Genetic modulation of oral anticoagulation with warfarin.
Cytochrome P450 CYP2C9 gene variants have been associated with hyperresponsiveness to small doses of warfarin and a higher bleeding complication rate. The aim of this study was to investigate whether CYP2C9 gene variants affect doses of drug prescribed to acquire the target anticoagulation intensity and the occurence of bleeding complications. In a cohort of 180 patients followed up at one specialized clinic from the start of the anticoagulation with warfarin, we have investigated whether CYP2C9 gene variants have affected doses of drug prescribed to acquire the target anticoagulation intensity and the incidence of bleeding complications. The adjusted dose required of warfarin was higher among patients with the CYP2C9*1 haplotype (5.6 mg) than those of patients carrying the CYP2C9*2 (4.7 mg; p = 0.007, Scheffé's test) or the CYP2C9*3 haplotype (4.0 mg; p <0.001, Scheffé's test). The occurrence of bleeding complications was more frequent among patients with the CYP2C9*2 and/or the CYP2C9*3 haplotype than in carriers of the CYP2C9*1 haplotype (OR: 2.57; 95% CI; 1.16-5.73). An interaction between the presence of local bleeding sources and the CYP2C9*2 and/or the CYP2C9*3 haplotype was observed (p <0.001). Patients with both local sites of potential bleeding and CYP2C9*2 and/or the CYP2C9*3 haplotype had the higher estimated risk of bleeding (OR: 12.81; 95% CI: 2.86-57.26). CYP2C9 gene variants modulate the anticoagulant effect of the dose of warfarin prescribed. The incidence of bleeding complications in CYP2C9*2 and CYP2C9*3 carriers was significantly higher than that in noncarriers and interacted with the presence of local bleeding sources.
Margaglione
M
M
Unitá di Aterosclerosi e Trombosi, IRCCS Casa Sollievo della Sofferenza, S Giovanni Rotondo, Italy. ate.tro@operapadrepio.it
Colaizzo
D
D
D'Andrea
G
G
Brancaccio
V
V
Ciampa
A
A
Grandone
E
E
Di Minno
G
G
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*; D013923:Thromboembolism / Q000188:drug therapy* / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase