Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes

Pharmacogenet Genomics. 2011 Jan;21(1):26-34. doi: 10.1097/FPC.0b013e32834154fb.


Background: Genome-wide association studies (GWAS) on warfarin and acenocoumarol showed that interindividual dosage variation is mainly associated with single nucleotide polymorphisms (SNPs) in VKORC1 and to a lesser extent in CYP2C9 and CYP4F2. For phenprocoumon dosage, the genes encoding CYP3A4 and ApoE might play a role.

Objective: To assess the association between common genetic variants within VKORC1, CYP2C9, CYP4F2, CYP3A4, and ApoE and phenprocoumon maintenance dosage, and to identify novel signals using GWAS.

Methods: We selected all participants from the Rotterdam study who were treated with phenprocoumon. For each SNP, we tested the association between the above-mentioned genotypes and age, sex, body mass index, and target INR adjusted-phenprocoumon maintenance dosage.

Results: Within our study population (N=244), VKORC1, CYP2C9, CYP4F2 genotypes together explained 46% of phenprocoumon maintenance dosage variation. Each additional VKORC1 variant allele reduced phenprocoumon maintenance dosage by 4.8 mg/week (P<0.0001) and each additional CYP2C9 variant allele by 2.2 mg/week (P=0.002). Each additional variant allele of CYP4F2 increased phenprocoumon dosage by 1.5 mg/week (P=0.022). Variant alleles of CYP3A41*B and ApoE showed no association with phenprocoumon dosage. Genome-wide significant SNPs were all related to VKORC1 activity. Best associated were two SNPs in complete linkage disequilibrium with each other and with SNPs within VKORC1: rs10871454 [Syntaxin 4A (STX4A)] and rs11150604 (ZNF646), each with a P value of 2.1×10⁻²². Each reduced phenprocoumon maintenance dosage weekly by 4.9 mg per variant allele.

Conclusion: Similar to earlier findings with warfarin and acenocoumarol, phenprocoumon maintenance dosage depended on polymorphisms in the VKORC1 gene. CYP2C9 and CYP4F2 were of modest relevance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anticoagulants / administration & dosage
  • Apolipoproteins E / genetics
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Cohort Studies
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P450 Family 4
  • Dose-Response Relationship, Drug
  • Female
  • Genetic Association Studies
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics*
  • Phenprocoumon / administration & dosage*
  • Polymorphism, Single Nucleotide* / drug effects
  • Polymorphism, Single Nucleotide* / physiology
  • Vitamin K Epoxide Reductases


  • Anticoagulants
  • Apolipoproteins E
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Cytochrome P450 Family 4
  • CYP3A4 protein, human
  • CYP4F2 protein, human
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases
  • Phenprocoumon