基因多态性对华法林稳态剂量和模型预测剂量的相关性研究

目的：研究扬州地区汉族人群CYP2C9、VKORC1基因型、性别、年龄、身高、体质量与华法林稳态剂量及计算机模型预测剂量的相关性。方法：收集扬州地区汉族人群使用华法林的患者，采用基因测序的方法检测CYP2C9和VKORC1基因型，同时记录患者的年龄、性别、身高、体质量、国家化标准比值（INR）、胺碘酮使用情况临床资料，并对这些临床资料进行相关分析及多元回归分析。结果：CYP2C9基因型检测有102例为野生AA型（91.9%），8例为杂合子AC型（7.21%），1例为突变CC型（0.9%）。VKORC1基因型检测有96例为突变纯合子AA型（86.49%），13例为杂合子GA型（11.71%），2例为野生GG型（1.80%），所有基因型分布符合Hardy-Weinberg遗传平衡。VKORC1 AA型患者华法林剂量明显低于较AG型，CYP2C9*3 AC型明显低于AA型（P<0.05）。对患者年龄、身高、体质量及不同基因型、模型预测剂量及稳态剂量进行相关性分析和多元回归分析，提示患者的年龄、体质量、CYP2C9和VKORC1基因多态性与华法林个体剂量相关，而相关性分析提示性别和身高对华法林剂量差异无统计学意义。本研究提示模型预测剂量与实际稳态剂量的相关系数为0.732，配对t检验预估剂量与稳态剂量之间无显著性差异。随访显示不良反应发生率为10.81%，均为轻微出血，所有基因型中AC/AA型患者出血发生率最高。结论：扬州地区汉族人群存在CYP2C9和VKORC1基因多态性，应用CYP2C9和VKORC1基因多态性和模型可以准确估测华法林剂量。

Correlation of gene polymorphism with stable dose and computer model-predicted dose of warfarin

OBJECTIVE To investigate the association of gender, age, height, body weight, cytochrome p4502C9 (CYP2C9) and vitamin K epoxide reductase complex (VKORC1) genotypes with stable dose and computer model-predicted dose of warfarin in Han population in Yanzhou of China.METHODS CYP2C9 and VKORC1 genotypes were determined by gene sequencing technique in patients who were Han Chinese and administered with stable warfarin dose. The clinical data including gender, body weight, height, INR, stable dose and computer model-predicted dose of warfarin were recorded and analyzed by correlation analysis and multivariate regression analysis.RESULTS CYP2C9 genotype showed 102 cases of AA type, 8 cases of AC type and 1 case of CC type, the frequencies of AA, AC and CC were 91.9%, 7.21% and 0.9%. The number of AA,GA and GG in VKORC1 were 96, 13 and 2 cases, respectively. The frequencies of AA, GA and GG were 86.49%, 11.71% and 1.80%. The stable warfarin dose was much lower in patients with CYP2C9 AC type than those with AA type, and in VKORC1 AA type than those with GA type (P<0.05). Correlation analysis and multivariate regression analysis showed that age, body weight, CYP2C9 and VKORC1 genotypes were related to warfarin dose. There was no significant difference of gender or age that related to warfarin dose. The correlation coefficient of stable dose and predicted dose was 0.732, t test showed that there was no significant difference between stable and predicted doses. The adverse reaction occurrence rate was 10.81%, all were minor bleeding. AC/AA genotype had the highest bleeding occurrence rate.CONCLUSION There are CYP2C9 and VKORC1 polymorphisms in Han Chinese in Yangzhou city, no significant difference between computer model predicted and stable dose. Computer model is accurate in predicting warfarin dose.