Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals

Elisa Danese, Sara Raimondi, Martina Montagnana, Angela Tagetti, Taimour Langaee, Paola Borgiani, Cinzia Ciccacci, Antonio J. Carcas, Alberto M. Borobia, Hoi Y. Tong, Cristina Dávila-Fajardo, Mariana Rodrigues Botton, Stephane Bourgeois, Panos Deloukas, Michael D. Caldwell, Jim K. Burmester, Richard L. Berg, Larisa H. Cavallari, Katarzyna Drozda, Min HuangLi Zi Zhao, Han Jing Cen, Rocio Gonzalez-Conejero, Vanessa Roldan, Yusuke Nakamura, Taisei Mushiroda, Inna Y. Gong, Richard B. Kim, Keita Hirai, Kunihiko Itoh, Carlos Isaza, Leonardo Beltrán, Enrique Jiménez-Varo, Marisa Cañadas-Garre, Alice Giontella, Marianne K. Kringen, Kari Bente Foss Haug, Hye Sun Gwak, Kyung Eun Lee, Pietro Minuz, Ming Ta Michael Lee, Steven A. Lubitz, Stuart Scott, Cristina Mazzaccara, Lucia Sacchetti, Ece Genç, Mahmut Özer, Anil Pathare, Rajagopal Krishnamoorthy, Andras Paldi, Virginie Siguret, Marie Anne Loriot, Vijay Kumar Kutala, Guilherme Suarez-Kurtz, Jamila Perini, Josh C. Denny, Andrea H. Ramirez, Balraj Mittal, Saurabh Singh Rathore, Hersh Sagreiya, Russ Altman, Mohamed Hossam A. Shahin, Sherief I. Khalifa, Nita A. Limdi, Charles Rivers, Aditi Shendre, Chrisly Dillon, Ivet M. Suriapranata, Hong Hao Zhou, Sheng Lan Tan, Vacis Tatarunas, Vaiva Lesauskaite, Yumao Zhang, Anke H. Maitland-van der Zee, Talitha I. Verhoef, Anthonius de Boer, Monica Taljaard, Carlo Federico Zambon, Vittorio Pengo, Jieying Eunice Zhang, Munir Pirmohamed, Julie A. Johnson, Cristiano Fava

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15 Scopus citations

Abstract

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the 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 of 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% confidence interval (CI) 7–10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. 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.

Original languageEnglish
Pages (from-to)1477-1491
Number of pages15
JournalClinical Pharmacology and Therapeutics
Volume105
Issue number6
DOIs
StatePublished - Jun 2019

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