CYP2C9-1075A>C及VKORC1-1639G>A基因多态性在服用华法林汉族人群中分布特性及其与药动学-药效学相关性

Distribution of CYP2C9-1075A > C and VKORC1-1639G > A Polymorphisms in a Chinese Han Population Taking Warfarin and Correlation with Pharmacokinetics and Pharmacodynamics

目的研究CYP2C9-1075A>C及VKORC1-1639G>A基因多态性在服用华法林汉族人群中分布特性及其与药动学-药效学相关性。方法 PCR-SSP法及基因测序技术检测CYP2C9-1075A>C及VKORC1-1639G>A基因型,UPLC-MS测定血药浓度,以国际标准化比值评价药效学。结果 313例服用华法林患者中检测到CYP2C9*3 AC 34例,CYP2C9*2AC 1例,基因突变率分别为10.86%和0.32%。CYP2C9*2和CYP2C9*3等位基因频率分别为2.86%和97.14%。VKORC1-1639 G>A AA 261例,GA 51例,基因突变率分别83.39%和16.29%。313例服用华法林患者血药浓度为(0.51±0.18)(0.21~2.51)mg·L^(-1),国际标准化比值为1.63±0.60(0.91~3.62)。基因多态性与药动学-药效学相关性研究为未显示具有统计学意义的差异。结论研究汉族人群CYP2C9-1075A>C及VKORC1-1639G>A基因多态性的分布特点,对制订安全有效的华法林给药方案具有重要的临床意义。

Objective To study the distribution of CYP2C9-1075A 〉 C and VKORC1-1639G 〉 A polymor- phisms in a Chinese Han population taking warfarin and the correlations with pharmacokinetics and pharmacody- namics. Methods CYP2C9 and VKORC1 genotypes were determined using the PCR-SSP assay. Gene sequencing was used to validate the results of PCR-SSP. UPLC-MS was used to detect the plasma concentration of warfarin. Interna- tional normalized ratio（INR） value was used to evaluate the clinical effect of wafarin. Results Among the 313 cases taking wafarin, 34 cases of CYP2C9 ＊ 3 -1075A 〉 C AC heterozygote carriers and 1 case CYP2C9 ＊ 2 heterozygote carrier were detected, but no case of CYP2C9 ＊ 2 or CYP2C9 ＊ 3 homozygote carrier was detected. The mutation rate of genes was 10.86% and 0.32% respectively and the allele frequencies for CYP2C9 ＊ 2 and CYP2C9 ＊ 3 were 2.86% and 97.14% respectively. 261 cases of AA homozygote carrier of VKORC1-1639 G 〉 A, and 51 ca- ses GA heterozygote carrier of VKORCl-1639 G 〉 A were detected. The mutation rate of genes was 83.39% and 16.29 % , respectively. Plasma concentrations of wafarin and INR values in 313 cases were （0.51 ± 0.18 ） （0.21 - 2.51 ） mg .L- 1 and 1.63 ± 0.60 （0.91 - 3.62 ） respectively. Conclusion The study of distribution of CYP2C9- 1075A 〉 C and VKORC1-1639G 〉 A gene polymorphisms in a Chinese Hart population is of clinical significance for determining a safe and effective dosage of wafarin.