Genetic and Clinical Determinants Influencing Warfarin Dosing in Children With Heart Disease
Genetic and Clinical Determinants Influencing Warfarin Dosing in Children With Heart Disease
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DOI：
10.1007/s00246-012-0592-1
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发表时间：
2013-04-01
影响因子：
1.6
通讯作者：
Jennings, Larry J.
中科院分区：
文献类型：
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作者：
Nguyenvu Nguyen;Anley, Peter;Jennings, Larry J.
华法林是一种常用的抗凝剂，治疗窗窄，抗凝效果多变。细胞色素P450 2C 9（CYP 2C 9）和维生素K环氧化物还原酶（VKORC 1）的单基因多态性已被证明会影响成人的华法林剂量。关于影响儿童华法林剂量的遗传和临床因素的数据不足。对接受长期华法林治疗的心脏病儿童患者进行VKORC 1和CYP 2C 9多态性检测。对达到稳定治疗国际标准化比值（INR）的儿童的临床和人口统计学资料进行了回顾。多元线性回归模型用于评估稳定华法林剂量与遗传或临床变量之间的关系。对50名儿童进行了VKORC 1和CYP 2C 9多态性检测; 37名患者（男性26名：女性11名）具有完整的数据，达到稳定的治疗INR，并被纳入剂量变异性分析。白色人种占73%，男性占70.3%。平均年龄为9.6岁（1.8-18.6岁）。平均体重为37.8 kg（7.7-95 kg）。Fontan生理和机械心脏瓣膜是长期华法林治疗的两种最常见适应症（25/37或67.6%）。12例患者（32.4%）有华法林治疗的千分之二适应症。3名患者记录了静脉或动脉凝块，5名患者发生卒中。29例患者（78.4%）存在先天性心脏病，包括Fontan生理学（20）、复杂双心室生理学（4）和先天性二尖瓣疾病（5）。获得性心脏病8例（21.6%），包括川崎病合并冠状动脉瘤（3例）、获得性二尖瓣疾病（3例）和马凡综合征（2例）。稳定的华法林剂量（mg/kg/天）与VKORC 1多态性（p < 0.0001）和目标治疗INR（p = 0.009）密切相关。华法林稳定剂量与年龄、体重、身高和BSA呈负相关（分别为p = 0.04、0.02、0.02和0.02）。不影响华法林剂量的因素包括CYP 2C 9多态性（p = 0.17）、合并用药（p = 0.85）、性别（p = 0.4）、种族（p = 0.14）、先天性心脏病（p = 0.09）和Fontan生理学（p = 0.76）。在纯合子野生型VKORC 1 CC儿童中观察到基因剂量效应，与携带杂合子TC或纯合子TT的儿童相比，这些儿童需要更高的华法林剂量（分别为p = 0.028和0.0004）。完整的多元线性回归模型显示，VKORC 1基因型占给药变异性的47%; CYPC 29占5%。总体而言，VKORC 1、CYP 2C 9、年龄和目标INR的组合占给药变异性的82%。在心脏病患儿中，VKORC 1基因型、年龄和目标INR是影响心脏病患儿华法林剂量的重要决定因素。未来儿童华法林给药方案应考虑遗传和临床因素。
Warfarin is a common anticoagulant with narrow therapeutic window and variable anticoagulation effects. Single gene polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) have been shown to impact warfarin dosing in adults. Insufficient data exists on genetic and clinical factors which influence warfarin dosing in children. Pediatric patients with heart disease who received long-term warfarin therapy were tested for VKORC1 and CYP2C9 polymorphisms. Clinical and demographic data were reviewed in those children who achieved stable therapeutic international normalized ratio (INR). Multiple linear regression modeling was used to assess relationships between stable warfarin doses and genetic or clinical variables. Fifty children were tested for VKORC1 and CYP2C9 polymorphisms; 37 patients (M 26: F 11) had complete data, achieved stable therapeutic INR, and were included in dose variability analysis. There were predominance of white race 73% and male sex 70.3%. The mean age was 9.6 years (1.8-18.6 years). The mean weight was 37.8 kg (7.7-95 kg). Fontan physiology and mechanical cardiac valves were two most common indications for chronic warfarin therapy (25/37 or 67.6%). Twelve patients (32.4%) had a parts per thousand yen2 indications for warfarin therapy. Three patients had documented venous or arterial clots, and 5 patients had strokes. Congenital heart disease was present in 29 patients (78.4%), including Fontan physiology (20), complex biventricular physiology (4), and congenital mitral valve disease (5). Acquired heart disease was present in 8 patients (21.6%), including Kawasaki disease with coronary aneurysms (3), acquired mitral valve disease (3), and Marfan syndrome (2). Stable warfarin dose (mg/kg/day) was strongly associated with VKORC1 polymorphism (p < 0.0001) and goal therapeutic INR (p = 0.009). Negative correlations were observed between stable warfarin dose and age, weight, height, and BSA (p = 0.04, 0.02, 0.02, and 0.02 respectively). Factors which did not influence warfarin dose included CYP2C9 polymorphism (p = 0.17), concurrent medications (p = 0.85), sex (p = 0.4), race (p = 0.14), congenital heart disease (p = 0.09), and Fontan physiology (p = 0.76). The gene-dose effect was observed in children with homozygous wild type VKORC1 CC, who required higher warfarin dose compared to those carrying heterozygous TC or homozygous TT (p = 0.028 and 0.0004 respectively). The full multiple linear regression model revealed that VKORC1 genotypes accounted for 47% of dosing variability; CYPC29 accounted for 5%. Overall, the combination of VKORC1, CYP2C9, age, and target INR accounted for 82% of dosing variability. In children with heart disease, VKORC1 genotypes, age, and target INR are important determinants influencing warfarin dosing in children with heart disease. Future warfarin dosing algorithm in children should factor both genetic and clinical factors.