Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Pediatrics, Yokohama City University, School of Medicine, Yokohama, Kanagawa, Japan.
Pharmacogenomics J. 2020 Apr;20(2):306-319. doi: 10.1038/s41397-019-0117-x. Epub 2019 Nov 1.
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, I = 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, I = 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, I = 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.
关于细胞色素 P450 2C9（CYP2C9）、维生素 K 环氧化物还原酶复合物亚基 1（VKORC1）和细胞色素 P450 4F2（CYP4F2）多态性对儿童华法林维持剂量的影响的研究结果存在争议。我们进行了系统评价和荟萃分析，以评估这些多态性对华法林在儿童中的维持剂量的影响。我们在 MEDLINE、EMBASE 和 Cochrane 对照试验中心注册库中没有任何语言限制地搜索了相关文献，检索时间从建库开始至 2017 年 7 月 23 日。剂量差异表示为标准化均数差（SMD）或均数差（MD）及 95%置信区间（CI）。本综述已在 PROSPERO 前瞻性系统评价注册库（CRD42015016172）中注册。荟萃分析共纳入 9 项研究（745 例患者）。与 CYP2C9 *1/*1 相比，CYP2C9 *1/*2、*1/*3、*2/*2、*2/*3 或 *3/*3 的患者需要较低的华法林维持剂量（SMD=-0.610，95%CI：-0.802 至-0.419，I=0%）。与 VKORC1-1639GG 相比，VKORC1-1639GA 或 AA 的患者需要较低的华法林维持剂量（SMD=-0.666，95%CI：-0.887 至-0.445，I=33%）。然而，CYP4F2 多态性与华法林维持剂量之间无相关性（MD=0.005mg/kg/day，95%CI：-0.006 至 0.015，I=0%）。这些结果不受敏感性分析的影响。我们的荟萃分析结果表明，CYP2C9 和 VKORC1 基因型状态影响儿童华法林的维持剂量，但 CYP4F2 不影响。
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