Genetic factors influencing warfarin dose in Black-African patients: a systematic review and meta-analysis.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high inter-individual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in Black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively while rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in Black Africans to evaluate genetic factors determining warfarin response

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

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((R)) 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 T variant may influence warfarin dose requirements in Brazilian patients, when associated with other genotypic, demographic and clinical factors.Sao Paulo Research Foundation (FAPESP)Graduate Program in Medical Sciences-FMUSPUniv Sao Paulo, Fac Med FMUSP, Heart Inst InCor, Lab Genet & Mol Cardiol, Sao Paulo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Sao Paulo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Sao Paulo, BrazilFAPESP: 2013/09295-3FAPESP: 2016/22507-8FAPESP: 2016/23454-5Web of Scienc

Data_Sheet_1_Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients.PDF

<p>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.</p

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

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.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

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

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.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]