CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis

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Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = −0.610, 95% CI: −0.802 to −0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = −0.666, 95% CI: −0.887 to −0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: −0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.

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We acknowledge Alanna Marson, a reference and instruction librarian of the hospital library and archives at the hospital for sick children, for help with the literature search. We also thank Conn Hastings, PhD, from Edanz Group ( for editing a draft of this paper.

Author information

SI and LRB initiated the study planning and all contributed to the study design. MT collected data, performed statistical analysis, interpreted the results, and drafted the paper. TK designed the study and collected data. TB, FK, SV, RH, KS, BC, AH, MW, HK, MT, TW, MY, KH, and KI provided data for the study. TK, LRB, and SI critically revised the paper. All authors read, provided feedback, and approved the final paper.

Correspondence to Shinya Ito.

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Conflict of interest

SI received grants from Novartis Pharma AG, grants from UCB Pharma Gmbh, personal fees from AbbVie, outside the submitted work; and he is a member of the American Society of Clinical Pharmacology & Therapeutics, and the Canadian Society of Pharmacology and Therapeutics. He is also one of the Associate Editors of “Clinical Pharmacology & Therapeutics”, which conducts peer-review and publishes articles, some of which include CPIC guidelines and original articles on pharmacogenomics/genetics. The remaining authors declare that they have no conflict of interest.

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Takeuchi, M., Kobayashi, T., Biss, T. et al. CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis. Pharmacogenomics J (2019) doi:10.1038/s41397-019-0117-x

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