Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients

Abstract

The ideal dose of the oral anticoagulant warfarin varies widely among patients, mainly due to genetic factors. Genetic variations that impact warfarin pharmacokinetics and the vitamin K cycle are plausible candidates for being associated with warfarin dose requirements. Therefore, the aim of this study was to assess whether polymorphisms in the ABCB1 and CYP4F2 genes were associated with stable warfarin dose requirements in Brazilian patients. This retrospective study included samples from 309 individuals. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A were performed by polymerase chain reaction followed by melting curve analysis (HRM-PCR) and TaqMan® genotyping assay, respectively. Stable doses were adjusted in a linear multiple regression model for age, gender, body mass index, self-reported race, use of amiodarone, CYP2C9 (*2 and *3), VKORC1 c.1639G>A, and ABCB1 c.3435C>T or CYP4F2 c.1297G>A. By performing a univariate analysis of variance, we found that the warfarin patients who carry ABCB1 c.3435T variant alleles (CT and TT genotypes) need fewer warfarin stable doses in comparison with the individuals that are CC wild-type: 2.5 (p = 0.003) and 4.3 (p < 0.001) mg/week less, respectively, for the overall group of patients on stable anticoagulation therapeutics (n = 309); and 5.5 (p = 0.006) and 10.2 (p < 0.001) mg/week less, respectively, for the self-declared non-white stable subgroup (n = 76). No statistically significant differences in dose requirements were observed according to CYP4F2 genotypes. In conclusion, our results suggest ABCB1 c.3435C>T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.

Polimorfismos genéticos CYP2C9 y VKORC1-1639 implicados en la farmacocinética y farmacodinámica de warfarina en población latinoamericana

“…Se encontraron 402 artículos científicos referidos a la farmacogenética de la warfarina, de estos 382 fueron excluidos por no incluir población latinoamericana. Se identificaron 20 artículos realizados en población latinoamericana, de estos, sólo once cumplieron con los criterios de inclusión, los restantes nueve artículos (Tavares, 2018;Valentín, 2014;Guerrero, 2009;Isaza, 2010;Raggio, 2005; Claudio-Campos, 2015; Parra, 2015; Villagra, 2010) fueron excluidos (Fig. 1).…”

“…Muchos factores clínicos y ambientales como la edad, sexo, raza, índice de masa corporal, comorbilidades (principalmente enfermedades renales o hepáticas), polimedicación (Zhang,2016), consumo de tabaco, dieta, metabolismo rápido de vitamina K, así como mutaciones genéticas afectan los requerimientos de dosis de warfarina (Bryk, 2018). Los polimorfismos genéticos en los genes de la subunidad 2C9 del complejo de citocromo P450 (CYP2C9) y la subunidad 1 del complejo de la vitamina K epóxido reductasa (VKORC1) se han asociado en un 40 % a 60 % con la variación en la respuesta interindividual a la warfarina (Flockhart, 2008;Dean, 2012;Tavares, 2018;Razavi, 2017;Wattanachai, 2017;.…”

Pharmacogenomics research and clinical implementation in Brazil

“…A considerably poorer performance was described for another PGx algorithm based on VKORC1 and CYP2C9 polymorphisms . In separate publications, the same group concluded that “genetic information on CYP2C9 and VKORC1 is important both for the initial dose‐finding phase and during maintenance treatment with warfarin”, “amiodarone influences warfarin maintenance dose” while not being associated with adverse events and CYP4F2 rs2108622 has no effect of warfarin dose requirements in their patients, whereas the ABCB1 c.3435T allele marginally affected the dose requirements . The direction of the latter effect was opposite to previously reported higher warfarin dose requirement in thrombophilic patients with the ABCB1 c.3435T allele .…”

Association Between Genetic Polymorphisms and Steady-State Plasma Concentration of Warfarin Optical Isomers

“…Whether P-glycoprotein acts on warfarin transport remains controversial. Studies have suggested that the C3435T polymorphism in the MDR1 gene does not affect the steady-state concentration of warfarin alone [13], whereas Tavares et al [14] reported different conclusions. Our data suggested that differences in the MDR1 genotype did not significantly affect warfarin plasma concentrations.…”