The c.-1639g>A polymorphism of the VKORC1 gene and his influence on the therapeutic response during oral anticoagulants use

Background/Aim. A single nucleotide polymorphism c.- 1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. Methods. Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose. Results. Out of 43 low dose patients, 40 (93 %) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001). Conclusion. VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5 % of our patients - carriers of AA genotype, before anticoagulation therapy initiation

The c.-1639g gt A polymorphism of the VKORC1 gene and his influence on the therapeutic response during oral anticoagulants use

Uvod/Cilj. Pojedinačni nukleotidni polimorfizam c.- 1639G gt A u promotorskom regionu gena za vitamin K epoksid- reduktazu (VKORC1), odgovoran je za varijabilnost odgovora u toku primene oralnih antikoagulanasa (OA). Cilj našeg istraživanja bio je da utvrdimo učestalost polimorfizma c.- 1639G gt A i njegov uticaj na dozu antikoagulansa acenokumarola, te da procenimo povezanost varijabilnosti u odgovoru na terapiju sa prisutnim polimorfizmom. Metode. U ispitivanje je bilo uključeno 200 bolesnika koji su primali OA (43 malu dozu, 127 srednju i 30 veliku dozu). Rezultati. Kod 40 (93%) bolesnika lečenih malom dozom OA, dokazano je prisustvo A-alela. U grupi koja je primala veliku dozu OA, 13 (43,3%) bolesnika bili su nosioci A-alela, heterozigoti (GA genotip), i nijedan od njih nije bio nosilac homozigotne varijante AA genotipa. Posmatrano u celini, u grupi sa AA genotipom doza održavanja OA bila je 10 mg nedeljno, sa GA 19 mg i sa GG genotipom 26 mg. Kod nosilaca GG genotipa bile su potrebne 2,6 puta veće doze antikoagulansa za postizanje terapijskog raspona INR u odnosu na nosioce AA genotipa (p lt 0,0001). Retrospektivnom analizom utvrđeno je da je 33 (16,5%) bolesnika u toku uvođenja terapije bilo predozirano, a kod 11 (5,5%) bolesnika predoziranost je bila udružena sa pojavom krvarenja. Od 33 predozirana bolesnika, 27 su bili nosioci AA genotipa, a šest nosioci GA genotipa (p lt 0,000001). Zaključak. Na individualnu osetljivost na antikoagulanse VKORC1 ima značajan uticaj. Nosiocima AA genotipa potrebne su 2,6 puta manje doze antikoagulansa za održavanje terapijskog raspona INR u odnosu na nenosioce. Farmakogenetski testovi mogli su da ukažu na visok rizik od predoziranja kod 28,5% naših bolesnika, nosioca AA genotipa, pre uvođenja terapije OA.Background/Aim. A single nucleotide polymorphism c.- 1639G gt A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G gt A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. Methods. Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose. Results. Out of 43 low dose patients, 40 (93 %) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p lt 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p lt 0.000001). Conclusion. VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5 % of our patients - carriers of AA genotype, before anticoagulation therapy initiation