CYP2C9及VKORC1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

Correlation of CYP2C9 and VKORC1 Polymorphisms with Warfarin Stable Dose and Computer Model-predicted Dose

目的研究湖北地区汉族人性别、年龄、身高、体重、细胞色素P450酶2C9基因(CYP2C9)和维生素K环氧化物还原酶复合体亚单位1(VKORC1)基因型与华法林稳态剂量及计算机模型预测剂量的相关性。方法收集湖北地区汉族人群临床使用华法林的患者,采用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测CYP2C9和VKORC1基因型,同时记录患者的年龄、性别、体重、身高、国际标准化比值(INR)、华法林稳态剂量和计算机模型预测剂量等临床资料,并对这些临床资料进行相关分析及多元回归分析。结果 435例患者的CYP2C9基因型检测显示402例为*1/*1型(92.41%)、30例为*1/*3型(6.90%)、3例*3/*3型(0.69%)。前两型患者华法林剂量分别为(2.91±1.12)mg/d、(1.91±0.85)mg/d,*1/*3型较*1/*1型华法林需求量少,差异有统计学意义(P<0.01)(CYP2C9基因型*3/*3型样本量太少,未参与组间比较);VKORC1基因型检测显示354例为AA型(81.4%)、77例为杂合子GA型(17.7%)、4例为纯合子GG型(0.9%)。患者华法林剂量分别为(2.58±0.94)mg/d、(3.82±1.52)mg/d、(5.62±1.77)mg/d,AA型较GA型华法林需求量少,两组间比较差异有统计学意义(P<0.01)(VKORC1基因型GG型样本量太少,未参与组间比较)。同时对患者的年龄、身高、体重、两种基因型、稳态剂量以及计算机模型预测剂量均分别行相关分析及多元回归分析,提示华法林剂量与患者的年龄、身高、体重及不同的基因型均有关,且相关分析提示计算机模型预测剂量与稳态剂量的相关系数为0.611,且有统计学意义;行稳态剂量的多元回归分析显示CYP2C9、VKORC1基因型、年龄、体重与稳态剂量相关,有统计学意义。结论在湖北地区汉族人群中,存在CYP2C9和VKORC1基因多态性,且不同基因型患者间华法林用量存在差异,同时华法林剂量与年龄、体重及不同的基因型有关,计算机模型预测剂量与稳态剂量存在相关性且有统计学意义。

Objective To investigate the association of gender ,age ,height ,body weight ,cytochrome P450 2C9（CYP2C9） and vitamin K epoxide reductase complex 1（VKORC1）genotypes with warfarin stable dose and computer model‐predicted dose in Han population in Hubei province of China.Methods CYP2C9 and VKORC1 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism（PCR‐RFLP）technique in patients who were Han Chinese and adminis‐tered with stable warfarin dose. Their clinical data including age ,gender ,body weight ,height ,international normalised ratio （INR） ,warfarin stable dose and computer model‐predicted dose were recorded and analyzed by correlation analysis and multi‐variate regression analysis.Results CYP2C9 genotyping showed that there were 402 cases of ＊1/＊1 type ,30 of ＊1/＊3 type and 3 of ＊3/＊3 type. The required warfarin dose was much lower in patients with CYP2C9 ＊1/＊3 type than those with＊1/＊1 type[（1.91 ± 0.85） mg/d vs. （2.91 ± 1.12） mg/d]with significant difference found（P〈0.01）.Comparison between groups didn＆#39;t include patients with ＊3/＊3 type due to the limited samples. VKORC1 genotyping showed that the frequencies of AA ,GA ,GG were 81.4% （354/435） ,17.7% （77/435）and 0.9% （4/435） ,respectively. The required warfarin dose in VKORC1 AA patients was significantly lower than that in GA patients [（2.58 ± 0.94） mg/d vs. （3.82 ± 1.52） mg/d] ,with statistically significant difference found（P〈0.01）.VKORC1 GG patients [warfarin dose ：（5.62 ± 1.77）mg/d] failed to enter the statistical analysis because of less sample size.Correlation analysis and multivariate regression analysis showed that age ,body weight , CYP2C9 and VKORC1 genotypes were related to warfarin dose. The correlation coefficient of warfarin stable dose and predicted dose was 0.611 ,and these was statistically significant difference（P〈0.01）.Multivariate regression analysis showed that there was statistical association between the warfarin stable dose and CYP 2C9 genotype ,VKORC1 genotype ,age or body weight.Conclusion There are CYP2C9 and VKORC1 polymorphisms in Han Chinese in Hubei province. There is a significant difference in daily mean warfarin dose between patients with different genotypes of CYP 2C9 and VKORC1. The warfarin dose is related to age ,body weight ,CYP2C9 and VKORC1 genotypes. There is a statistical correlation between warfarin stable dose and computer model‐predicted dose.