VKORC1基因多态性与川崎病并发冠状动脉瘤患儿华法林稳定剂量相关性研究

Correlation research of VKORC1 gene polymorphism and warfarin maintenance dosage in Kawasaki disease children with coronary artery aneurysms

目的评估VKORC1基因多态性对川崎病(KD)患儿华法林稳定剂量的影响。方法对临床诊断KD巨大冠状动脉瘤(GCAA)、口服稳定剂量华法林≥2个月,同时期INR稳定在2.0~2.5≥2个月的患儿在华法林使用前或后行CYP2C9*2(rs1799853)、CYP2C9*3(rs1057910)和VKORC1(rs9923231)基因多态性检测,评估VKORC1基因多态性、调整华法林剂量时的年龄、体重、身高、体表面积与华法林稳定剂量的相关性。评估KD患儿华法林稳定剂量的主要影响因素,随访观察应用华法林后出现的不良反应。结果 42例进入本文分析,其中男35例,女7例,年龄为0.5~6.7岁,稳定华法林剂量为(1.47±0.45)mg·d^(-1),经体重矫正后稳定华法林剂量为(0.11±0.033)mg·kg^(-1)·d^(-1)。VKORC1 CT型6例、TT型36例,经体重矫正后华法林稳定剂量分别为(0.16±0.043)、(0.10±0.021)mg·kg^(-1)·d^(-1),差异有统计学意义(P<0.05)。检测基因之后用药比检测之前用药达稳态时间缩短(P<0.05)。多元回归分析显示,经体重矫正华法林稳态剂量(mg·kg^(-1)·d^(-1))=0.039+0.061×VKORC1 rs9923231基因型(1 if TT,2 if CT),R2为43.8%,华法林VKORC1 rs9923231基因型可解释6个月至7岁KD患儿华法林稳定剂量个体差异的43.8%。未经体重矫正华法林稳态剂量(mg·d^(-1))=-0.407+0.088×体重+0.580×VKORC1 rs9923231基因型(1if TT,2 if CT),体重和VKORC1 rs9923231基因型的R2分别为43.7%和19.5%,根据最佳回归模型得到的华法林稳定剂量预测公式可解释6个月至7岁川崎病儿童华法林稳定剂量个体差异的63.2%,其中VKORC1基因多态性、体重的贡献分别是19.5%和43.7%。因能解释更多华法林稳态剂量的个体差异,未经体重矫正华法林稳态剂量预测公式优于经体重矫正稳态剂量预测公式。结论 VKORC1 rs9923231基因型是影响6个月至7岁KD并发CAA患儿华法林稳定剂量的遗传因素之一,体重是华法林稳定剂量的主要影响因素。对于常规剂量INR易超标伴出血或不能达到目标INR的患儿,药物基因筛查有助于快速、有效指导用药,减少出血的并发症。

Objective To analyze the relationship of VKORC1 gene polymorphism and warfarin maintenance dosage in Kawasaki disease children with coronary artery aneurysms aged from 6 months to 7 years.Methods Clinical data of children under stable warfarin treatment for Kawasaki disease patients with coronary artery aneurysms and undergone genetic testing for VKORC1 were analyzed retrospectively.Associations of VKORC1 polymorphisms and clinical variables on warfarin maintenance dosage were assessed and a warfarin stable dosing algorithm was derived based on genetic and non-genetic factors.Results Data of a total of 42 cases(0.5-6.7 years old)were collected.Thirty-five patients were male and 7 patients were female.The Warfarin maintenance dosage was 1.47±0.45 mg·d-1,and the weight-normalized Warfarin maintenance dosage was 0.11±0.033 mg·kg-1·d-1.The group comparing VKORC1 TT genotypes(0.10±0.021 mg·kg-1·d-1)required significantly lower daily doses than CT group(0.16±0.043 mg·kg-1·d-1),P<0.01.Compared with the children who underwent gene detection after warfarin,warfarin stability time was obviously shorten and the incidence of bleeding has a decreasing trend in children who underwent gene detection before warfarin.Two linear regression models were builed by setting different dependent variables:1.Warfarin dose(mg·kg-1·d-1)=0.039+0.061×VKORC1 rs9923231(1 if TT,2 if CT),VKORC1 rs9923231 had significant influence on interindividual variation in warfarin stable dose,which contributed 43.8%.2.Warfarin dose in(mg·d-1)=-0.407+0.088×weight+0.580×VKORC1 rs9923231(1if TT,2 if CT),In the full regression model,the combination of VKORC1 and weight explained 63.2%of dosing variability,VKORC1 and weight contributed 19.5%,43.7%respectively.The second warfarin stable dosing algorithm was superior to the first algorithm for higher R 2.Conclusion In Kawasaki disease population with coronary artery aneurysms aged from 6 months to 7 years,VKORC1 is the main genetic factor relative to warfarin maintenance dosage.Weight is the main influence factor to warfarin maintenance dosage.The warfarin stable dosing algorithm may be useful for helping clinicians to prescribe warfarin with greater safety and efficiency.