Warfarin dose related to apolipoprotein E (APOE) genotype.
OBJECTIVE
Warfarin is an anticoagulant which acts through interference with the recycling of vitamin K in the liver, leading to reduced activation of several clotting factors. Apolipoprotein E plays a central role in the uptake of the lipid-soluble vitamin K. The apolipoprotein E (APOE) alleles E2, E3 and E4 encode the three major isoforms of apolipoprotein E. The aim of this project was to evaluate whether variation in the APOE gene influences warfarin dose.


METHODS
We genotyped APOE in 183 warfarin-treated patients. Information about warfarin dose, prothrombin time, age, gender, body weight, treatment indication and duration, other diseases and concurrent medication was taken from the patients' medical records. Cytochrome P450 2C9 genotyping had been performed previously, and patients were stratified according to CYP2C9 genotype.


RESULTS
Patients homozygous for APOE*E4 tended to receive higher warfarin doses than others. Among CYP2C9 extensive metabolisers, APOE*E4 homozygous patients received significantly higher warfarin doses than patients with one or no E4 alleles; 56.9 compared with 34.3 and 34.6 mg/week, (Bonferroni corrected P=0.008 and 0.007, respectively). APOE genotype explains 6% of warfarin dose variance among CYP2C9 extensive metabolisers (analysis of variance, P=0.009).


CONCLUSIONS
Previous studies have shown that individuals carrying the APOE*E4 allele have a faster uptake of lipoproteins into the liver and lower levels of circulating vitamin K than others. It is therefore plausible that patients carrying E4 alleles have an enhanced uptake of vitamin K into the liver and require higher doses of warfarin to compensate for this.
Kohnke
Hugo
H
Department of Medical Sciences, Clinical Pharmacology, University Hospital, 75185, Uppsala, Sweden.
Sörlin
Kristina
K
Granath
Göran
G
Wadelius
Mia
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000378:metabolism* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001281:Atrial Fibrillation / Q000188:drug therapy; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011655:Pulmonary Embolism / Q000188:drug therapy; D020246:Venous Thrombosis / Q000188:drug therapy; D014859:Warfarin / Q000378:metabolism* / Q000627:therapeutic use
D000925:Anticoagulants; D001057:Apolipoproteins E; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases