Pharmacogenetics of acenocoumarol in patients with extreme dose requirements.
BACKGROUND
There is currently intense debate as to whether pharmacogenetic algorithms for estimating the initial dose of coumarins provide a more accurate dose than the fixed-dose approach. Recently, it has been suggested that the greatest benefit of pharmacogenetic algorithms is observed in patients with extreme dose requirements.


OBJECTIVE
To identify clinical and genetic factors that better characterize patients who need extreme acenocoumarol doses for steady anticoagulation state.


METHODS
We reviewed 9538 patients with a steady acenocoumarol dose from three Spanish hospitals, selecting 83 who took <or= 5.00 mg week(-1) (percentile 5, p5) and 203 taking >or= 30.00 mg week(-1) (p95). We also selected patients matched by gender and age taking 13.50-14.00 mg week(-1) (p50). We genotyped VKORC1 (rs9923231), CALU (rs1043550), GGCX (rs699664), CYP2C9 (rs1799853; rs1057910), CYP4F2 (rs2108622) and F7 (rs5742910) single-nucleotide polymorphisms (SNPs).


RESULTS
Comparison between p5 and p95 revealed five parameters with significant differences: body surface area (BSA) (P = 0.006), age, VKORC1, CYP2C9 and CYP4F2 genotypes (all P < 0.001). First VKORC1, and second, CYP2C9 SNPs played a strong effect by determining extreme doses, particularly in p95. Only one out of 203 p95 had the VKORC1 A-1639A genotype, but this subject was CYP2C9*1/*1. In contrast, nine out of 83 p5 carried the VKORC1 G-1639G genotype, although six of them were CYP2C9*3 homozygotes and another two were heterozygotes. Surprisingly, CYP4F2 V433M SNP displayed prevalences that suggest that its influence might only be evident when patients are treated with high doses.


CONCLUSIONS
Two clinical data, age and BSA, and three SNPs in the VKORC1, CYP2C9 and CYP4F2 genes strongly predict outlier patients treated with acenocoumarol.
Pérez-Andreu
V
V
University of Murcia, Centro de Hemodonación, Murcia, Spain.
Roldán
V
V
López-Fernández
M F
MF
Antón
A I
AI
Alberca
I
I
Corral
J
J
Montes
R
R
García-Barberá
N
N
Ferrando
F
F
Vicente
V
V
González-Conejero
R
R
D000074:Acenocoumarol / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001483:Base Sequence; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol