Impact of incorporating ABCB1 and CYP4F2 polymorphisms in a pharmacogenetics-guided warfarin dosing algorithm for the Brazilian population

Autor(es)

Tavares, Leticia C. ^[1] ; Duarte, Nubia E. ^[2] ; Marcatto, Leiliane R. ^[1] ; Soares, Renata A. G. ^[1] ; Krieger, Jose E. ^[1] ; Pereira, Alexandre C. ^[1] ; Junior Lima Santos, Paulo Caleb ^{[1, 3]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med FMUSP, Heart Inst InCor, Lab Genet & Mol Cardiol, Sao Paulo, SP - Brazil

^[2] Univ Nacl Colombia, Dept Math & Stat, Manizales, Caldas - Colombia

^[3] Univ Fed Sao Paulo UNIFESP, Escola Paulista Med, Dept Pharmacol, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY; v. 74, n. 12, p. 1555-1566, DEC 2018.
• Citações Web of Science: 2

Resumo

PurposeInterpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population.MethodsTwo independent cohorts of patients treated with warfarin (n=832 and n=133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan (R) assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates.ResultsThe inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R-2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%).ConclusionAlthough our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated. (AU)

• Processo FAPESP: 16/22507-8 - Avaliação do impacto da inclusão de polimorfismos nos genes ABCB1 e CYP4F2 em algoritmo farmacogenético para dosagem personalizada do anticoagulante varfarina
• Beneficiário: Letícia Camargo Tavares
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 16/23454-5 - Avaliação de algoritmo estimador de dose de varfarina em pacientes sem dose estável
• Beneficiário: Leiliane Rodrigues Marcatto
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/09295-3 - Avaliação farmacogenética para fármacos do sistema cardiovascular com foco na implementação
• Beneficiário: Paulo Caleb Júnior de Lima Santos
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores