Department of Pediatrics, Faculty of Medicine, University of British Columbia (UBC), Vancouver, BC, Canada; Pharmaceutical Outcomes Programme, B.C. Children's Hospital, Vancouver, BC, Canada.
Pediatr Blood Cancer. 2014 Jun;61(6):1055-62. doi: 10.1002/pbc.24932. Epub 2014 Jan 29.
Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children.
Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay.
With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C93 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model.
This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.
尽管有大量证据支持将药物遗传学方法应用于成人华法林治疗，但有关遗传因素对华法林治疗儿童的影响的证据有限，特别是在临床结局方面。我们评估了 CYP2C9/VKORC1/CYP4F2 基因型以及维生素 K 和凝血途径中其他基因的变异在儿童华法林剂量和相关临床结局中的作用。
收集了 93 名（年龄≤18 岁）接受华法林治疗的儿童的临床和遗传数据。使用定制的检测方法对 93 个选定的单核苷酸多态性进行 DNA 基因分型。
我们的队列平均年龄为 4.8 岁，与大多数先前的研究相比，其中包括更多的幼儿。总体而言，体重、适应证、VKORC1-1639G/A 和 CYP2C9*2/3 解释了 76.3%的剂量变异性，基因型占变异性的 21.1%。使用基于儿科基因型的剂量模型，实际和预测的华法林剂量之间存在很强的相关性（R²=0.68；P<0.001）。VKORC1 基因型对治疗开始时达到治疗性国际标准化比值（INR）的时间（P=0.047）和达到过度抗凝（INR>4；P=0.024）的时间有显著影响。CYP2C93 携带者在接受华法林治疗时也有更高的大出血风险（调整后的 OR=11.28）。CYP2C9 中的另一个变体（rs7089580）在多变量临床和遗传模型中与华法林剂量显著相关（P=0.020）。
这项研究证实了 VKORC1/CYP2C9 基因型在年轻儿科患者群体中对华法林剂量的重要性，并表明遗传因素对儿童临床结局有影响。此外，我们发现 CYP2C9 中的另一个变体可能与儿童华法林剂量有关。
