基于CYP2C9与VKORC1基因多态性的心脏瓣膜置换术后华法林个体化给药剂量预测的3种模型算法比较

Comparison of three model algorithms for individualized dose prediction of warfarin after heart valve replacement based on CYP2C9 and VKORC1 gene polymorphisms

目的了解泸州及周边地区汉族人群CYP2C9与VKORC1基因多态性分布情况并评价3种常用华法林剂量预测算法的差异。方法选取2018年6月至2019年7月在西南医科大学附属医院心脏大血管外科行心脏瓣膜置换术的120例泸州及周边地区汉族患者为研究对象,用PCR-微阵列基因芯片法检测其CYP2C9430、CYP2C91075与VKORC1-1639位点的基因型,对3个基因位点基因型的分布情况进行分析。基于基因检测结果与患者生理、病理信息,分别用国际华法林药物基因组协会(IWPC)公式、Warfarin Dosing网站、中国公式计算患者个体化剂量,对比3种算法计算剂量的差异。结果CYP2C91075位点AA与AC型的患者分别占90.83%和9.17%,VKORC1-1639位点AA、AG、GG型的患者分别占88.33%、10.83%和0.83%,未检出CYP2C9*2。检出的5种基因型组合中华法林计算剂量最高的基因型为CYP2C9*1/*1&VKORC1 GG。中国公式的计算剂量与国际公认的IWPC公式与Warfarin Dosing网站的计算剂量相关度均较高。结论泸州及周边地区汉族人群中存在CYP2C91075与VKORC1-1639位点的基因多态性,建议患者服用华法林前先进行该组基因位点的多态性检测,利用计算因素更全面的中国公式与Warfarin Dosing网站计算剂量,并在后期持续监测国际标准化比值以获得更好的预后。

Objective To investigate the distribution of CYP2C9 and VKORC1 gene polymorphisms in Luzhou and its neighbouring regions and analyze the correlation of the three commonly used warfarin dose prediction algorithms.Methods A total of 120 patients who underwent heart valve replacement in the Department of Cardiovascular and Vascular Surgery of the Affiliated Hospital of Southwest Medical University from June 2018 to July 2019 were enrolled in the study.The genotype of CYP2C9430,CYP2C91075 and VKORC1-1639 were detected by PCR-gene chip technique.The genotype distributions of the three genes were analyzed,then the individualized doses of patients were calculated by using three algorithms,the International Warfarin Pharmacogenomics Association(IWPC)formula,Warfarin Dosing website and the Chinese formula,based on the results and the patient′s physiological and pathological information.The predicted doses calculated by using the three algorithms were compared.Results The frequencies of AA and AC at CYP2C91075 of Han population in Luzhou and surrounding areas were 90.83%and 9.17%,and the frequencies of AA,AG and GG at VKORC1-1639 were 88.33%,10.83%and 0.83%,respectively.CYP2C9*2 mutation was found.The Chinese formula prediction results were highly correlated with the results of IWPC formula and the Warfarin Dosing website.Conclusion There are polymorphisms at CYP2C91075 and VKORC1-1639 in Han population of Luzhou and surrounding areas.It is recommended that patients could test the gene polymorphism of those two genes before taking warfarin,then use the Chinese formula and the Warfarin Dosing website to predict the dose,and continuously monitor the international normalized ratio value in the later period for better prognosis.