Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: A potential role of CYP4F2 and GGCX polymorphisms

•The impact of genetic polymorphisms on VKAs dose in Slavic population was assessed•VKORC1c.-1639A allele carriers required a lower dose of VKAs than the non-carriers•Carriers of CYP2C9 *2 and/or *3 required a lower dose of warfarin than *1*1•CYP4F2 c.1297A was associated with higher dose of acenocoumarol and warfarin•Possession of GGCX c.2084 + 45G was associated with lower warfarin dose

IntroductionVKORC1 and cytochrome CYP2C9 genetic variants contribute largely to inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Cytochrome P450 4 F2 isoform (CYP4F2), gamma-glutamyl carboxylase (GGCX) and apolipoprotein E (APOE) polymorphisms have been suggested to be of minor significance.Materials and MethodsWe sought to assess the impact of those polymorphisms on dose requirements in Central-Eastern European cohort of 479 patients receiving acenocoumarol (n = 260) or warfarin (n = 219).ResultsThere were no differences between the acenocoumarol and warfarin groups with regard to the gender, age, body mass index and international normalized ratio. The VKORC1 c.-1639A allele carriers required a lower dose of acenocoumarol and warfarin than the non-carriers (28.0 [21.0-35.0] vs. 42.0 [28.0-56.0] mg/week, p < 0.0001; 35.0 [28.0-52.0] vs. 52.0 [35.0-70.0] mg/week, p = 0.0001, respectively). Carriers of *2 and/or *3 variant alleles for CYP2C9 also required a lower dose of warfarin as compared with *1*1 carriers (35.0 [31.5-52.5] vs. 43.8 [35.0-60.2] mg/week, p = 0.02; 35.0 [23.5-35.0] vs. 43.8 [35.0-60.2] mg/week, p < 0.0001, respectively). Similarly, possession of G allele of GGCX c.2084 + 45 polymorphism was associated with lower warfarin dose (35.0 [26.3-39.2] vs. 45.5 [35.0-65.1] mg/week, p = 0.03). No effect of CYP2C9*2,-*3 and GGCX c.2084 + 45G > C polymorphisms on acenocoumarol dosage was observed. Interestingly, carriers of CYP4F2 c.1297A variant required a higher dose of acenocoumarol and warfarin than non-carriers (43.8 [35.0-60.2] vs. 35.0 [35.0-52.5] mg/week, p = 0.01; 35.0 [28.0-52.5] vs. 28.0 [28.0-42.0] mg/week, p = 0.05).ConclusionsWe have shown for the first time, that besides VKORC1 and CYP2C9 genetic variants, the CYP4F2 c.1297A and GGCX c.2084 + 45G have a moderate effect on VKAs dose requirements in Slavic population from Central-Eastern Europe.