfarin metabolism in an unselected patient cohort attending an anticoagulant clinic (n=186).
  
  
  METHODS
  Genotyping of ten SNPs in five candidate genes (VKORC1, CYP2C9, CALU, EPHX and GGCX) was carried out by ABI PRISM SNaPshot multiplex method.
  
  
  RESULTS
  We confirm the association between high-frequency SNPs, VKORC1 c.-1639G>A and CYP2C9 *2/*3 and warfarin sensitivity, and contribute additional evidence that the VKORC1 p.Asp36Tyr variant is recurrent and independently associated with warfarin resistance in our population. Other SNPs made little contribution.
  
  
  CONCLUSIONS
  Warfarin sensitivity was predicted by known VKORC1 and CYP2C9 SNPs. However, resistance associated with p.Asp36Tyr in VKORC1 would not be predicted by the usual markers. Despite its relatively low frequency (3/186 or 1.6%) clinical considerations may warrant its inclusion in pharmacogenetic screening for initial warfarin dosing in clinic populations with a heterogeneous population base.
authors.affiliation: Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Shuen
authors.forename: Betty Y L
authors.initials: BY
authors.lastname: Wong
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.forename: Rita
authors.initials: R
authors.lastname: Selby
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
mesh_terms: D019943:Amino Acid Substitution; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004252:DNA Mutational Analysis; D054796:Drug Dosage Calculations; D004351:Drug Resistance / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D006899:Mixed Function Oxygenases / Q000235:genetics*; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases