肇庆地区人群华法林相关基因CYP2C9*3和VKORC1的多态性分布研究及指导价值

目的 探讨广东省肇庆地区人群华法林相关基因细胞色素P450复合物亚基2C9（CYP2C9）和维生素K环氧还原酶复合物亚基1（VKORC1）多态性分布，并比较性别和中国西双版纳傣族、北京汉族、南方汉族间差异性的分布，为临床医生精准使用华法林进行抗凝治疗提供理论基础。方法 选取2019年5月-2022年1月于肇庆市第一人民医院进行华法林相关基因检测的患者122例，所有患者均采用数字荧光分子杂交技术对CY92C9^*3和VKORC1进行基因多态性检测，比较患者性别间和中国西双版纳傣族、北京地区汉族、南方地区汉族间的基因多态性分布情况，并对比基于药物基因组学指导下的华法林使用剂量与常规剂量使用华法林治疗后2~3 d后国际标准化比值（INR）达标率。结果 122例检测样本中，CY92C9^*3基因位点AA、AC、CC基因型所占的比例分别为95.90%、4.10%、0，C等位基因和T等位基因频率分别为97.95%和2.05%；VKORC1基因位点GG、GA、AA基因型分别为0.82%、19.67%、79.51%，A等位基因和C等位基因频率分别为10.66%和89.34%。不同性别间CY92C9^*3与VKORC1的基因型分布和等位基因分布差异均无统计学意义（P>0.05）。通过已有的数据库进行对比，肇庆地区的CY92C9^*3基因型、等位基因与1000 Genomes Project （1000 GP）西双版纳傣族、北京汉族与南方汉族对比无统计学差异（P>0.05）；但与1000 GP北京汉族对比，VKORC1的基因型和等位基因频率有统计学差异（P<0.05）；与1000GP西双版纳傣族对比，VKORC1的等位基因频率有统计学差异（P<0.05）；华法林在基因组学指导下的剂量与常规剂量治疗后INR达标率差异有统计学意义（P<0.01）。结论 肇庆地区人群存在CY92C9^*3和VKORC1基因多态性，其中VKORC1基因可能存在地域的差异，进行华法林相关基因检测可以为临床制定个体化华法林抗凝方案提供重要的参考价值。

Study on polymorphism distribution of warfarin related genes and its guiding value in Zhaoqing area population

Objective To investigate the polymorphism distribution of warfarin-related genes CY92C9^*3 and VKORC1 in Zhaoqing area of Guangdong province, and to compare the distribution of gender differences and differences among Dai nationality in Xishuangbanna, Han nationality in Beijing and Han nationality in southern China, so as to provide a theoretical basis for clinicians to accurately use warfarin for anticoagulant therapy.Methods A total of 122 patients who underwent warfarin-related gene detection in Zhaoqing First People''s Hospital from May 2019 to January 2022 were selected.All patients were tested for gene polymorphism of CY92C9^*3 and VKORC1 by digital fluorescence molecular hybridization.The distribution of gene polymorphisms between genders and among Dai nationality in Xishuangbanna, Han nationality in Beijing and Han nationality in southern China were compared, and the INR compliance rate of 2-3 days of warfarin treatment guided by pharmacogenomics was compared with that of conventional warfarin treatment.Results In 122 samples, the proportions of AA, AC and CC genotype of CY92C9^*3 locus were 95.90%, 4.10% and 0, respectively, and the frequencies of C allele and T allele were 97.95% and 2.05%, respectively.GG, GA and AA genotypes of VKORC1 were 0.82%, 19.67% and 79.51%, respectively.The frequencies of A allele and C allele were 10.66% and 89.34%, respectively.There were no significant differences in genotype and allele distribution of CY92C9^*3 and VKORC1 between different genders(P> 0.05).There was no significant difference in CY92C9^*3 genotype and allele between Zhaoqing and 1000 GP Dai nationality of Xishuangbanna, Han nationality of Beijing and Han nationality of south China(P> 0.05).However, there were significant differences in genotype and allele frequency of VKORC1 compared with 1000 GP Beijing Han(P<0.05).And there was significant differences in allele frequency of VKORC1 compared with 1000 GP Dai nationality of Xishuangbanna(P<0.05).The INR compliance rate of warfarin under the guidance of genomics was significantly different from that of conventional treatment(P<0.05).Conclusion CY92C9^*3 and VKORC1 gene polymorphisms exist in Zhaoqing population, among which VKORC1 gene may have regional differences, and warfarin-related gene detection can provide important reference value for clinical development of individual warfarin anticoagulation program.