Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study.
BACKGROUND
In this prospective cohort study, we have undertaken a comprehensive evaluation of clinical parameters along with variation in 29 genes (including CYP2C9 and VKORC1) to identify factors determining interindividual variability in warfarin response.


METHODS
Consecutive patients (n=311) were followed up prospectively for 26 weeks. Several outcomes chosen to capture both warfarin efficacy and toxicity were assessed. Univariate and multiple regression analyses were undertaken to assess the combined effect of clinical and genetic factors.


RESULTS
CYP2C9 was the most important gene determining initial anticoagulant control, whereas VKORC1 was more important for stable anticoagulation. Novel associations with some clinical outcomes were found with single nucleotide polymorphisms in the cytochrome 450 genes CYP2C18 and CYP2C19, which were independent of the associations observed with CYP2C9 and in genes encoding CYP3A5, protein S and clotting factor V, although the variability explained by these genes was small. On the basis of the results of microcosting, adverse events were shown to be a significant predictor of total cost.


CONCLUSIONS
Accurate prediction of warfarin dose requirement needs to take into account multiple genetic and environmental factors, the contributions of which vary in the induction and maintenance phases of treatment.
Jorgensen
Andrea L
AL
Department of Pharmacology, Centre for Medical Statistics and Health Evaluation, The University of Liverpool, UK.
Al-Zubiedi
Sameh
S
Zhang
Jieying Eunice
JE
Keniry
Andrew
A
Hanson
Anita
A
Hughes
Dyfrig A
DA
Eker
Diane van
Dv
Stevens
Lisa
L
Hawkins
Karen
K
Toh
Cheng H
CH
Kamali
Farhad
F
Daly
Ann K
AK
Fitzmaurice
David
D
Coffey
Alison
A
Williamson
Paula R
PR
Park
Brian Kevin
BK
Deloukas
Panos
P
Pirmohamed
Munir
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000191:economics* / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004777:Environment; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D016896:Treatment Outcome; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000191:economics* / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C082185:CYP2C18 protein, human; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases