The effect of CYP4F2, VKORC1 and CYP2C9 in influencing coumarin dose. A single patient data meta-analysis in more than 15,000 individuals

Elisa Danese, Raimondi Sara, Martina Montagnana, Angela Tagetti, Taimour Langaee, Paola Borgiani, Cinzia Ciccacci, Antonio J Carcas, Alberto M Borobia, Hoi Y Tong, Cristina Davila 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 Beltran, Enrique Jimenez-Varo, Marisa Cañadas-Garre, Alice Giontella, Marianne Kristiansen 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 Lindi, 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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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.
Original languageEnglish
JournalClinical Pharmacology and Therapeutics
Early online date02 Dec 2018
DOIs
Publication statusEarly online date - 02 Dec 2018

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