Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals
Danese, Elisa; Raimondi, Sara; Montagnana, Martina; Tagetti, Angela; Langaee, Taimour; Borgiani, Paola; Ciccacci, Cinzia; Carcas, Antonio J; Borobia, Alberto M; Tong, Hoi Y; Dávila-Fajardo, Cristina; Botton, Mariana Rodrigues; Bourgeois, Stephane; Deloukas, Panos; Caldwell, Michael D; Burmester, Jim K; Berg, Richard L; Cavallari, Larisa H; Drozda, Katarzyna; Huang, Min; Zhao, Li-Zi; Cen, Han-Jing; Gonzalez-Conejero, Rocio; Roldan, Vanessa; Nakamura, Yusuke; Mushiroda, Taisei; Gong, Inna Y; Kim, Richard B; Hirai, Keita; Itoh, Kunihiko; Isaza, Carlos; Beltrán, Leonardo; Jiménez-Varo, Enrique; Cañadas-Garre, Marisa; Giontella, Alice; Kringen, Marianne Kristiansen; Bente Foss Haug, Kari; Gwak, Hye Sun; Lee, Kyung Eun; Minuz, Pietro; Lee, Ming Ta Michael; Lubitz, Steven A; Scott, Stuart; Mazzaccara, Cristina; Sacchetti, Lucia; Ramirez, Andrea H; Zhang, Yumao; Maitland-van der Zee, Anke H; Verhoef, Talitha I; de Boer, Anthonius
(2019) Clinical Pharmacology and Therapeutics, volume 105, issue 6, pp. 1477 - 1491
(Article)
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
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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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ISSN: 0009-9236
Publisher: Nature Publishing Group
Note: This article is protected by copyright. All rights reserved.
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