Polymorphisms in factor II and factor VII genes modulate oral anticoagulation with warfarin.
OBJECTIVE
There is very considerable inter-individual variability in warfarin dosages necessary to achieve target therapeutic anticoagulation. The variability is largely genetically determined but can only partly be explained by genetic variability in the cytochrome CYP2C9 locus. Polymorphisms within the genes coding for vitamin K-dependent proteins have been suggested to predict sensitivity to warfarin therapy.


METHODS
In a cohort of 147 patients followed-up at one specialized clinic from the start of anticoagulation with warfarin, we investigated whether factor II (Thr165Met; G20210A) and factor VII polymorphisms (G-402A; G-401T) affected the doses of warfarin necessary to acquire the target intensity of anticoagulation.


RESULTS
Regardless of the presence of confounding variables, the mean adjusted dose of warfarin required was higher among patients with the factor II Thr/Thr 165 genotype (4.2 mg) than among patients carrying the Met165 allele (2.9 mg; p=0.041) and higher in carriers of the factor VII GG-401 genotype (4.1 mg) than in those with the T-401 allele (3.1 mg; p=0.029). No significant effect was found for factor II A20210G and factor VII G-402A polymorphisms. All together, the genetic variants investigated accounted for about a quarter (r2: 0.261) of the inter-individual variability calculated in the present setting.


CONCLUSIONS
Genetic variants of factor II and factor VII modulate the mean daily dose of warfarin required to achieve a target intensity of anticoagulation.
D'Ambrosio
Rosa Lucia
RL
Istituto di Genetica Medica, Dipartimento di Scienze Biomediche, Università di Foggia, Italy.
D'Andrea
Giovanna
G
Cappucci
Filomena
F
Chetta
Massimiliano
M
Di Perna
Pasquale
P
Brancaccio
Vincenzo
V
Grandone
Elvira
E
Margaglione
Maurizio
M
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004351:Drug Resistance / Q000235:genetics; D005167:Factor VII / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011516:Prothrombin / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000925:Anticoagulants; D014859:Warfarin; D005167:Factor VII; D011516:Prothrombin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases