Hawcutt D B, Ghani A A, Sutton L, Jorgensen A, Zhang E, Murray M, Michael H, Peart I, Smyth R L, Pirmohamed M
1] Institute of Translational Medicine, University of Liverpool, Liverpool, UK [2] Department of Research, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Pharmacogenomics J. 2014 Dec;14(6):542-8. doi: 10.1038/tpj.2014.31. Epub 2014 Jul 8.
Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants and analysed for CYP2C92, 3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first 6 months' treatment time spent within the target International Normalised Ratio (INR) range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C92 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (odds ratio (OR; per additional copy) 4.18, 95% confidence interval (CI) 1.42, 12.34). CYP2C92 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR (heterozygotes vs homozygotes) 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population.
华法林用于儿科人群，但尚未为儿童开发纳入药物遗传学数据的给药算法。先前的研究已经估算了细胞色素P450 2C9（CYP2C9）和维生素K环氧化物还原酶复合体亚单位1（VKORC1）基因多态性对稳定华法林剂量的影响，但关于治疗范围内的时间、初始剂量和不良反应的数据有限。招募了参与者（n = 97），收集了所有参与者的常规临床数据和唾液DNA样本，并分析了CYP2C92、3和VKORC1 - 1639基因多态性。VKORC1 - 1639与在前6个月治疗时间内处于目标国际标准化比值（INR）范围内的比例更高相关，占时间比例方差的额外9.5%。CYP2C92与治疗开始时INR值超过目标范围的可能性更大相关（优势比（OR；每增加一个拷贝）4.18，95%置信区间（CI）1.42，12.34）。CYP2C92和VKORC1 - 1639与较低的剂量需求相关，占稳定剂量方差的近12%。VKORC1 - 1639与轻度出血并发症的可能性增加相关（OR（杂合子与纯合子相比）4.53，95% CI 1.59，12.93）。这些数据显示了VKORC1 - 1639和CYP2C9*2与服用华法林儿童的INR值之间的新关联，同时也重复了先前关于稳定剂量需求的研究结果。为使用华法林的儿童开发药物基因组学给药算法有可能改善该人群的临床护理。
