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Blood, 15 January 2005, Vol. 105, No. 2, pp. 645-649.
Prepublished online as a Blood First Edition Paper on September 9, 2004; DOI 10.1182/blood-2004-06-2111.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin
Giovanna D'Andrea,
Rosa Lucia D'Ambrosio,
Pasquale Di Perna,
Massimiliano Chetta,
Rosa Santacroce,
Vincenzo Brancaccio,
Elvira Grandone, and
Maurizio Margaglione
From the Unita' di Aterosclerosi e Trombosi, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), "Casa Sollievo della Sofferenza," S. Giovanni Rotondo, Foggia; the Divisione di Ematologia, Unità di Coagulazione, Ospedale "A. Cardarelli," Napoli; and the Istituto di Genetica Medica, Dipartimento di Scienze Biomediche, Università di Foggia, Foggia, Italy.
Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability is largely genetically determined, and it can be only partly explained by genetic variability in the cytochrome CYP2C9 locus. In 147 patients followed from the start of anticoagulation with warfarin, we have investigated whether VKORC1 gene mutations have affected doses of drug prescribed to acquire the target anticoagulation intensity. Two synonymous mutations, 129C>T at Cys43 and 3462C>T at Leu120, and 2 missense mutations, Asp38Tyr and Arg151Gln, were identified. None of these mutations was found to affect the interindividual variability of warfarin prescribed. Finally, 2 common polymorphisms were found, 1173C>T in the intron 1 and 3730G>A transition in the 3' untranslated region (UTR). Regardless of the presence of confounding variables, the mean adjusted dose required of warfarin was higher (6.2 mg) among patients with the VKORC1 1173CC genotype than those of patients carrying the CT (4.8 mg; P = .002) or the TT genotype (3.5 mg; P < .001). In the present setting, VKORC1 and CYP2C9 genetic variants investigated accounted for about a third (r2, 0.353) of the interindividual variability. Genetic variants of the VKORC1 gene locus modulate the mean daily dose of drug prescribed to acquire the target anticoagulation intensity.
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