Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos

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El Rouby, Nihal ^{[1, 2, 3]} ; Rodrigues Marcatto, Leiliane ^[4] ; Claudio, Karla ^[5] ; Camargo Tavares, Leticia ^[4] ; Steiner, Heidi ^[6] ; Botton, Marianna R. ^[7] ; Lubitz, Steve A. ^{[8, 9, 10]} ; Fallon, Echo N. ^[11] ; Yee, Kevin ^[11] ; Kaye, Justin ^[12] ; Scott, Stuart A. ^[7] ; Karnes, Jason ^[4] ; Caleb Junior de Lima Santos, Paulo ^[13] ; Duconge, Jorge ^[5] ; Cavallari, Larisa H. ^{[1, 2]}

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^[1] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32611 - USA

^[2] Univ Florida, Ctr Pharmacogen & Precis Med, Gainesville, FL 32611 - USA

^[3] Univ Cincinnati, James L Winkle Coll Pharm, Dept Pharm Practice & Adm Sci, Cincinnati, OH - USA

^[4] Univ Sao Paulo, Lab Genet & Mol Cardiol, Fac Med FMUSP, Heart Inst InCor, Sao Paulo - Brazil

^[5] Univ Puerto Rico, San Juan, PR 00936 - USA

^[6] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 - USA

^[7] Icahn Sch Med Mt Sinai, New York, NY 10029 - USA

^[8] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 - USA

^[9] Harvard Med Sch, Boston, MA 02115 - USA

^[10] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 - USA

^[11] Banner Univ, Med Ctr Tucson, Tucson, AZ - USA

^[12] Univ Arizona, Coll Med, Tucson, AZ - USA

^[13] Univ Fed Sao Paulo, EPM Unifesp, Escola Paulista Medicina, Dept Pharmacol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CTS-CLINICAL AND TRANSLATIONAL SCIENCE; v. 14, n. 1 SEP 2020.
• Citações Web of Science: 0

Resumo

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped forVKORC1c.-1639G> A, commonCYP2C9variants,CYP4F2{*}3, andNQO1{*}2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort,VKORC1andCYP2C9variants were associated with lower warfarin dose (beta = -0.29,P < 2.0 x 10(-16); beta = -0.21,P = 4.7 x 10(-7), respectively) whereasCYP4F2andNQO1variants were associated with higher dose (beta = 0.10,P = 2 x 10(-4); beta = 0.10,P = 0.01, respectively). Associations withVKORC1(beta = -0.14,P = 2.0 x 10(-16)),CYP2C9(beta = -0.07,P = 5.6 x 10(-10)), andCYP4F2(beta = 0.03,P = 3 x 10(-3)), but notNQO1{*}2(beta = 0.01,P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants inVKORC1,CYP2C9, andCYP4F2with warfarin dose in Latinos from the United States and Brazil. (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: 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