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Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes.
- Source :
-
Pharmacogenetics and genomics [Pharmacogenet Genomics] 2011 Jan; Vol. 21 (1), pp. 26-34. - Publication Year :
- 2011
-
Abstract
- 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.<br />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.<br />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.<br />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.<br />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.
- Subjects :
- Aged
Aged, 80 and over
Anticoagulants administration & dosage
Apolipoproteins E genetics
Cohort Studies
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP3A genetics
Cytochrome P450 Family 4
Dose-Response Relationship, Drug
Female
Genetic Association Studies
Genome-Wide Association Study
Humans
Male
Middle Aged
Vitamin K Epoxide Reductases
Aryl Hydrocarbon Hydroxylases genetics
Cytochrome P-450 Enzyme System genetics
Mixed Function Oxygenases genetics
Phenprocoumon administration & dosage
Polymorphism, Single Nucleotide drug effects
Polymorphism, Single Nucleotide physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1744-6880
- Volume :
- 21
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Pharmacogenetics and genomics
- Publication Type :
- Academic Journal
- Accession number :
- 21063236
- Full Text :
- https://doi.org/10.1097/FPC.0b013e32834154fb