Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals
Publication date
2019-06
Authors
Danese, Elisa
Raimondi, Sara
Montagnana, Martina
Tagetti, Angela
Langaee, Taimour
Borgiani, Paola
Ciccacci, Cinzia
Carcas, Antonio J
Borobia, Alberto M
Tong, Hoi Y
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taverne
Abstract
The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.
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Danese, E, Raimondi, S, Montagnana, M, Tagetti, A, Langaee, T, Borgiani, P, Ciccacci, C, Carcas, A J, Borobia, A M, Tong, H Y, Dávila-Fajardo, C, Botton, M R, Bourgeois, S, Deloukas, P, Caldwell, M D, Burmester, J K, Berg, R L, Cavallari, L H, Drozda, K, Huang, M, Zhao, L-Z, Cen, H-J, Gonzalez-Conejero, R, Roldan, V, Nakamura, Y, Mushiroda, T, Gong, I Y, Kim, R B, Hirai, K, Itoh, K, Isaza, C, Beltrán, L, Jiménez-Varo, E, Cañadas-Garre, M, Giontella, A, Kringen, M K, Bente Foss Haug, K, Gwak, H S, Lee, K E, Minuz, P, Lee, M T M, Lubitz, S A, Scott, S, Mazzaccara, C, Sacchetti, L, Ramirez, A H, Zhang, Y, Maitland-van der Zee, A H, Verhoef, T I & de Boer, A 2019, 'Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals', Clinical Pharmacology and Therapeutics, vol. 105, no. 6, pp. 1477-1491. https://doi.org/10.1002/cpt.1323