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

Author(s):Show less -

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]}

Affiliation:Show less -

^[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

• Document type: Journal article
• Source: CTS-CLINICAL AND TRANSLATIONAL SCIENCE; v. 14, n. 1 SEP 2020.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 16/22507-8 - Impact assessment of the inclusion of ABCB1 and CYP4F2 genes polymorphisms in pharmacogenetic-guided algorithm for personalized warfarin dosing
• Grantee: Letícia Camargo Tavares
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 13/09295-3 - Pharmacogenetic of cardiovascular system drugs focusing on implementation
• Grantee: Paulo Caleb Júnior de Lima Santos
• Support Opportunities: Research Grants - Young Investigators Grants